MCRPC Treatment COE Articles

Articles

  • A Contemporary Update on Sipuleucel-T for Men with Metastatic Castrate-Resistant Prostate Cancer

    Despite warranted concerns regarding the overdiagnosis and overtreatment of many cases of biologically indolent prostate cancer, prostate cancer remains the second leading cause of cancer-related death in the United States behind only lung cancer.1 With current treatment paradigms, nearly all patients who die of prostate cancer first receive androgen-deprivation therapy and then progress to castrate-resistant prostate cancer.

    Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
    References: 1. Siegel, R. L., & Miller, K. D. (2018). Jemal A (2018) cancer statistics. Ca Cancer J Clin68(1), 7-30.
    2. Lowrance, William T., Mohammad Hassan Murad, William K. Oh, David F. Jarrard, Matthew J. Resnick, and Michael S. Cookson. "Castration-resistant prostate cancer: AUA Guideline Amendment 2018." The Journal of urology 200, no. 6 (2018): 1264-1272.
    3. Goldman, Bruce, and Laura DeFrancesco. "The cancer vaccine roller coaster." Nature biotechnology 27, no. 2 (2009): 129-139.
    4. Kantoff, Philip W., Celestia S. Higano, Neal D. Shore, E. Roy Berger, Eric J. Small, David F. Penson, Charles H. Redfern et al. "Sipuleucel-T immunotherapy for castration-resistant prostate cancer." New England Journal of Medicine 363, no. 5 (2010): 411-422.
    5. Higano, Celestia S., Andrew J. Armstrong, A. Oliver Sartor, Nicholas J. Vogelzang, Philip W. Kantoff, David G. McLeod, Christopher M. Pieczonka et al. "Real‐world outcomes of sipuleucel‐T treatment in PROCEED, a prospective registry of men with metastatic castration‐resistant prostate cancer." Cancer 125, no. 23 (2019): 4172-4180.
    6. Anassi, Enock, and Uche Anadu Ndefo. "Sipuleucel-T (provenge) injection: the first immunotherapy agent (vaccine) for hormone-refractory prostate cancer." Pharmacy and Therapeutics 36, no. 4 (2011): 197.
    Published April 21, 2020
  • A prospective study examining elder-relevant outcomes in older adults with prostate cancer undergoing treatment with chemotherapy or abiraterone.

    BACKGROUND - Treatment of metastatic castration-resistant prostate cancer (mCRPC) with chemotherapy improves disease control and survival in fit older men (age 65+) but its impact on function is not clear. We hypothesized that chemotherapy would impair daily function in older men with mCRPC.

    Published February 24, 2016
  • A Review of Comprehensive Bone Health Management Strategies for Men with Prostate Cancer

    Published in Everyday Urology - Oncology Insights: Volume 4, Issue 4

    Published Date: December 2019

    Bone health is a critical area of unmet need among men with advanced prostate cancer. Age increases the risk for fragility fractures among both men and women, and older men with fragility fractures are at higher risk of subsequent death than are women.1-3 Systemic anti-androgen therapies for prostate cancer, while life-prolonging, accelerate bone loss by tipping the balance of bone homeostasis toward bone resorption, which further increases patients’ risk of fragility fractures.4

    Published January 20, 2020
  • Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer

    BACKGROUND: Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer.
    Published June 5, 2017
  • ASCO 2020: Impact of Olaparib vs Physician’s Choice of New Hormonal Agent on Burden of Pain in mCRPC: PROfound

    (UroToday.com) In the Phase III PROfound study, olaparib significantly improved radiographic progression-free survival (primary endpoint) versus physician’s choice of new hormonal agent (enzalutamide or abiraterone) in patients with mCRPC and homologous recombination repair (HRR) gene alterations.1 In patients with alterations in BRCA1BRCA2 and/or ATM (cohort A), time to pain progression was also significantly improved by olaparib versus physician’s choice of new hormonal agent. At the virtual ASCO 2020 annual meeting, Fred Saad, MD, and colleagues reported additional pain analyses evaluated in the overall study population (cohort A and B).
    Published May 29, 2020
  • ASCO 2020: TALAPRO-2: a Placebo-Controlled Phase III Study of Talazoparib Plus Enzalutamide for Patients with First-Line Metastatic Castration-Resistant Prostate Cancer

    (UroToday.com) While highly prevalent genetic changes have yet to be identified in patients with advanced prostate cancer, alterations in DNA mismatch repair (MMR), also known as DNA damage repair (DDR), are increasingly common as patients progress through the natural history of the disease process. Identification of these alterations has opened novel treatment options and the potential for targeted therapy using poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors. 
    Published May 31, 2020
  • ASCO GU 2019: Final Analysis of LATITUDE, A Phase III in Patients with Newly Diagnosed High-risk Metastatic Castration-naïve Prostate Cancer

    San Francisco, CA (UroToday.com) The LATITUDE study,1 published in July 2017, was a phase III randomized, clinical trial that evaluated the efficacy of abiraterone acetate and prednisone with androgen deprivation therapy (ADT) in men with newly-diagnosed, castration sensitive, metastatic prostate cancer. 1199 men were randomized to receive ADT with abiraterone and prednisone, versus ADT with dual placebos. The primary endpoints of this study were overall survival and radiographic progression-free survival. This study showed that ADT+ abiraterone and prednisone conferred a survival benefit over ADT alone, but also showed that there was an improvement in patient-reported outcomes (PROs) over the course of the trial.
    Published February 15, 2019
  • ASCO GU 2020: (CARD) Pain Response and Health-Related Quality of Life Analysis in Patients with Metastatic Castration-Resistant Prostate Cancer

    San Francisco, California (UroToday.com) During the Rapid Abstract Session A: Prostate Cancer session at the Annual ASCO GU 2020 meeting in San Francisco, CA, Dr. Karim Fizazi presented results from the analysis evaluating changes in pain and health-related quality of life associated (HRQL) with cabazitaxel (CBZ) and androgen-signaling-targeted inhibitor (ARTA) during the CARDstudy. The CARD study was a multicenter, randomized, open-label study, and reported superior radiographic progression-free survival and overall survival with CBZ vs. abiraterone or enzalutamide in patients with mCRPC who progressed on docetaxel and within 12 months on a previous alternative ARTA.

    Published February 14, 2020
  • ASCO GU 2020: Overall Survival in Men with Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer Receiving Bicalutamide Followed by Enzalutamide or Abiraterone

    San Francisco, CA (UroToday.co) The addition of bicalutamide to ongoing ADT has been approved for patients with hormone sensitive prostate cancer. This drug is also commonly used with ADT in the castrate resistant prostate cancer setting.

    Published February 16, 2020
  • ASCO GU 2020: Treatment Decision Making in Metastatic Prostate Cancer

    San Francisco, California (UroToday.com) Multiple treatment options exist for men with metastatic prostate cancer, and guidelines do not define optimal treatment selection for a given patient. This provides an opportunity for shared decision-making in which physicians communicate treatment purpose, risks, and benefits, and patients communicate personal values/preferences that can be used to determine treatment collectively. Shared decision-making is associated with superior health outcomes (blood pressure, glucose control) in non-cancer populations, but whether it is used in metastatic prostate cancer has not been described.

    Published February 15, 2020
  • Astellas and Pfizer Announce Positive Top-Line Results from Phase 3 ARCHES Trial of XTANDI® (enzalutamide) in Men with Metastatic Hormone-Sensitive Prostate Cancer

    San Francisco, CA USA (UroToday.com) -- Astellas Pharma Inc. President and CEO: Kenji Yasukawa, Ph.D., and Pfizer Inc. announced that the Phase 3 ARCHES trialevaluating XTANDI® (enzalutamide) plus androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC) met its primary endpoint, significantly improving radiographic progression-free survival (rPFS) versus ADT alone. The preliminary safety analysis of the ARCHES trial appears consistent with the safety profile of XTANDI in previous clinical trials in castration-resistant prostate cancer (CRPC). Detailed results will be submitted for presentation at an upcoming medical congress.
    Published December 20, 2018
  • AUA 2018: Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2018

    San Francisco, CA (UroToday.com) David F. Jarrard, MD provided an update on the CRPC AUA guideline amendment at 113th Annual Scientific Meeting of the American Urological Association (AUA). Dr. Jarrard highlights, the six index patients associated with the CRPC guidelines assists in clinical decision making, representing the most common clinical scenarios that are encountered in clinical practice. Guideline statements are developed to provide a rational basis for treatment based on currently available published data. The purpose of this guideline amendment is essentially to update current management of index patient 1: asymptomatic non-metastatic CRPC (nmCRPC).
    Published May 21, 2018
  • Beyond First-line Treatment of Metastatic Castrate-resistant Prostate Cancer

    In the previous review article (“First-line treatment of metastatic castrate-resistant prostate cancer”), metastatic castrate-resistant prostate cancer (mCRPC) and its approved first-line treatment options were elaborated. Unfortunately, all mCRPC patients will eventually progress despite evidence-based first-line treatments that patients receive. Therefore, an appropriate treatment strategy must be formalized. The working group of the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II (RADAR II) study attempted to offer recommendations on identifying disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific (CRPC) treatments.1 They recommended a layering approach comprised of approved therapies with unique or complementary mechanisms of action.1 According to this working group 12 Phase III studies evaluating combinations, layering, or sequencing of these agents are required to help improve clinical outcomes in the castrate clinical state. Following first-line treatment options for mCRPC patients, only second-line treatments given after treatment with docetaxel have been extensively assessed and these are detailed below.

    Second-line treatment options for metastatic castrate-resistant prostate cancer

    Cabazitaxel

    Cabazitaxel is a new taxane drug with activity in docetaxel-resistant cancers. In the TROPIC study, a Phase III prospective randomized trial, cabazitaxel plus prednisone was compared to mitoxantrone plus prednisone in 755 mCRPC patients, who progressed after or during treatment with docetaxel2 (Figure 1). Patients received a maximum of ten cycles of cabazitaxel or mitoxantrone plus prednisone. Overall survival (OS) was the primary end-point, being significantly longer in cabazitaxel-treated patients (median: 15.1 vs. 12.7 months p < 0.0001). Progression-free survival (PFS) was significantly improved as well (median: 2.8 vs. 1.4 months, p < 0.0001), and prostate-specific antigen (PSA) response rate was also better (39.2% vs. 17.8%, p < 0.0002). Grade 3-4 adverse events developed more significantly in patients taking cabazitaxel, particularly hematological adverse effects (68.2% vs. 47.3%, p < 0.0002).3 Therefore, cabazitaxel should be given with prophylactic granulocyte colony-stimulating factor and needs to be administered by physicians with expertise in handling neutropenia and sepsis.4 When compared to docetaxel in the first-line setting, cabazitaxel was not shown to be superior.5


    figure 1 TROPIC design

    Figure 1
    . TROPIC study design

    Abiraterone following docetaxel

    The COU-AA-301 was a large Phase III randomized trial with a total of 1,195 mCRPC patients being randomised in a 2:1 ratio to abiraterone acetate plus prednisone or placebo plus prednisone (Figure 2). Abiraterone is an antiandrogen agent which inhibits the 17α-hydroxylase/C17,20-lyase (CYP17) enzyme. Initial positive results of this trial were reported after a median follow-up of 12.8 months6 and confirmed by the final analysis.7 All patients in this trial failed at least one chemotherapy regimen, which included docetaxel. The primary end-point was OS, and in the final analysis, after a median follow-up of 20.2 months there was a clear advantage to the abiraterone arm (median survival of 15.8 vs.11.2 months, HR: 0.74, p < 0.0001). The benefit for abiraterone remained in all secondary endpoints as well (PSA, radiologic tissue response, time to PSA or objective progression). No significant difference between the treatment arms was seen in the rate of grade 3-4 adverse events, aside from a higher rate of mineralocorticoid-related side-effects (mainly grade 1-2 fluid retention, edema, and hypokalaemia).7

    figure 2 COU AA 301

    Figure 2. COU-AA-301 study design

    Enzalutamide after docetaxel

    The AFFIRM trial randomized 1,199 mCRPC patients in a 2:1 fashion to enzalutamide, a nonsteroidal antiandrogen, or placebo (Figure 3). All accrued patients had progressed after docetaxel treatment.8 The planned interim analysis of the AFFIRM study was published in 2012 and after a median follow-up of 14.4 months, a clear benefit was shown for the enzalutamide-treated patients (median survival of 18.4 vs. 13.6 months, HR: 0.63, p < 0.001).8 This led to the recommendation to halt and unblind the study. Importantly, the observed benefit occurred irrespective of age, baseline pain intensity, and type of progression. Enzalutamide was also beneficial in patients with visceral metastases. The final analysis with longer follow-up had confirmed the OS results despite the crossover and extensive post-progression therapies. Enzalutamide also conferred a clear advantage in all the secondary endpoints (PSA, soft tissue response, quality of life, time to PSA or objective progression).8 No significant difference in the rate of side-effects was observed in the two groups, with a lower incidence of grade 3-4 adverse events in the enzalutamide arm. Importantly, enzalutamide-treated patients had a 0.6% incidence of seizures compared to none in the placebo arm.8


    figure 3 AFFIRM trial

    Figure 3. AFFIRM trial design

    Apalutamide
    Radium-223

    Radium-223 is a targeted alpha therapy and is the only bone-specific drug that has been associated with a survival benefit in the mCRPC space. The ALSYMPCA trial was a large Phase III trial accruing 921 symptomatic mCRPC patients, who failed or were unfit for docetaxel chemotherapy.13 In this trial, patients were randomized to six injections of radium-223 or placebo, plus standard of care in both arms (Figure 4). The primary end-point was OS, and radium-223 significantly improved median OS by 3.6 months (HR: 0.70, p < 0.001).13 Radium-223 also conferred prolonged time to first skeletal event, improvement in pain scores and quality of life.13 No significant difference was noted in the rate of adverse effects between the treatment arms, aside from slightly more haematologic toxicity and diarrhea with radium-223.13 Whether patients were pretreated with docetaxel did not affect the benefit and safety of radium-223.14 Due to safety concerns, the label of radium-223 was restricted to use after docetaxel and at least one AR targeted agent.15 Importantly, the ERA-223 study assessed the effectiveness of early use of radium-223 together with abiraterone acetate and prednisolone (Figure 5). Unfortunately, this trial showed significant safety risks, especially with fractures and more deaths. Therefore, this combination is currently not recommended. These safety risks were more significant in patients without the concurrent use of antiresorptive agents.16


    figure 4 ALSYMPCA trial

    Figure 4
    . ALSYMPCA trial design



    figure 5 EERA 223 trial

    Figure 5. ERA 223 study design

    Third line treatment following treatment with docetaxel and one hormonal treatment for metastatic castrate-resistant prostate cancer


    Currently, there are no clear guidelines or recommendations regarding which treatment option is appropriate in this setting and this is open for debate. The choice for further treatment after docetaxel and one line of hormonal treatment for mCRPC is unclear.17 The available options include radium-223 or second-line chemotherapy (cabazitaxel). In unselected patients, subsequent treatments are expected to have a lower benefit than with earlier use18. There is also evidence that cross-resistance between enzalutamide and abiraterone exists.19,20 There is a unique subset of patients worth mentioning with tumors demonstrating homozygous deletions or deleterious mutations in DNA-repair genes. In these patients Poly(ADP-ribose) polymerase (PARP) inhibitors have been reported to confer high rates of response. Therefore, patients who were previously treated with docetaxel and at least one novel hormonal agent; and whose tumors demonstrated homozygous deletions or deleterious mutations in DNA-repair genes showed an 88% response rate to Olaparib, a PAPR inhibitor.21 This represents an example of how treatment can be tailored according to the tumor mutation profile.22 In a randomized Phase II study of mCRPC patients, olaparib combined with abiraterone was compared to placebo and abiraterone. This study demonstrated a clinical benefit in olaparib-treated patients, regardless if mutations in DNA-repair genes existed.23 However, this combination treatment was shown to be toxic with significant side effects reported in 34% of patients vs. only 18% in the placebo arm.23 

    For patients with mismatch repair deficiency, the PD-1 inhibitor pembrolizumab was approved by the FDA for all tumors, including PCa. More specifically, pembrolizumab demonstrated antitumor activity and disease control with acceptable safety in RECIST-measurable and bone-predominant mCRPC, which was previously treated with docetaxel and novel AR antagonists.24 

    In the COMET-1 trial 1028 patients with progressive mCRPC after treatment with docetaxel and abiraterone and/or enzalutamide were randomly assigned at a 2:1 ratio to either cabozantinib 60 mg, a tyrosine kinase inhibitor, or prednisone 5 mg twice per day.25 The primary endpoint was OS, and the secondary endpoint included bone scan response after 12 weeks of treatment. Additional exploratory analyses included radiographic PFS (rPFS) and effects on circulating tumor cells, bone biomarkers, serum PSA, and symptomatic skeletal events.25 This trial demonstrated that cabozantinib did not significantly improve OS compared with prednisone in heavily pre-treated mCRPC patients (median OS was 11.0 months with cabozantinib and 9.8 months with prednisone, HR 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = 0.213).25 Cabozantinib had some activity in improving bone scan response, rPFS, symptomatic skeletal events, and bone biomarkers but not PSA outcomes.25

    Changing and sequencing treatment in metastatic castrate-resistant prostate cancer


    There are several open questions and dilemmas regarding when to change treatment in mCRPC patients and what is the most appropriate treatment sequence.

    The appropriate time to change treatment in mCRPC patients is not entirely clear. No controversy exists regarding the need to change treatment when patients have symptomatic progression of their metastatic disease. Despite the many available treatment options to date, no head to head comparison has been made publicly available, while data assessing the correct sequence of treatment is being assessed. As data are lacking, physicians have been using the ECOG performance score to stratify patients before deciding on the “appropriate” treatment plan. Men with a good performance status are likely to tolerate more treatments as opposed to men with lower performance scores.

    The National Comprehensive Cancer Network (NCCN) considers the onset of visceral disease to be a detrimental factor. Patients with liver metastases have especially poor outcomes for as of yet an unknown reason. In a meta-analysis including over 8,000 mCRPC patients who were enrolled in Phase III trials, patients with lymph-node- only disease appeared to have the best OS (median, 31.6 months; 95% CI, 27.9 to 36.6 months), with patients with lung and bone metastases having shorter and similar median OS (19.4 months [95% CI, 17.8 to 20.7 months] vs. 21.3 months [20.8 to 21.9], respectively), and patients with liver metastases demonstrating the worst OS (median, 13.5 months; 95% CI, 12.7 to 14.4 months).26 Therefore, the type of metastases the patient has can be used as a guide to when and how aggressive the treatment strategy should be.

    Abiraterone and enzalutamide are highly active agents harboring a substantial effect on PFS, with trials comparing monotherapy with prednisone or placebo.27,28 However, a subset of patients will not respond to these drugs. A patient who does not respond well will require a change of treatment. It is therefore important to see these patients frequently once starting therapy and assess their response. If no PSA decline is witnessed, the treatment needs to be changed.

    When considering the appropriate treatment sequence in mCRPC, there are no clear guidelines or recommendations to date, and our limited knowledge is based mainly on retrospective data. In one non-randomized retrospective study, PFS, OS, and PSA responses from consecutive patients with chemotherapy-naïve mCRPC were compared between those who received abiraterone followed by enzalutamide and those who received enzalutamide followed by abiraterone.29 Initially, a slight improvement in patients who started with abiraterone and transitioned to enzalutamide was seen with improved PFS. An expanded retrospective study confirmed the general trend, showing that patients who started with abiraterone and then transitioned to enzalutamide had better PFS (median, 455 days [95% CI, 385 to 495 days]) than patients who started with enzalutamide and transitioned to abiraterone (median, 296 days; 95% CI, 235 to 358 days).30 However, OS was not significantly different between the groups.30 Furthermore, the authors of an ongoing randomized Phase II study comparing abiraterone vs. enzalutamide in patients with treatment-naïve mCRCP reported their interim results.31 After a median follow-up of 22.3 months, a PSA decline of more than 50% occurred in 34% of abiraterone treated patients compared to 4% in the enzalutamide treated patients (p<0.001).31 Additionally, the median time to PSA progression on 2nd-line therapy was 2.7 vs 1.3 months (HR 0.38, 95% CI 0.26-0.56) in favor of abiraterone.31 Lastly, the median OS was not reached vs 24.3 months (HR 0.82, 95% CI 0.53-1.27) in favor of abiraterone.31 As data regarding appropriate treatment sequencing is still being collected and analyzed, many physicians currently base their decision on which medication to start according to the adverse effects that we want to avoid. Abiraterone is commonly associated with edema, and therefore should be avoided in men with congestive heart failure,27 while enzalutamide is more likely to cause central nervous system toxicity and should probably be avoided in older patients.32 

    Radioligand therapy for metastatic castrate-resistant prostate cancer patients


    PSMA-PET/CT imaging has significantly become more common in recent years. This has led to the emergence of a new field of radioligand directed therapy among heavily pretreated mCRPC patients. PCa metastases express PSMA, making it a promising approach to developing new tracers for targeted radionuclide therapies. PSMA is a non-secreted type II transmembrane protein produced almost exclusively by prostatic tissue and on tumor-associated neovasculature.33 Unlike other biomarkers, such as PSA, which may decrease with increasing neoplastic de-differentiation, PSMA has been shown to be upregulated in high-grade, de-differentiated PCa.34 

    Since 2015, several institutional studies have reported promising response rates and a favorable safety profile for radioligand therapy with 177Lu-PSMA-617 in mCRPC patients.35-37 However, these studies had small sample sizes and questionable generalizability. To addresses these limitations, a large multicenter German analysis assessed a cohort of patients treated with 177Lu-PSMA-617.38 This study included 145 mCRPC patients treated with 177Lu-PSMA-617 at 12 centers undergoing 1-4 therapy cycles. The study reported an overall biochemical response rate of 45% after all therapy cycles, with 40% of patients responding after a single cycle. Notably, negative predictors of the biochemical response included elevated alkaline phosphatase and the presence of visceral metastases.38

    In a large meta-analysis published in 2017, 10 studies were assessed including 369 patients. This meta-analysis assessed the safety and efficacy of 177-Lutetium in mCRPC patients.39 The pooled proportion of patients with any PSA decline was 68% (95% CI: 61–74%); and the pooled proportion of patients with 450% PSA decline was 37% (95% CI: 22–52).39 This meta-analysis suggested promising early results for the treatment of mCRPC patients, especially in patients treated with the more recently developed radioligands, with approximately two-thirds of them showing a biochemical response.39 

    Although 177Lu-PSMA-617 is the most well-studied radioligand to date, there are additional compounds in development and undergoing initial testing. These include 177Lu-J591, 90Y-J591, 131I-MIP 1095, 177Lu-PSMA-I&T, and 225Ac-PSMA-617.40

    Treatment and prevention of skeletal-related events


    Patients with mCRPC commonly endure painful bone metastases with external beam radiotherapy (EBRT) being a highly effective treatment.41 Possible complications due to bone metastases include vertebral collapse or deformity, pathological fractures, and spinal cord compression. Cementation can be an effective treatment for a painful spinal fracture, clearly improving both pain and quality of life.42 However, standard palliative surgery can still be offered for managing osteoblastic metastases.43 Impending spinal cord compression is an emergency event that must be recognized as soon as possible. Patients should be educated to recognize the warning signs. If this is suspected, high-dose corticosteroids must be given and an MRI is required. A neurosurgeon or orthopedic surgeon consultation needs to be planned to discuss a possible decompression, followed by EBRT.44

    Zoledronic acid, a bisphosphonate, has been evaluated in mCRPC patients in an attempt to reduce skeletal-related events (SRE). 643 mCRPC patients with bone metastases were randomized to receive zoledronic acid, 4 or 8 mg every three weeks for fifteen consecutive months, or placebo.45 The 8 mg dose was poorly tolerated without showing a significant benefit. However, at 15 and 24 months of follow-up, the 4 mg dose conferred fewer SREs compared to the placebo group (44 vs. 33%, p = 0.021), and less pathological fractures (13.1 vs. 22.1%, p = 0.015). Additionally, the time to first SRE was longer in the zoledronic acid group. However, no survival benefit was seen in any prospective trial assessing bisphosphonates.

    Denosumab is a fully human monoclonal antibody directed against RANKL (receptor activator of nuclear factor kappa-B ligand). It is a key mediator of osteoclast formation, function, and survival. In non-metastatic CRPC, denosumab has been associated with increased bone-metastasis-free survival compared to placebo (median benefit: 4.2 months, HR: 0.85, p = 0.028).44 Like zoledronic acid, this benefit did not translate into a survival difference and neither the FDA or the EMA had approved denosumab for this indication.46 A Phase III trial compared the efficacy and safety of denosumab (n = 950) with zoledronic acid (n = 951) in mCRPC patients. Denosumab was shown to be superior to zoledronic acid in delaying or preventing SREs, as shown by time to first SRE (pathological fracture, radiation or surgery to bone, or spinal cord compression) of 20.7 vs. 17.1 months, respectively (HR: 0.82, p = 0.008). However, these findings were not associated with any survival benefit, and in a recent post-hoc re-evaluation of end-points, denosumab had actually shown an identical rate of SREs to zoledronic acid.47 It is critical to remember that these medications are associated with substantial toxicity, of 5% and 8.2% in non-metastatic CRPC and mCRPC, respectively.47,48 All patients are required to be examined by a dentist prior to initiating this therapy, as the risk of jaw necrosis is increased by several risk factors including a history of trauma, dental surgery or dental infection.49 and the number of years the medication is used.

    Recently, the randomized, double-blind Phase III trial (COMET-2; NCT01522443) was published, comparing cabozantinib, to mitoxantrone + prednisone in mCRPC patients with narcotic-dependent pain from bone metastases.50 All patients had progressed after treatment with docetaxel and either abiraterone or enzalutamide.50 The primary endpoint was pain response at week 6 and confirmed again at week 12. Enrollment was terminated early because cabozantinib did not demonstrate any survival benefit in mCRPC patients in the companion COMET-1 trial,25 described earlier. At study closure of the COMET-2 trial, only 119 patients were randomized. The trial demonstrated no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone.50

    Future and ongoing trials


    There are currently 24 registered ongoing Phase III trials involving mCRPC patients.

    Some studies worth mentioning with much-anticipated results include the following:

    1. The combination of abiraterone and Olaparib as first-line therapy in mCRPC patients (NCT03732820)
    2. A study assessing the role of Rucaparib (a PARP inhibitor) vs. physician’s choice therapy in mCRPC patients (TRITON3 trial - NCT02975934)
    3. The combination of pembrolizumab with various other medications including enzalutamide (NCT03834493 - as part of the MK-3475-641/KEYNOTE-641 trial), docetaxel (NCT03834506 - as part of the MK-3475-921/KEYNOTE-921 trial), and olaparib (NCT03834519 – as part of the MK-7339-010/KEYLYNK-010)
    4. The ACIS trial, which will assess the combination of apalutamide, and abiraterone + prednisone in mCRPC patients (NCT02257736)
    5. A study assessing Masitinib (a tyrosine kinase inhibitor) plus docetaxel (NCT03761225)
    6. The combination of Talazoparib (a PARP inhibitor) + plus enzalutamide (NCT03395197),
    7. The combination of Atezolizumab (an anti-PD-L1 monoclonal antibody) + enzalutamide (NCT03016312)
    8. The combination of docetaxel and Radium-223 (NCT03574571)
    9. A study assessing 177Lu-PSMA-617 in mCRPC patients (NCT03511664)
    10. The IPATential150 trial – assessing the combination of Ipatasertib (an orally administered, ATP-competitive, selective AKT inhibitor) plus abiraterone (NCT03072238)

    Conclusions


    Substantial progress has been made in the mCRPC space in the last several years. Optimal management of mCRPC patients is a growing challenge as more potential treatments are added to the armamentarium. Choosing the right treatment for the right patient, and the correct sequence and combination of the increasing number of available medications will be the main challenge in the years to come. We currently lack level one evidence regarding the proper sequence and/or combination of current available medications, and physicians are faced with making these decisions without supporting data. Patients will most likely benefit from unique medications with complementary mechanisms of action in order to avoid cross-resistance. An important unmet clinical need thus far consists of acquiring evidence about the efficacy, safety, and tolerability of combination regimens, and optimized approaches for identifying patients most suited for specific treatments.

    Published Date: November 19th, 2019

    Written by: Hanan Goldberg, MD
    References:
    1. Crawford ED, Petrylak DP, Shore N, et al. The Role of Therapeutic Layering in Optimizing Treatment for Patients With Castration-resistant Prostate Cancer (Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II). Urology. Jun 2017;104:150-159.
    2. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. Oct 2 2010;376(9747):1147-1154.
    3. Scher HI, Mazumdar M, Kelly WK. Clinical trials in relapsed prostate cancer: defining the target. J Natl Cancer Inst. Nov 20 1996;88(22):1623-1634.
    4. Resnick MJ, Lacchetti C, Penson DF. Prostate cancer survivorship care guidelines: American Society of Clinical Oncology practice guideline endorsement. J Oncol Pract. May 2015;11(3):e445-449.
    5. Oudard S, Fizazi K, Sengelov L, et al. Cabazitaxel Versus Docetaxel As First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer: A Randomized Phase III Trial-FIRSTANA. J Clin Oncol. Oct 1 2017;35(28):3189-3197.
    6. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. New England Journal of Medicine. 2011;364(21):1995-2005.
    7. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. Oct 2012;13(10):983-992.
    8. Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine. 2012;367(13):1187-1197.
    9. Rathkopf D, Scher HI. Androgen receptor antagonists in castration-resistant prostate cancer. Cancer J. Jan-Feb 2013;19(1):43-49.
    10. Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. Mar 15 2012;72(6):1494-1503.
    11. Rathkopf DE, Morris MJ, Fox JJ, et al. Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J Clin Oncol. Oct 1 2013;31(28):3525-3530.
    12. Rathkopf DE, Antonarakis ES, Shore ND, et al. Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone. Clin Cancer Res. Jul 15 2017;23(14):3544-3551.
    13. Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. New England Journal of Medicine. 2013;369(3):213-223.
    14. Hoskin P, Sartor O, O'Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. Nov 2014;15(12):1397-1406.
    15. European Medicines Agency (EMA). EMA restricts use of prostate cancer medicine Xofigo. https://www.ema.europa.eu/en/news/ema-restricts-use-prostate-cancer-medicine-xofigo.
    16. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. Mar 2019;20(3):408-419.
    17. de Bono JS, Smith MR, Saad F, et al. Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302. Eur Urol. Apr 2017;71(4):656-664.
    18. Badrising S, van der Noort V, van Oort IM, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer. Apr 1 2014;120(7):968-975.
    19. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer. New England Journal of Medicine. 2014;371(11):1028-1038.
    20. Attard G, Borre M, Gurney H, et al. Abiraterone Alone or in Combination With Enzalutamide in Metastatic Castration-Resistant Prostate Cancer With Rising Prostate-Specific Antigen During Enzalutamide Treatment. J Clin Oncol. Sep 1 2018;36(25):2639-2646.
    21. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. New England Journal of Medicine. 2015;373(18):1697-1708.
    22. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. New England Journal of Medicine. 2015;372(26):2509-2520.
    23. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. Jul 2018;19(7):975-986.
    24. Antonarakis ES, Goh JC, Gross-Goupil M, et al. Pembrolizumab for metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Updated analysis of KEYNOTE-199. Journal of Clinical Oncology. 2019;37(7_suppl):216-216.
    25. Smith M, De Bono J, Sternberg C, et al. Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1. J Clin Oncol. Sep 1 2016;34(25):3005-3013.
    26. Halabi S, Kelly WK, Ma H, et al. Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer. J Clin Oncol. May 10 2016;34(14):1652-1659.
    27. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. Jan 10 2013;368(2):138-148.
    28. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. Jul 31 2014;371(5):424-433.
    29. Maughan BL, Luber B, Nadal R, Antonarakis ES. Comparing Sequencing of Abiraterone and Enzalutamide in Men With Metastatic Castration-Resistant Prostate Cancer: A Retrospective Study. Prostate. Jan 2017;77(1):33-40.
    30. Terada N, Maughan BL, Akamatsu S, et al. Exploring the optimal sequence of abiraterone and enzalutamide in patients with chemotherapy-naive castration-resistant prostate cancer: The Kyoto-Baltimore collaboration. Int J Urol. Jun 2017;24(6):441-448.
    31. Khalaf D, Annala M, Finch DL, et al. Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI+P) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mCPRC): Results for 2nd-line therapy. Journal of Clinical Oncology. 2018;36(15_suppl):5015-5015.
    32. Pilon D, Behl AS, Gozalo L, et al. Assessment of central nervous system (CNS) and dose reduction events in patients treated with abiraterone acetate plus prednisone (AA+P) or enzalutamide (ENZ). Journal of Clinical Oncology. 2016;34(15_suppl):5078-5078.
    33. Kulkarni HR, Singh A, Schuchardt C, et al. PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013. J Nucl Med. Oct 2016;57(Suppl 3):97s-104s.
    34. Baum RP, Kulkarni HR, Schuchardt C, et al. 177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy. J Nucl Med. Jul 2016;57(7):1006-1013.
    35. Ahmadzadehfar H, Eppard E, Kurpig S, et al. Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer. Oncotarget. Mar 15 2016;7(11):12477-12488.
    36. Kratochwil C, Giesel FL, Stefanova M, et al. PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 177Lu-Labeled PSMA-617. J Nucl Med. Aug 2016;57(8):1170-1176.
    37. Rahbar K, Schmidt M, Heinzel A, et al. Response and Tolerability of a Single Dose of 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer: A Multicenter Retrospective Analysis. J Nucl Med. Sep 2016;57(9):1334-1338.
    38. Rahbar K, Ahmadzadehfar H, Kratochwil C, et al. German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients. J Nucl Med. Jan 2017;58(1):85-90.
    39. Calopedos RJS, Chalasani V, Asher R, Emmett L, Woo HH. Lutetium-177-labelled anti-prostate-specific membrane antigen antibody and ligands for the treatment of metastatic castrate-resistant prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. Sep 2017;20(3):352-360.
    40. Awang ZH, Essler M, Ahmadzadehfar H. Radioligand therapy of metastatic castration-resistant prostate cancer: current approaches. Radiat Oncol. May 23 2018;13(1):98.
    41. Dy SM, Asch SM, Naeim A, Sanati H, Walling A, Lorenz KA. Evidence-based standards for cancer pain management. J Clin Oncol. Aug 10 2008;26(23):3879-3885.
    42. Frankel BM, Monroe T, Wang C. Percutaneous vertebral augmentation: an elevation in adjacent-level fracture risk in kyphoplasty as compared with vertebroplasty. Spine J. Sep-Oct 2007;7(5):575-582.
    43. Frankel BM, Jones T, Wang C. Segmental polymethylmethacrylate-augmented pedicle screw fixation in patients with bone softening caused by osteoporosis and metastatic tumor involvement: a clinical evaluation. Neurosurgery. Sep 2007;61(3):531-537; discussion 537-538.
    44. Marco RA, Sheth DS, Boland PJ, Wunder JS, Siegel JA, Healey JH. Functional and oncological outcome of acetabular reconstruction for the treatment of metastatic disease. J Bone Joint Surg Am. May 2000;82(5):642-651.
    45. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. Oct 2 2002;94(19):1458-1468.
    46. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. Mar 5 2011;377(9768):813-822.
    47. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. Jan 7 2012;379(9810):39-46.
    48. Stopeck AT, Fizazi K, Body JJ, et al. Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer. Jan 2016;24(1):447-455.
    49. Aapro M, Abrahamsson PA, Body JJ, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol. Mar 2008;19(3):420-432.
    50. Basch EM, Scholz M, de Bono JS, et al. Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint. Eur Urol. Jun 2019;75(6):929-937.
    Published November 19, 2019
  • Biomarkers to Select Patients with Prostate Cancer for PD-1/PD-L1 Blockade

    (UroToday.com) In conjunction with the Scientific Congress held as part of the American Society of Clinical Oncology’s (ASCO) Annual Meeting in May 2020, an Educational Symposium was convened on August 8 to 10th. In a session entitled “Immune Checkpoint Blockade for Prostate Cancer: Niche Role or Next Breakthrough?”, Dr. Matt Rettig from the University of California Los Angeles’s Jonsson Comprehensive Cancer Center and the West Los Angeles VA Medical Center presented a plenary talk discussing the use of biomarkers to select patients for immune checkpoint blockade with PD-1/PD-L1 inhibitors.

    Published August 8, 2020
  • Bone-Targeted Therapy in Prostate Cancer

    Zoledronic acid

    To maintain bone integrity during bone remodeling, homeostasis of osteoblasts increasing bone mass and osteoclasts resorbing bone is required. Bisphosphonates are rapidly absorbed on the bone surface and inhibit osteoclast activity by affecting cytoskeletal dynamics. The Phase III Zoledronic acid 039 trial showed that among men with metastatic castration-resistant prostate cancer (mCRPC), a greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2%, p =0.021) or those who received zoledronic acid at 8 mg (38.5%, p = 0.222
    Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
    References: 1. Norgaard M, Jensen AO, Jacobsen JB, Cetin K, Fryzek JP, Sorensen HT. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol. 2010;184(1):162-167.
    2. Gartrell BA, Coleman R, Efstathiou E, et al. Metastatic Prostate Cancer and the Bone: Significance and Therapeutic Options. Eur Urol. 2015;68(5):850-858.
    3. Klaassen Z, Howard LE, de Hoedt A, et al. Factors predicting skeletal-related events in patients with bone metastatic castration-resistant prostate cancer. Cancer. 2017;123(9):1528-1535.
    4. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94(19):1458-1468.
    5. Smith MR, Halabi S, Ryan CJ, et al. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance). J Clin Oncol. 2014;32(11):1143-1150.
    6. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813-822.
    7. Smith MR, Saad F, Oudard S, et al. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. 2013;31(30):3800-3806.
    8. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65(2):467-479.
    9. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
    10. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):408-419.
    11. Vignani F, Bertaglia V, Buttigliero C, Tucci M, Scagliotti GV, Di Maio M. Skeletal metastases and impact of anticancer and bone-targeted agents in patients with castration-resistant prostate cancer. Cancer Treat Rev. 2016;44:61-73.
    12. Basch E, Autio KA, Smith MR, et al. Effects of cabozantinib on pain and narcotic use in patients with castration-resistant prostate cancer: results from a phase 2 nonrandomized expansion cohort. Eur Urol. 2015;67(2):310-318.
    13. Araujo JC, Mathew P, Armstrong AJ, et al. Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study. Cancer. 2012;118(1):63-71.
    14. Araujo JC, Trudel GC, Saad F, et al. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 2013;14(13):1307-1316.
    15. Nelson JB. Endothelin receptor antagonists. World J Urol. 2005;23(1):19-27.
    16. Nelson JB, Love W, Chin JL, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. 2008;113(9):2478-2487.
    Published December 10, 2019
  • CARG tool’s ability to predict older prostate cancer patients’ risk of toxicity: Beyond the Abstract

    Prostate cancer is one of the leading causes of cancer death in American men and mostly affects men above age 65. [1]  The American Cancer Society predicts 161,360 new cases of prostate cancer and 26,730 deaths from prostate cancer in the United States in the year 2017. [1]  Although fewer than 10% of people are diagnosed with de novo metastatic disease, many men with early stage prostate cancer will eventually develop metastatic disease. The initial treatment of metastatic disease is androgen deprivation therapy, but this is only effective for a few years, after which the disease continues to progress.  At this point it is referred to as metastatic castrate resistant prostate cancer (mCRPC).  About 10-20% of people are diagnosed with mCRPC within 5 years of a diagnosis of prostate cancer, but more than 50% of patients with mCRPC die within 3 years. [2]  mCRPC is currently defined as the progression of the prostate cancer despite castrate levels of testosterone (usually defined as <1.7nmol/L). [2]  Progression to mCRPC is typically associated with worsening symptoms, declining quality of life and worsening pain.  However, mCRPC may be helped by other forms of hormone therapy such as the androgen receptor axis-targeted (ARAT) agents Abiraterone and Enzalutamide because it is not completely hormone-refractory. [3]  Patients who become resistant to ARAT therapy usually are considered for chemotherapy. [4]  In 2004, docetaxel became the standard of care for mCRPC. Later, cabazitaxel was also found to be beneficial in patients with mCRPC that progressed after receiving docetaxel therapy. [2]

    Chemotherapy

    Chemotherapy remains the treatment of choice in symptomatic mCRPC, but survival benefits after undergoing chemotherapy are modest (on the order of a few months).  In comparison to mitoxantrone (the prior standard chemotherapy agent), docetaxel was associated with better pain control, quality of life and more frequent PSA responses. [5]  However, chemotherapy can also be associated with significant toxicity, with 18-44% rates of grade 3 or higher toxicity.  National Cancer Institute Common Terminology Criteria for Adverse Events defines grade 3 as severe, grade 4 as life-threatening or disability and grade 5 as death. [6]  Common toxicities from chemotherapy include neutropenia, generalized weakness, bone pain, fatigue, peripheral edema and mucositis.  The most common grade 3 to 5 toxicities with docetaxel are: neutropenia, leucopenia, anemia, fatigue, infection and dehydration. [5]

    Currently, there is a need to find tools that can help identify men who may be more or less likely to experience serious toxicity from chemotherapy because it could help during treatment decision-making. Predicting toxicities would help doctors determine the side effects and toxicities that specific patients might develop before prescribing the treatment.  This way, it would make it easier for them to determine which treatment method would work, at which dose and method of delivery.  Making a more informed decision can be important in this setting because of the increased risk of death or functional decline.  It is especially helpful to be able to predict these toxicities in older adults because the risk of toxicity increases with age.  In practice, chemotherapy is less likely to be given to older adults due to the concerns about their ability to tolerate it. [6]  Many older adults tend to place an increasing value on avoiding treatments that adversely affect their quality of life or functional independence. [7]  Since older adults have a higher risk of toxicity and place an increasing importance on quality of life, oncologists may find it harder to suggest the best treatment option.  Hence, it would be useful to be able to predict toxicities from chemotherapy.  This advancement in toxicity prediction would also help select up-front treatment modifications such as dose reduction or the addition of colony-stimulating factors to reduce toxicity.

    Tools such as the Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 5-point scale are currently used to determine risk by assessing a patient’s level of function and capability to perform self-care.  Although this tool is a prognostic factor for survival and may help select which patients should not get chemotherapy, it is a poor predictor of toxicity risk because it is subjective, being subject to bias and high interobserver variability. [8]  Oncologist judgement in stratifying patients into those at lower or higher risk of toxicity may be better, but it has rarely been formally compared against measures such as the ECOG PS.  Finally, the agreement between currently used tools such as PS and clinical judgement by oncologists is still quite low. [9]

    Our study sought to identify tools that could help inform treatment decision-making by improving the ability to predict a patient’s risk of chemotherapy toxicity.  Distinguishing men at lower and higher risk of severe toxicity in men with mCRPC would help make better treatment decisions and allow a more informed decision about the risks and benefits of chemotherapy.  In patients with very high risks of toxicity that may counterbalance any perceived benefits, there are four main options besides conventional dose chemotherapy: (a) reduced-dose chemotherapy; (b) use of colony-stimulating factors to reduce neutropenia and related complications; (c) alternative, gentler agents or clinical trials of novel therapies; (d) best supportive care.  While our study did not focus on which treatment might be best, we sought to validate the Vulnerable Elders Survey-13 (VES-13) and Cancer and Aging Research Group (CARG) tool in mCRPC with the goal of helping a clinician’s judgment. 

    VES-13

    The VES-13 is a brief (3-4 minutes), self-report tool that measures vulnerability.  The initial purpose of developing this tool was to better screen older persons at risk of health deterioration. [10]  In the original study, vulnerable older people were defined as persons age 65 and older who were at increased risk of functional decline or death over 2 years. [10]  The instrumental activities of daily living (IADLs) and activities of daily living (ADLs) that the VES-13 focuses on include shopping, performing light housework, managing finances, preparing meals, using the telephone, bathing, dressing, transferring, toileting, walking across the room, and eating. [10]   However, its ability to predict grade 3-5 chemotherapy toxicity has yet to be studied. 

    CARG 

    The CARG tool uses a combination of 11 parameters, including age, tumor and treatment characteristics, laboratory data, and specific geriatric assessment parameters to help predict grade 3-5 chemotherapy toxicity in older patients with cancer.  It categorizes people into low, intermediate and high risk of severe chemotherapy toxicity, in our case grade 3+ chemotherapy toxicity.  It does include a geriatric assessment questionnaire with 6 domains: functional status, co-morbidity, psychological state, social activity, social support, and nutrition.  The purpose of developing the CARG tool was to identify risk factors for chemotherapy toxicity in older adults undergoing various chemotherapy regimens and create a user-friendly risk stratification schema for chemotherapy toxicity. [6]  The CARG tool was derived from a study of 500 patients undergoing a variety of chemotherapy regimens for various solid tumors. The CARG tool was recently validated externally [11] and helps to identify patients at greatest risk of chemotherapy toxicity.  Although the CARG tool has been proven in a mixed cohort of patients with various cancers, there are no validation data for patients with mCRPC, and only 10% of the patients in the original study had genitourinary cancers. [6]  Since different chemotherapy regimens have different toxicity risks, it is important to validate such tools in a more homogeneous cohort to ensure findings are similar to mixed cohorts. 

    Oncologist Judgment

    For our study, we had each patient’s medical oncologist rate the patient’s risk of chemotherapy toxicity on a 10-point scale.  “Oncologists are left with little guidance when it comes to identifying risk factors other than chronologic age or performance status, neither of which has been shown to predict well in heterogeneous older adult populations.” [6] 

    Methods

    We recruited men aged 65 or older with mCRPC who were starting either first-line chemotherapy (receiving chemotherapy for the first time) or second-line chemotherapy (stopped first-line chemotherapy because of disease progression, toxicity, or other reasons).  All but two (4%) participants received docetaxel-based chemotherapy, and the majority (n=29, 63%) received the standard dose of 75 mg/m2 every 3 weeks.  Ten (22%) received a dose of 60 mg/m2, whereas 5 (11%) received a lower dose than this.  Subjects were recruited either prior to starting chemotherapy or within the first two cycles as long as there was no dose reduction.  Men unable to come for study visits or with a life expectancy of less than 3 months, a major neuropsychiatric abnormality, or limited English were excluded from the study.

    We collected socio-demographic and medical information on all subjects at baseline, as well as physical performance measures (grip strength, timed up and go, and timed chair stands).  The CARG and VES-13 tools were administered as well.  The CARG toxicity prediction model was used to stratify patients into three groups (low, intermediate, and high risk) based on risk for grade 3+ chemotherapy toxicity.  The VES-13 was used to measure vulnerability, which was defined by a score of 3 or greater.  This cut-off point follows the conventional scoring system, but we also examined cut-offs of 2 or greater and 4 or greater.  We also asked each subject’s treating physician to provide an estimate of the risk of chemotherapy toxicity on a scale from 1 (lowest risk) to 10 (highest risk).  Oncologists were not told the results of the other assessment tools used in the study. 

    Following the baseline visit, follow-up assessments were performed after each cycle of chemotherapy (every 3 weeks) and after the final cycle.  At each visit, a trained research coordinator recorded chemotherapy-related toxicities using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4).  Laboratory-based toxicities such as neutropenia were based on blood tests performed every three weeks.  These same procedures were followed to record toxicity for men who were recruited after already having started chemotherapy, including for cycles administered before being enrolled on the study.

    Sample sizes were based on the assumption that we would see the same rate of toxicity as in the original CARG study (i.e. 30% risk of grade 3+ toxicity for the low risk group, 52% for intermediate, and 83% for high) [6] and that equal proportions of patients would be enrolled in each risk group (i.e. one-third for each).  Based on these assumptions, we calculated that we would require 45 patients. 

    Results

    46 men were recruited for the study with a mean age of 75.  These participants had a median PSA level at baseline of 243.7 ng/mL and had relatively few other major medical problems (median Charlson Comorbidity Index score of 0).  Although participants had a fairly high performance status (mean Karnofsky score of 77%), 50% were considered vulnerable based on the VES-13.  Based on the CARG tool, only 2 (4%) patients were considered low risk, 29 (63%) were intermediate, and 15 (33%) were high risk of severe chemotherapy toxicity. 

    Grade 3+ and grade 2 chemotherapy toxicity were experienced by 20% and 67% of patients, respectively.  The most common grade 3-5 toxicities were neutropenia (30%), generalized weakness (23%), and bone pain (15%), and the most common grade 2 toxicities were fatigue (35%), peripheral edema (7%), and mucositis (7%).

    Grade 3+ toxicity was observed in 0 (0%), 5 (17%) and 4 (27%) patients in low, intermediate, and high CARG risk groups respectively, suggesting an incremental pattern across risk groups.  However, this pattern was not statistically significant (p = 0.65).  22% of patients considered vulnerable by the VES-13 experienced grade 3+ toxicity, compared to 17% of patients considered non-vulnerable (p = 0.71).  Age, comorbidity, Karnofsky performance score, and baseline physical performance measures did not seem to be predictors of grade 3+ toxicity.  In addition, oncologist judgment of toxicity risk was a relatively poor predictor of actual toxicity.

    The ability of the CARG tool to predict grade 2 toxicity appeared to be higher than the ability of the VES-13 to predict these toxicities, but this was not statistically significant, likely due to our small sample size (p = 0.072 for CARG, 0.75 for VES-13).  Limiting the analyses to only those participants who were recruited prior to starting chemotherapy did not alter the findings.

    The rates of grade 3+ toxicity found in our cohort were relatively low overall: only 20% compared to the 53% observed in the original CARG study.  The same pattern was found in the three individual risk groups, with lower rates of toxicities observed in each compared to the original CARG study.  However, the rate of toxicity in our cohort was similar to rates reported in other studies of older men with mCRPC.  For example, the TAX327 trial by Tannock et al. reported severe adverse events in 26% of subjects, and grade 3+ neutropenia in 32%. [5]

    Although we did not find statistically significant results for either of the tools tested, we did observe three key findings in our study.  First, the risk of grade 3+ toxicity with docetaxel-based chemotherapy in the mCRPC population is lower overall and across CARG risk groups compared to the rates observed in the original study, which used data from patients with a variety of cancers.  However, we still found that there was a gradient of toxicity risk across the different CARG risk groups (i.e. 0% in low, 17% in moderate, and 27% in the high risk group).  Therefore, there is a need for further validation studies conducted with older men with mCRPC.

    Second, our data on the performance of the VES-13 are the first in this population.  Even though our findings were negative, we believe they warrant further investigation because of the ease of use and emerging value of the VES-13 in other geriatric oncology settings (e.g. 12).  Third, we also provided the first data looking at oncologist judgment of toxicity risk, and compared that to the CARG and VES-13 tools.  For tools to be useful in a busy clinical setting, they must provide better predictive ability than the usual clinical care.  Therefore, further investigation in this area is important.

    Some other limitations include the fact that we conducted our study at a single academic cancer center, limiting generalizability, and did not use the CRASH tool, another popular tool for predicting toxicities. [13]  Future studies should directly compare the CRASH and CARG tools in the mCRPC setting.  Lastly, the 10-point rating scale we used for oncologist predictions has not been validated in this context, and we did not provide any numerical anchors.  Therefore, the different ratings may have meant different things to different oncologists.  Further investigation is warranted in these areas.

    Conclusion

    In summary, toxicity with docetaxel in a cohort of older men in usual clinical practice was lower than predicted by the CARG tool.  Although the CARG tool appeared to differentiate those at lower versus higher risk of chemotherapy toxicity and was better than clinician judgement or ECOG PS, a larger validation study is needed.

    Written By: Thavalis Ja, Rathore Ma, Breunis Ha, Alibhai SMHa,b,c
    a. Department of Medicine, University Health Network 

    b. Department of Medicine, University of Toronto 
    c. Institute of Health Policy, Management and Evaluation, University of Toronto 

    References 

    1. American Cancer Society. Key statistics for prostate cancer [Internet]. American Cancer Society Inc.; 2016 [updated 2017 Jan 5]. Available from https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html 
    2. Nussbaum N, George DJ, Abernethy AP, Dolan CM, Oestreicher N, Flanders S, Dorff TB. Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science. Prostate Cancer and Prostatic Diseases. 2016 Jun 1;19(2):111-21. 
    3. American Cancer Society. Prostate cancers [Internet]. American Cancer Society Inc.; 2016 [updated 2016 Mar 11]. Available from https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html 
    4. Chi K, Hotte SJ, Joshua AM, North S, Wyatt AW, Collins LL, Saad F. Treatment of mCRPC in the AR-axis-targeted therapy-resistant state. Annals of Oncology. 2015 Oct 1; 26(10):2044-56.
    5. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. New England Journal of Medicine. 2004 Oct 7; 351(15):1502-12.
    6. Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, Lichtman SM, Gajra A, Bhatia S, Katheria V, Klapper S. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. Journal of Clinical Oncology. 2011 Aug 1; 29(25):3457-65.
    7. Rose JH, O'Toole EE, Dawson NV, Lawrence R, Gurley D, Thomas C, Hamel MB, Cohen HJ. Perspectives, preferences, care practices, and outcomes among older and middle-aged patients with late-stage cancer. Journal of Clinical Oncology. 2004 Dec 15; 22(24):4907-17. 
    8. Kelly CM, Shahrokni A. Moving beyond Karnofsky and ECOG performance status assessments with new technologies. Journal of Oncology. 2016 Mar 15; 6186543.
    9. Sørensen JB, Klee M, Palshof T, Hansen HH. Performance status assessment in cancer patients. An inter-observer variability study. British Journal of Cancer. 1993 Apr; 67(4):773-5.
    10. Saliba D, Elliott M, Rubenstein LZ, Solomon DH, Young RT, Kamberg CJ, Roth C, MacLean CH, Shekelle PG, Sloss EM, Wenger NS. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. Journal of the American Geriatrics Society. 2001 Dec 1; 49(12):1691-9.
    11. Hurria A, Mohile S, Gajra A, Klepin H, Muss H, Chapman A, et al.  Validation of a Prediction Tool for Chemotherapy Toxicity in Older Adults With Cancer.  Journal of Clinical Oncology. 2016 Jul 10; 34(20:2366-71.
    12. Luciani A, Ascione G, Bertuzzi C, Marussi D, Codeca C, Di Maria G, et al.  Detecting disabilities in older patients with cancer: comparison between comprehensive geriatric assessment and vulnerable elders survey-13.  Journal of Clinical Oncology. 2010 Apr 20; 28(12):2046-50.
    13. Extermann M, Boler I, Reich RR, Lyman GH, Brown RH, DeFelice J, et al. Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. 2011 Nov 9; 118(13):3377-86.
    Read the Abstract
    Published June 1, 2017
  • Chemotherapy in Prostate Cancer- When, Why and How

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 4
    Published Date: December 2017

    Until 2010, our treatment armamentarium for prostate cancer (PC) was fairly limited. Patients received local therapy for non-metastatic disease, androgen deprivation therapy (ADT) for hormone-naïve metastatic disease, denosumab and zoledronic acid for metastatic castration-resistant prostate cancer (mCRPC), and bisphosphonates or docetaxel for symptomatic mCRPC.
    Published February 28, 2018
  • Contemporary Radiotherapy Clinical Trials for Prostate Cancer

    Localized Treatment – Optimizing Fractionation

    Several trials have recently focused on delineating the optimal radiotherapy fractionation schedule for the primary treatment of prostate cancer. In 2016, efficacy results of the Dutch HYPRO trial were published, assessing hypofractionated radiotherapy compared with conventionally fractionated radiotherapy among patients with intermediate-risk to high-risk T1b-T4NX-N0MX-M0 localized prostate cancer.1 Patients were assigned 1:1 to either hypofractionated radiotherapy of 64.6 Gy (19 fractions of 3.4 Gy, three fractions per week) or conventionally fractionated radiotherapy of 78.0 Gy (39 fractions of 2.0 Gy, five fractions per week) with a primary endpoint of relapse-free survival. There were 804 patients assessed in the intention-to-treat analysis, of which 407 were assigned hypofractionated radiotherapy and 397 were allocated to conventionally fractionated radiotherapy. Additionally, 67% of patients received concomitant androgen deprivation therapy (ADT) for a median duration of 32 months (IQR 10-44). Over a median follow-up of 60 months (IQR 51-69), treatment failure was reported in 21% of patients, including 20% in the hypofractionation group and 22% in the conventional fractionation group. The 5-year relapse-free survival was 80.5% (95% CI 75.7-84.4) for patients assigned hypofractionation and 77.1% (71.9-81.5) for those allocated conventional fractionation (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.63-1.16; log-rank p=0.36). Based on these results, the authors noted that this current regimen of hypofractionated radiotherapy was not superior to conventional radiotherapy.

    The CHHiP trial was a multi-center, randomized, Phase III trial, designed as a non-inferiority clinical trial, randomizing men with pT1b-T3aN0M0 prostate cancer 1:1:1 to conventional (74 Gy delivered in 37 fractions over 7.4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3.8 weeks) all delivered with intensity-modulated techniques.2 Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. The primary endpoint was time to biochemical or clinical failure, and the critical hazard ratio for non-inferiority was 1.208. In this large trial, 3,216 men were enrolled from 71 centers and randomly assigned: 1,065 patients to the 74 Gy group, 1,074 patients to the 60 Gy group, and 1,077 patients to the 57 Gy group. The median follow-up was 62.4 months (IQR 53.9-77.0) over which the proportion of patients who were biochemical or clinical failure-free at five years was 88.3% (95% CI 86.0-90.2) in the 74 Gy group, 90.6% (95% CI 88.5-92.3) in the 60 Gy group, and 85.9% (95% CI 83.4-88.0) in the 57 Gy group. The 60 Gy hypofractionated schedule was non-inferior to the conventional 74 Gy schedule (HR 0.84, 90% CI 0.68-1.03, p noninferiority = 0.0018), but non-inferiority was not possible for 57 Gy hypofractionation compared with 74 Gy (HR 1.20, 90% CI 0.99-1.46, p noninferiority = 0.48). 

    Based on these initial studies, recent interest has related to even more intense radiotherapy fractionation. The Scandinavian HYPO-RT-PC randomized controlled Phase III trial was initially presented at ESTRO 2018, and subsequently published in Lancet Oncology.3 This trial randomized men with intermediate and high-risk prostate cancer to either conventional fractionating (n = 602; 78.0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultrahypofractionated (n=598; 42.7 Gy in seven fractions, three days per week for 2.5 weeks). The primary endpoint was time to biochemical or clinical failure. The estimated failure-free survival at five years was 84% (95% CI 80-87) in both treatment groups, with an adjusted HR of 1.002 (95% CI 0.758-1.325; log-rank p=0.99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 [28%] of 569 patients vs 132 [23%] of 578 patients; p=0.057). Based on these results, there has been support for the use of ultra-hypofractionated radiotherapy for prostate cancer.

    However, despite encouraging results regarding biochemical/relapse-free survival as described above, studies have not demonstrated an overall survival (OS) benefit. Patients in the NRG Oncology RTOG 0126 trial that had intermediate-risk prostate cancer were randomized to 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions.4 Over a median follow-up of 8.4 years in 1,499 patients, there was no difference in OS between the 751 men in the 79.2-Gy arm and the 748 men in the 70.2-Gy arm. The 8-year rates of OS were 76% with 79.2 Gy and 75% with 70.2 Gy (HR 1.00, 95% CI, 0.83-1.20), and the 8-year cumulative rates of distant metastases were 4% for the 79.2-Gy arm and 6% for the 70.2-Gy arm (HR 0.65, 95% CI, 0.42-1.01). As the above trials continue to mature, it will be imperative to evaluate survival outcomes. However, adoption of hypofractionation needn’t require improved survival or toxicity outcomes – on the basis of equivalence, improvements in the patient experience/convenience and cost would support the adoption of this approach.

    Localized Disease – Optimizing Androgen Deprivation Therapy (ADT)

    A second initiative of recent radiotherapy trials has been delineating the appropriate dose of ADT given concurrently with radiotherapy. The DART01/05 GICOR trial was a randomized, controlled Phase III trial assessing high-dose radiotherapy with short-term or long-term ADT for patients with T1c-T3b N0M0 prostate cancer with intermediate-risk and high-risk features.5 Patients were randomly assigned 1:1 to receive either four months of ADT combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term ADT group) or the same treatment followed by 24 months of adjuvant ADT (long-term ADT group), stratified by prostate cancer risk group (intermediate risk vs high risk). In this Spanish multi-center trial, 178 patients were randomly assigned to receive short-term ADT and 177 to receive long-term ADT. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term ADT than among those receiving short-term ADT: 90% (95% CI 87-92) vs 81% (95% CI 78-85), HR 1.88, 95% CI 1.12-3.15. Furthermore, the 5-year OS (95% vs 86%; HR 2.48, 95% CI 1.31-4.68) and 5-year MFS (94% vs 83%; HR 2.31, 95% CI 1.23-3.85) rates were also significantly better in the long-term ADT group than in the short-term ADT group. Not surprisingly, the authors noted that the effect of long-term ADT on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. 

    In 2016, the results of the EORTC 22991 randomized trial were published.6 This trial assessed if biochemical disease-free survival (DFS) is improved by adding six months of androgen suppression to primary radiotherapy for intermediate- or high-risk localized prostate cancer. Among 819 patients, the median patient age was 70 years, 74.8% were intermediate risk and 24.8% were high risk. At 7.2 years median follow-up, radiotherapy plus androgen suppression significantly improved biochemical DFS (HR 0.52, 95% CI 0.41-0.66), as well as clinical progression-free survival (HR 0.63, 95% CI 0.48-0.84).

    Long-term follow-up of the D’Amico trial assessing ADT plus radiotherapy versus ADT alone for patients with localized, unfavorable risk prostate cancer was published in 20157. This analysis importantly showed that underlying comorbidity significantly modified the benefit of ADT: in patients with moderate or severe comorbidity, use of radiotherapy alone was associated with decreased cardiac mortality (HR 0.17, 95% CI 0.06-0.46), non-prostate cancer mortality (HR 2.79, 95% CI 1.02-7.60), and overall mortality (HR 0.36, 95% CI 0.19-0.67). Conversely, in men with no or minimal comorbidity, radiotherapy alone was associated with an increased risk of overall mortality and prostate cancer mortality, without coinciding decreases in cardiac mortality or non-prostate cancer mortality.

    The prior standard ADT duration was 28-36 months when combined with radiotherapy for high-risk disease. As such, the TROG RADAR trial assessed whether the addition of 12 months of adjuvant ADT, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive six months of ADT and prostate radiotherapy.8 In 2019, this trial reported 10-year outcomes. There were 1,071 patients randomized to radiotherapy plus six months of ADT or radiotherapy plus 18 months of ADT. This trial found that 18 months of ADT plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than six months of ADT plus radiotherapy (HR 0.70, 95% CI 0.50-0.98), but the addition of zoledronic acid to this treatment regimen is not beneficial. Finally, the PCS IV Trial randomized 630 patients with a median follow-up of 9.4 years to radiotherapy plus 18 months of ADT or radiotherapy plus 36 months of ADT.9 The 5-year OS rates were 91% for long term ADT arm (95% CI 88-95%) and 86% for short term ADT arm (95% CI 83-90%, p=0.07). The quality of life analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 months of ADT.           

    Localized Disease – Addition of Chemotherapy

    The benefit of adding chemotherapy in the treatment of very high-risk disease has also been recently evaluated. Rosenthal et al.10 published the multicenter randomized NRG Oncology RTOG 0521 clinical trial, which enrolled patients with high-risk nonmetastatic disease between 2005 and 2009. Patients were randomly assigned (n=563) to receive standard long-term ADT plus radiotherapy with or without adjuvant chemotherapy. Over a median follow-up of 5.7 years, the 4-year OS rate was 89% (95% CI, 84% to 92%) for ADT and radiotherapy, compared to 93% (95% CI, 90% to 96%) for ADT and radiotherapy plus chemotherapy (HR 0.69, 90% CI 0.49-0.97). Six-year rate of distant metastasis was 14% for ADT and radiotherapy and 9.1% for ADT and radiotherapy plus chemotherapy, (HR 0.60, 95% CI 0.37-0.99).

    Treatment after Radical Prostatectomy

    For decades, urologists and radiation oncologists have debated the optimal timing, location, and dose of radiotherapy, in addition to the utilization of ADT among those experiencing biochemical recurrence after radical prostatectomy. The much-anticipated NRG Oncology/RTOG 0534 SPPORT trial reported initial results at the 2019 ASTRO meeting.11 This trial randomized 1,736 patients to either (i) salvage radiotherapy to the prostate bed, (ii) salvage radiotherapy to the prostate bed plus ADT, or (iii) salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes. The 5-year freedom from progression rate was 71% for salvage radiotherapy to the prostate bed, 81% for salvage radiotherapy to the prostate bed plus ADT, and 87% for salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes. Based on only 108 patients with metastasis, there were minimal differences between the three arms with regards to metastasis-free survival. It is likely that with continued follow-up, these results will likely continue to favor salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes.

    Previously, Shipley et al. assessed whether antiandrogen therapy with radiation therapy improves cancer control and prolong OS among patients with biochemical recurrence.12 In this trial, there were 760 patients who had undergone radical prostatectomy with lymphadenectomy and had biochemically recurrent disease who were randomized to radiation therapy and to receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary endpoint was the OS rate; the actuarial rate of OS at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (HR 0.77, 95% CI 0.59 to 0.99). The 12-year incidence of death from prostate cancer was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (p < 0.001). Finally, the cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (p = 0.005). As such, the addition of antiandrogen improved clinical outcomes and OS in patients with biochemical recurrence after radical prostatectomy.

    Several randomized trials assessing adjuvant vs salvage radiotherapy have been presented earlier this year at academic conferences, but have yet to be published. 

    Radiotherapy in the Setting of Metastatic Disease

    Several trials have recently assessed the impact of radiotherapy to the prostate in the setting of metastatic disease, given retrospective evidence that patients may derive a survival benefit for treatment to the primary prostate tumor. The HORRAD trial was a multi-center randomized controlled trial recruiting 432 patients with a prostate-specific antigen (PSA) >20ng/ml and primary bone metastatic prostate cancer on bone scan (between 2004 and 2014).13 Patients were randomized to either ADT with external beam radiotherapy or ADT alone. The median PSA level was 142ng/ml and 67% of patients had more than five osseous metastases. Over a median follow up of 47 months, the median OS was 45 months (95% CI, 40.4-49.6) in the radiotherapy group and 43 months (95% CI, 32.6-53.4) in the control group (p = 0.4; HR 0.90, 95% CI 0.70-1.14). The median time to PSA progression in the radiotherapy group was 15 months (95% CI, 11.8-18.2), compared with 12 months (95% CI, 10.6-13.4) in the control group.

    Despite the negative results from HORRAD, there was much anticipation for the results of the STAMPEDE arm H clinical trial assessing the efficacy of radiotherapy to the primary in M1 disease.14 This study randomized 2,061 to either standard systemic treatments (ADT +/- chemotherapy) versus standard systemic treatments (ADT +/- chemotherapy) plus radiotherapy to the primary. There were 819 (40%) men that had a low metastatic burden, 1,120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0.76, 95% CI 0.68-0.84) but not OS (HR 0.92, 95% CI 0.80-1.06). In a prespecified subgroup analysis, patients receiving radiotherapy to the prostate among patients with low metastatic burden, there was a significant improvement in OS (HR 0.68, 95% CI 0.52-0.90).

    The SABR-COMET trial was an important trial published in 2019 assessing stereotactic body radiotherapy to oligometastatic disease.15 The objective of this study was to assess the standard of care of palliative treatments with or without stereotactic body radiotherapy in up to five metastatic lesions. The trialist’s hypothesis was that patients with oligometastatic disease will have improved outcomes with treatment of their metastatic sites. This study included any cancer (primarily breast, prostate, colorectal, and lung) who were then randomized 1:2 to standard of care versus standard of care plus stereotactic body radiotherapy. The standard of care was at the discretion of the physician and the primary endpoint was OS. There were 99 patients at 10 centers and median follow-up was 25.5 months. Median OS was 28 months (95% CI 19-33) in the control group versus 41 months (26-not reached) in the stereotactic body radiotherapy group (HR 0.57, 95% CI 0.30-1.10; p =0.090). Adverse events of grade 2 or worse occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the stereotactic body radiotherapy group (p=0.026), an absolute increase of 20% (95%CI 5-34). Treatment-related deaths occurred in three (4.5%) of 66 patients after stereotactic body radiotherapy, compared with none in the control group. The authors concluded that stereotactic body radiotherapy was associated with a 13-month increase in OS and doubling of progression-free survival (PFS).

    Conclusions

    The last five years have seen several important and practice-changing clinical trials for the treatment of prostate cancer with radiotherapy. Early results suggest that ultra-hypofractionation may make primary treatment with radiotherapy an attractive, less arduous option, however long-term OS results for hypofractionation will be important. There is little doubt that the addition of ADT to radiotherapy in high-risk patients for primary treatment and those experiencing biochemical failure after radical prostatectomy improves outcomes. Furthermore, based on results from the STAMPEDE Arm H clinical trial, many clinicians are now treating the prostate primary among men with low-volume metastatic disease. Finally, ongoing studies utilizing stereotactic body radiotherapy to metastatic sites will be important as we focus on improving quality as well as quantity of life for patients with advanced, heavily treated prostate cancer.

    Published Date: January 6th, 2020

    Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
    References: 1. Incrocci L, Wortel RC, Alemayehu WG, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17(8):1061-1069.
    2. Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17(8):1047-1060.
    3. Widmark A, Gunnlaugsson A, Beckman L, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet. 2019;394(10196):385-395.
    4. Michalski JM, Moughan J, Purdy J, et al. Effect of Standard vs Dose-Escalated Radiation Therapy for Patients With Intermediate-Risk Prostate Cancer: The NRG Oncology RTOG 0126 Randomized Clinical Trial. JAMA Oncol. 2018;4(6):e180039.
    5. Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16(3):320-327.
    6. Bolla M, Maingon P, Carrie C, et al. Short Androgen Suppression and Radiation Dose Escalation for Intermediate- and High-Risk Localized Prostate Cancer: Results of EORTC Trial 22991. J Clin Oncol. 2016;34(15):1748-1756.
    7. D'Amico AV, Chen MH, Renshaw A, Loffredo M, Kantoff PW. Long-term Follow-up of a Randomized Trial of Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer. JAMA : the journal of the American Medical Association. 2015;314(12):1291-1293.
    8. Denham JW, Joseph D, Lamb DS, et al. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial. Lancet Oncol. 2019;20(2):267-281.
    9. Nabid A, Carrier N, Martin AG, et al. Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial. Eur Urol. 2018;74(4):432-441.
    10. Rosenthal SA, Hu C, Sartor O, et al. Effect of Chemotherapy With Docetaxel With Androgen Suppression and Radiotherapy for Localized High-Risk Prostate Cancer: The Randomized Phase III NRG Oncology RTOG 0521 Trial. J Clin Oncol. 2019;37(14):1159-1168.
    11. Pollack A, Karrison TG, Balogh AG. Short term Androgen Deprivation Therapy Without or With Pelvic Lymph Node Treatment Added to Prostate Bed Only Salvage Radiotherapy: The NRG Oncology/RTOG 0534 SPPORT Trial. ASTRO. 2019.
    12. Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med. 2017;376(5):417-428.
    13. Boeve LMS, Hulshof M, Vis AN, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019;75(3):410-418.
    14. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
    15. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-2058.
    Published January 6, 2020
  • EAU 2019: Conclusions from Recent Oncology Meetings Regarding: Castration-Resistant Prostate Cancer

    Barcelona, Spain (UroToday.com) In this session, Dr. Evans presented a review of some of the most important studies in the castrate-resistant prostate cancer space published in the past year. First, from ESMO 2018, in a phase 3 randomized controlled trial, radium 223 with abiraterone (ERA 223) did not demonstrate improved symptomatic skeletal-related event-free or overall survival compared to abiraterone with placebo. Clinical fractures were more common in the abiraterone and radium group. Based on the data from the study, the use of radium 223 in combination with abiraterone was not recommended.
    Published March 19, 2019
  • EAU 2019: PROpel: Olaparib Combined with Abiraterone as First-Line Therapy In mCRPC

    Barcelona, Spain (UroToday.com) PARP inhibitors have been increasingly recognized for their potential therapeutic role in patients with advanced prostate cancer, particularly in the setting of DNA repair defects. Prior work by Dr. Clarke and colleagues demonstrated, in a phase II clinical trial (NCT01972217), that olaparib (given as tablets, 300 mg bid) in combination with abiraterone (1000 mg od plus prednisone/prednisolone 5 mg bid) significantly prolonged radiologic progression-free survival (rPFS) compared with abiraterone alone (median 13.8 vs 8.2 months; HR 0.65, 95% CI 0.44–0.97, P=0.034) in patients with mCRPC in the second-line metastatic setting who received prior docetaxel1. Building on this, the authors are now taking this to a randomized phase III multi-institution international clinical trial – but as a first-line therapy for patients with mCRPC.
    Published March 19, 2019
  • EAU 2019: The Advances in the Treatment of Castrate Resistant Prostate Cancer

    Barcelona, Spain (UroToday.com) Dr. Robert Van Soest presented on the recent advances in the treatment of castrate-resistant prostate cancer (CRPC). The current therapeutic options in metastatic hormone-sensitive prostate cancer (mHSPC), and the 1st and 2nd treatment lines of metastatic CRPC are shown in Figure 1.
    Published March 21, 2019
  • EAU 2020: The Best Sequence for M+ Castrate-resistant Prostate Cancer in 2020

    (UroToday.com) Dr. Alison Birtle gave a talk on the ever-changing treatment paradigm of advanced prostate cancer (Figure 1). Metastatic castrate-resistant prostate cancer (mCRPC) is a lethal disease with huge heterogeneity. The same patient can have coexistence of androgen receptor-dependent and independent tumor cells. The sequencing of therapies is even more important given the use of upfront docetaxel and androgen receptor-targeted therapies (ARTA).

    Published July 18, 2020
  • EAU PCa 17: Castration resistant prostate cancer: Drug selection and treatment sequencing

    Vienna, Austria (UroToday.com) Dr. Bertrand Tombal from Belgium provided a discussion during the General Updates on Systemic Treatments at the EAU Update on Prostate Cancer, focusing on drug selection and treatment sequencing among men with castration resistant prostate cancer (CRPC). As Dr. Tombal notes, the drug portfolio for men with CRPC in 2017 is quite vast, including docetaxel, abiraterone (pre/post docetaxel), enzalutamide (pre/post docetaxel), cabazitaxel (post-docetaxel), Sipuleucel-T (pre-docetaxel), and radium-223 (post-docetaxel or in docetaxel unfit).
    Published September 18, 2017
  • EAU PCa 17: Hormone-naïve metastatic disease: How to treat it?

    Vienna, Austria (UroToday.com) Dr. Axel Merseburger from Germany started the session on General Updates on Systemic Treatments at the EAU Update on Prostate Cancer discussing how best to treat patients with hormone-naïve metastatic prostate cancer (mHNPC). 
    Published September 22, 2017
  • Embarrassment of Riches: Therapies that Improve Overall Survival in mCRPC

    Published in Everyday Urology - Oncology Insights: Volume 1, Issue 1
    Published Date: March, 2016

    Before 2004, there was an unmet need for survival prolonging therapies in men with castration-resistant prostate cancer (CRPC). Palliative therapeutic options were the standard of care. As a result, there was a pervasive nihilism regarding the therapeutic management of men with advanced prostate cancer, especially after they ceased responding to androgen suppressive therapy.
    Published October 4, 2016
  • ESMO 2019: CARD: Randomized, Open-label Study of Cabazitaxel vs Abiraterone or Enzalutamide in Metastatic Castration-resistant Prostate Cancer

    Barcelona, Spain (UroToday.com) Multiple therapeutic options have been approved for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC), including the second-generation anti-androgens abiraterone and enzalutamide, and chemotherapy with docetaxel or cabazitaxel. However, the appropriate order in which to stagger these therapies is not uniformly clear. With regards to anti-androgens, there is the suggestion that enzalutamide may be effective after progression on abiraterone and less suggestion that abiraterone is effective after enzalutamide. Additionally, while many patients do respond to newer anti-androgen therapies, a subset of patients progress within a year or less, representing a more aggressive disease phenotype that may benefit from chemotherapy rather than another anti-androgen.

    Published October 1, 2019
  • ESMO 2019: Docetaxel for Hormone-Naïve Prostate Cancer: Results from Long-term Follow-up of Non-metastatic Patients in the STAMPEDE Randomised Trial - A Medical Oncologist's Perspective

    Barcelona, Spain (UroToday.com) Multiple studies have shown the efficacy of docetaxel in metastatic hormone-sensitive and castration-resistant prostate cancer, though there is ongoing debate regarding the impact that metastatic disease burden has on docetaxel use in the hormone-sensitive setting. The STAMPEDE group has previously presented data suggesting that docetaxel is also beneficial with regards to failure free-survival1 in the non-metastatic patients who are beginning long-term hormonal therapy. 
    Published September 29, 2019
  • ESMO 2019: Efficacy and Safety of Nivolumab in Combination With Docetaxel in Men With Metastatic Castration-Resistant Prostate Cancer in CheckMate 9KD - Medical Oncologist Perspective

    Barcelona, Spain (UroToday.com) Relative to other solid tumors, prostate cancer is viewed as an immunologically “cold” tumor with less robust responses to immunotherapy than other diseases such as melanoma or lung cancer. Early data from trials of immunotherapy in metastatic castration resistant prostate cancer (mCRPC) do however suggest that a small percentage of patients respond to this approach and may have durable benefit. A recent analysis has suggested that mCRPC patients with deficient DNA mismatch repair or high levels of DNA microsatellite instability may uniquely benefit from immunotherapy.1 Many research efforts are now focused on ways to augment immunotherapy response in mCRPC, including through combination chemotherapy and immunotherapy regimens.

    In an ESMO 2019 poster, Karim Fizazi, MD, PhD, and colleagues report interim analysis of the nivolumab (anti-PD1) plus docetaxel treatment arm from the CheckMate 9KD trial (NCT03338790). This represents Arm B of the trial, which includes chemotherapy naïve mCRPC patients with pre-assessed homologous recombination deficiency (HRD) status. Patients were treated with up to 10 cycles of combination 360 mg nivolumab every three weeks and 75 mg/m2 docetaxel every three weeks, then switched to 480 mg nivolumab every 4 weeks for up to two years up until progression or intolerance. Primary endpoints are overall response rate and prostate specific antigen (PSA) response rate. Secondary endpoints include radiographic progression free survival (PFS) and safety. Exploratory correlative studies included association with response and HRD as well as with tumor mutational burden (TMB).

    The overall response rate for the 19 patients assessed with measurable disease was 37% with one complete response and six partial responses. The PSA response rate was 46.3%. The median radiographic PFS was 8.2 months, with 71.5% of patients free of radiographic progression at six months of follow-up. 93% of patients reported treatment-related adverse effects, with 49% at the grade 3/4 level. The most common grade 3/4 adverse events were neutropenia (29.3%), febrile neutropenia (9.8%), diarrhea (7.3%) and asthenia (7.3%).


    Table4_ESMO2019.png


    The median tumor mutational burden in the overall trial is 3.51 Mut/Mb. Of patients with measurable disease, seven were positive for a mutation associated with HRD (HRD+), 12 were not. Of all patients, 16 were HRD+, 24 were not. While only one HRD+ patient had either a complete or partial response by imaging where as six lacking HRD had such a response, this comparison is very limited due to small sample size. Overall, there was no clear association between overall response rate or PSA response rate and either TMB or HRD status. These data are summarized in Table 4 above and Table 5 below.

    Table5_ESMO2019.png

    While future plans are being developed for larger trials with this combination, given the history of negative docetaxel combination trials in mCRPC, a biomarker-based approach may be more likely to identify patients that respond to therapy.

    Presented by: Karim Fizazi, MD, PhD, Medical Oncologist, Head of the Department of Cancer Medicine at the Institut Gustave Roussy, Veillejuif, France

    Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology Congress (#ESMO19), September 27th-October 1st, 2019, Barcelona, Spain

    References: 

    1. Abida W, Cheng ML, et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. 2019 Apr 1;5(4):471-478. 
    Published September 29, 2019
  • ESMO 2019: GALAHAD - A Phase 2 Study of Niraparib in Patients with mCRPC and Biallelic DNA-Repair Gene Defects, A Pre-Specified Interim Analysis

    Barcelona, Spain (UroToday.com) Patients with metastatic castration-resistant prostate cancer (mCRPC) and disease progression after androgen receptor (AR) targeted therapy and taxane-based chemotherapy have a poor prognosis and few options for treatment. Preliminary evidence suggests that PARP inhibition is effective for patients with mCRPC and DNA repair defects (DRD). Niraparib is a highly selective PARP inhibitor with activity against the PARP-1 and PARP-2 DNA-repair polymerases and is approved as maintenance therapy for recurrent ovarian cancer.
    Published September 29, 2019
  • ESMO 2019: Invited Discussant - PROfound: A Phase 3 Study of Olaparib versus Enzalutamide or Abiraterone for mCRPC with Homologous Recombination Repair Gene Alterations

    Barcelona, Spain (UroToday.com) Following oral presentation of the PROfound study of olaparib in metastatic castration-resistant prostate cancer (mCRPC) patients with selected homologous recombination repair defects in their tumors, Dr. Eleni Efstathiou discussed the findings and posed the question of whether this study should be considered practice-changing.

    Published October 1, 2019
  • ESMO 2019: Preliminary Results from the TRITON2 Study of Rucaparib in Patients with DNA Damage Repair-deficient mCRPC: Updated Analyses

    Barcelona, Spain (UroToday.com) Rucaparib is a PARP inhibitor and has shown antitumor activity in patients with mCRPC and a deleterious DNA damage repair-deficient gene alteration. Initial results from the phase II TRITON2 study evaluating rucaparib in men who have progressed on an androgen receptor directed therapy and chemotherapy demonstrated confirmed radiographic and PSA responses in 44.0% and 51.1% of patients with a deleterious BRCA1/2 alteration, initially presented at ESMO 2018

    Published September 29, 2019
  • ESMO 2019: PROfound: Phase 3 Study of Olaparib versus Enzalutamide or Abiraterone for mCRPC with Homologous Recombination Repair Gene Alterations

    Barcelona, Spain (UroToday.com) Though significant progress has been made in elucidating molecular alterations in metastatic castration-resistant prostate cancer (mCRPC), no biomarker-selected targeted therapeutic options have existed in this disease until today. Dr. Hussain and colleagues presented analysis of the PROfound study, a randomized phase III biomarker driven trial in mCRPC of olaparib in patients harboring alterations in selected DNA damage repair genes that contribute to homologous recombination repair.

    Published October 1, 2019
  • ESMO 2019: PROfound: Phase 3 Study of Olaparib vs. Enzalutamide or Abiraterone for Metastatic Castration-Resistant Prostate Cancer with Homologous Recombination Repair Gene Alterations

    Barcelona, Spain (UroToday.com) Despite significant progress in systematic therapy, metastatic castration-resistant prostate cancer (mCRPC) continues to be a lethal disease. mCRPC is molecularly heterogeneous, as up to 30% of mCRPC harbor deleterious alterations in DNA damage repair genes, including those with direct and indirect roles in homologous recombination repair. These loss-of-function alterations in homologous recombination repair genes are associated with response to PARP inhibition, of which BRCA1, BRCA2, and ATM are the most well characterized.

    Published October 1, 2019
  • Ethnic Variation in Prostate Cancer Detection: A Feasibility Study for Use of the Stockholm3 Test in a Multiethnic U.S. Cohort - Beyond the Abstract

    African American men are known to have nearly twice the incidence of prostate cancer and more than double the risk of prostate cancer mortality compared to Caucasian men.  There are several possible mechanisms for this including risk factors such as lifestyle, diet, genetic risk, inequalities in access to high-quality care, or other socioeconomic factors, however, the contribution of biology in prostate cancer risk is not well understood in this population.
    Written by: Hari T. Vigneswaran, Andrea Discacciati, Peter H. Gann, Henrik Grönberg, Martin Eklund, Michael R. Abern
    References:
    1. Darst, B.F., et al., A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry. Eur Urol, 2020.
    2. Haiman, C.A., et al., Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans. PLoS Genet, 2011. 7(5): p. e1001387.
    3. Gronberg, H., et al., Prostate cancer screening in men aged 50-69 years (STHLM3): a prospective population-based diagnostic study. Lancet Oncol, 2015. 16(16): p. 1667-76.
    4. Vigneswaran, H.T., et al., Ethnic variation in prostate cancer detection: a feasibility study for use of the Stockholm3 test in a multiethnic U.S. cohort. Prostate Cancer Prostatic Dis, 2020.
    Published August 17, 2020
  • European Commission Approves Abiraterone Acetate + Prednisone for Early Stage Prostate Cancer

    Truckee, CA (UroToday.com) Janssen-Cilag International NV (Janssen) announced that the European Commission (EC) has granted approval to broaden the existing marketing authorisation for ZYTIGA® (abiraterone acetate) plus prednisone / prednisolone to include an earlier stage of metastatic prostate cancer than its current indications. Abiraterone acetate plus prednisone / prednisolone can now be used for the treatment of newly-diagnosed high-risk metastatic hormone-sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT).1 
    “Prostate cancer is the most common form of cancer in men throughout Europe and today’s decision helps to fill a critical medical need for these patients. We hope to significantly improve the lives of many men across Europe living with this disease and the approval of this treatment in an earlier stage of prostate cancer helps address this,” said Professor Karim Fizazi, principal investigator of the LATITUDE trial and Head of the Medical Oncology Department at Institute Gustave Roussy, France. 
    The EC’s decision follows a recommendation from the Committee for Medical Products for Human Use (CHMP)2 that was based on data from the multinational, multicentre, randomised, double-blind, placebo-controlled Phase 3 study, LATITUDE. The trial was designed to determine if newly diagnosed patients with metastatic prostate cancer, who are naïve to castration and have high-risk prognostic factors, would benefit from the addition of abiraterone acetate and prednisone to androgen deprivation therapy (ADT) vs ADT alone.3 Data were presented at the 2017 American Society of Clinical Oncology congress in Chicago, USA and published in the New England Journal of Medicine. 
    “This EC approval is a major step forward for men living with prostate cancer across Europe and offers patients with newly diagnosed high-risk metastatic hormone-sensitive prostate cancer a new treatment option. We are encouraged by the data we have seen to date and remain committed to transforming outcomes for prostate cancer patients,” said Dr. Ivo Winiger-Candolfi, Oncology Solid Tumor Therapy Area Lead, Janssen Europe, Middle East and Africa. 
    Abiraterone acetate plus prednisone / prednisolone has already been approved by the European Commission (EC) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in adult men who are asymptomatic or mildly symptomatic after failure of ADT in whom chemotherapy is not yet clinically indicated and in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.4 

    In the LATITUDE study, the safety profile of ADT in combination with abiraterone acetate plus prednisone was consistent with prior studies in patients with mCRPC. Most common adverse events were elevated incidences of mineralocorticoid-related hypertension and hypokalemia in the ADT in combination with abiraterone acetate plus prednisone arm compared with ADT and placebos.3 The observed degrees of hypertension and hypokalemia were both medically manageable. They only rarely required treatment discontinuation and seldom led to serious consequences.3 

    References
    1 EC website. Community register of medicinal products for human use. ZYTIGA product information. 
    2 European Medicines Agency. ZYTIGA CHMP meeting highlights. 
    3 Fizazi, K. et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. New England Journal of Medicine 2017; 377:352-360.
    4 ZYTIGA® summary of product characteristics (February 2017). 

    Related Content

    Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer

    ESMO 2017: Indirect Comparison of Abiraterone Acetate and Docetaxel for Treatment of Metastatic “Hormone-Sensitive” Prostate Cancer


    CHMP Recommends Abiraterone Acetate to Include Earlier Stage Prostate Cancer Patients


    Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy


    LATITUDE abstract from ASCO 2017


    Published November 20, 2017
  • Expanding Treatment Options in Non-metastatic Castrate-resistant Prostate Cancer

    Prostate cancer (PCa) is the second most common form of cancer diagnosed in US men. It represents 19% of newly diagnosed cancers, and the third leading cause of cancer death, accounting for an estimated 39,430 deaths in 2018.1 
    Written by: Hanan Goldberg MD, Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA
    References:
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. Jan 2018;68(1):7-30.
    2. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol. Nov 1994;152(5 Pt 2):1821-1825.
    3. Tombal B, Miller K, Boccon-Gibod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. May 2010;57(5):836-842.
    4. Karantanos T, Evans CP, Tombal B, Thompson TC, Montironi R, Isaacs WB. Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level. Eur Urol. Mar 2015;67(3):470-479.
    5. Saad F, Hotte SJ. Guidelines for the management of castrate-resistant prostate cancer. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. 2010;4(6):380-384.
    6. Alpajaro SIR, Harris JAK, Evans CP. Non-metastatic castration resistant prostate cancer: a review of current and emerging medical therapies. Prostate Cancer Prostatic Dis. Mar 2019;22(1):16-23.
    7. Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. Jun 2015;4(3):365-380.
    8. Sharifi N, Dahut WL, Steinberg SM, et al. A retrospective study of the time to clinical endpoints for advanced prostate cancer. BJU Int. Nov 2005;96(7):985-989.
    9. Macomson B, Lin JH, Tunceli O, et al. Time to metastasis or death in non-metastatic castrate resistant prostate cancer (nmCRPC) patients by National Comprehensive Cancer Network (NCCN) risk groups. Journal of Clinical Oncology. 2017;35(15_suppl):5027-5027.
    10. Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of Prostate Cancer Clinical States and Mortality in the United States: Estimates Using a Dynamic Progression Model. PLoS One. 2015;10(10):e0139440.
    11. Lowrance WT, Murad MH, Oh WK, Jarrard DF, Resnick MJ, Cookson MS. Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2018. J Urol. Dec 2018;200(6):1264-1272.
    12. Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. Apr 20 2016;34(12):1402-1418.
    13. Liede A, Arellano J, Hechmati G, Bennett B, Wong S. International prevalence of nonmetastatic (M0) castration-resistant prostate cancer (CRPC). Journal of Clinical Oncology. 2013;31(15_suppl):e16052-e16052.
    14. Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. New England Journal of Medicine. 2018;378(15):1408-1418.
    15. Virgo KS, Rumble RB, Singer EA. Second-Line Hormonal Therapy for Men With Chemotherapy-Naive Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion Summary. J Oncol Pract. Jul 2017;13(7):459-461.
    16. Crawford ED, Stone NN, Yu EY, et al. Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology. Mar 2014;83(3):664-669.
    17. Sartor AO, Tangen CM, Hussain MH, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. Jun 2008;112(11):2393-2400.
    18. Murray NP, Reyes E, Tapia P, Badínez L, Orellana N. Differential expression of matrix metalloproteinase-2 expression in disseminated tumor cells and micrometastasis in bone marrow of patients with nonmetastatic and metastatic prostate cancer: theoretical considerations and clinical implications-an immunocytochemical study. Bone marrow research. 2012;2012:259351-259351.
    19. Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of Hybrid (6)(8)Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med. May 2015;56(5):668-674.
    20. Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. J Nucl Med. Aug 2015;56(8):1185-1190.
    21. Umbehr MH, Muntener M, Hany T, Sulser T, Bachmann LM. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysis. Eur Urol. Jul 2013;64(1):106-117.
    22. Geynisman DM, Plimack ER, Zibelman M. Second-generation Androgen Receptor-targeted Therapies in Nonmetastatic Castration-resistant Prostate Cancer: Effective Early Intervention or Intervening Too Early? Eur Urol. Dec 2016;70(6):971-973.
    23. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol. Nov 1993;11(11):2167-2172.
    24. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. Nov 10 2005;23(32):8253-8261.
    25. Shah RB, Mehra R, Chinnaiyan AM, et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. Dec 15 2004;64(24):9209-9216.
    26. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet. Apr 29 2000;355(9214):1491-1498.
    27. Schweizer MT, Zhou XC, Wang H, et al. Metastasis-free survival is associated with overall survival in men with PSA-recurrent prostate cancer treated with deferred androgen deprivation therapy. Ann Oncol. Nov 2013;24(11):2881-2886.
    28. Schroder FH, Tombal B, Miller K, et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study. BJU Int. Jul 2010;106(2):182-187.
    29. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. May 8 2009;324(5928):787-790.
    30. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2018;378(26):2465-2474.
    31. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2019;380(13):1235-1246.
    32. El-Amm J, Aragon-Ching JB. The Current Landscape of Treatment in Non-Metastatic Castration-Resistant Prostate Cancer. 2019;13:1179554919833927.
    33. Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. Mar 15 2012;72(6):1494-1503.
    34. Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine. 2012;367(13):1187-1197.
    35. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. Jul 31 2014;371(5):424-433.
    36. Xie W, Regan MM, Buyse M, et al. Metastasis-Free Survival Is a Strong Surrogate of Overall Survival in Localized Prostate Cancer. J Clin Oncol. Sep 20 2017;35(27):3097-3104.
    37. Shore ND. Darolutamide (ODM-201) for the treatment of prostate cancer. Expert Opin Pharmacother. Jun 2017;18(9):945-952.
    38. Smith MR, Saad F, Oudard S, et al. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. Oct 20 2013;31(30):3800-3806.
    39. Nelson JB, Love W, Chin JL, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. Nov 1 2008;113(9):2478-2487.
    40. Miller K, Moul JW, Gleave M, et al. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. Jun 2013;16(2):187-192.
    41. Beinart G, Rini BI, Weinberg V, Small EJ. Antigen-presenting cells 8015 (Provenge) in patients with androgen-dependent, biochemically relapsed prostate cancer. Clin Prostate Cancer. Jun 2005;4(1):55-60.
    42. Madan RA, Gulley JL, Schlom J, et al. Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy. Clin Cancer Res. Jul 15 2008;14(14):4526-4531.
    43. Ogita S, Tejwani S, Heilbrun L, et al. Pilot Phase II Trial of Bevacizumab Monotherapy in Nonmetastatic Castrate-Resistant Prostate Cancer. ISRN oncology. 2012;2012:242850-242850.
    44. Ryan CJ, Crawford ED, Shore ND, et al. The IMAAGEN Study: Effect of Abiraterone Acetate and Prednisone on Prostate Specific Antigen and Radiographic Disease Progression in Patients with Nonmetastatic Castration Resistant Prostate Cancer. J Urol. Aug 2018;200(2):344-352.
    45. Hussain M, Corn PG, Michaelson MD, et al. Phase II study of single-agent orteronel (TAK-700) in patients with nonmetastatic castration-resistant prostate cancer and rising prostate-specific antigen. Clin Cancer Res. Aug 15 2014;20(16):4218-4227.
    46. Fizazi K, Jones R, Oudard S, et al. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol. Mar 1 2015;33(7):723-731.
    Published January 22, 2020
  • First-line Treatment for Metastatic Castrate-resistant Prostate Cancer

    In 2019 Prostate cancer (PCa) accounts for nearly 1 in 5 new diagnoses of cancer in men in the USA.1 In the last several years the overall prostate cancer (PCa) incidence rate declined by approximately 7% per year.1 The sharp drop in incidence has been commonly attributed to decreased prostate-specific antigen (PSA) testing from 2008 to 2013. The decreased use of PSA screening was caused by the United States (US) Preventive Services Task Force recommendations against routine PSA screening. This was a grade D recommendation specifically in men aged 75 years and older, which was declared in 2008, and later on expanded to all men in 2011, due to rising concerns of overdiagnosis and overtreatment.2 Although the prevalence of PSA testing stopped decreasing and stabilized from 2013 to 2015,3 the effect of screening reduction on the incidence of advanced disease is still unclear. An analysis of a large cancer registry covering 89% of the US population reported that the overall decline in PCa incidence is, in fact, masking an increase in distant-stage diagnoses from 2010 across age and race.4

    Regardless of the treatment given, approximately 20%-30% of patients with localized PCa progress to metastatic disease, commonly treated with hormonal therapy.5 This can be given through surgical castration (bilateral orchiectomy) or through medical castration using androgen deprivation therapy (ADT). Both methods achieve a castrate level of serum testosterone which is regarded as the standard of care for treating metastatic hormone-sensitive PCa (mHSPC). However, mHSPC is destined to progress to metastatic castrate-resistant prostate cancer (mCRPC).6 The castrate-resistant prostate cancer (CRPC) state is defined as disease progression despite reaching castrate testosterone levels (serum testosterone < 50 ng/dL or 1.7 nmol/L), and can present as either a continuous rise in serum PSA levels, progression of pre-existing disease, and/or the appearance of new metastases.7 CRPC has a median survival of approximately three years8 and is associated with a significant deterioration of quality of life.9 The exact mechanism of transition from mHSPC to mCRPC is still unclear. However, it is known that despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive PCa progression in CRPC.10 This has led to the development of novel agents aimed at further decreasing androgen production or blocking AR function. However, there are other biologic pathways that function independently of androgen signaling and also result in CRPC.

    Several significant shifts have occurred in the treatment options of the mHSPC space resulting in substantial survival benefit (please see “The rapidly evolving management strategy of metastatic Hormone-Sensitive Prostate Cancer” link), including the introduction of chemotherapy in the CHAARTED study11 and STAMPEDE trial,12 the addition of abiraterone acetate and prednisone in the LATITUDE study13 and STAMPEDE trial,14 the addition of enzalutamide in the ARCHES trial15 and the ENZAMET study,16 and lastly, the addition of apalutamide, an oral nonsteroidal anti-androgen, which like enzalutamide, binds directly to the ligand-binding domain of the AR and prevents AR translocation, DNA binding, and AR-mediated transcription.17 The TITAN trial showed overall survival (OS) benefit in apalutamide-treated mHSPC patients.18 Apalutamide has also shown benefit over placebo in the non-metastatic CRPC (nmCRP) setting in the SPARTAN phase 3 placebo-controlled trial,19 similar to the benefit shown by enzalutamide-treated nonmetastatic castrate-resistant prostate cancer (nmCRPC) patients, in the PROSPER trial20 (please see “The novel treatments for the non-metastatic castrate-resistant prostate cancer” link). These treatment advances in the mHSPC and nmCRPC setting have raised the question of which treatment options should be offered to patients in the mCRPC setting.21

    The treatment of men with CRPC has dramatically changed over the last 15 years. Prior to 2004, when patients failed primary ADT, treatments were administered solely for palliation. The landmark trials by Tannock et al.22 and Petrylak et al.23 in 2004 were the first to introduce docetaxel chemotherapy in mCRPC patients that were shown to improve their survival. However, since docetaxel was FDA approved, five additional beneficial agents showing a survival advantage have been FDA-approved based on randomized clinical trials (Table 1). These include enzalutamide, and abiraterone, which specifically affect the androgen axis, sipuleucel-T, which stimulates the immune system;24 cabazitaxel, which is another chemotherapeutic agent;25 and radium-223, a radionuclide therapy.26 Other treatments for mCRPC have shown to improve outcomes but have yet been approved by the FDA and will be discussed in another review. Due to the substantial increase in multiple FDA-approved therapeutic agents in patients with CRPC, clinicians are challenged with a plethora of treatment options and multitude potential sequences of these agents, making clinical decision-making in mCRPC significantly more complex.

    Table 1. Agents that have been approved for the treatment of metastatic castrate-resistant prostate cancer in the US

    table 1 atents approved for treatment of mCRPC

    mCRPC is usually a debilitating disease, and patients will most likely benefit from a management strategy formalized by a multidisciplinary team consisting of urologists, medical oncologists, radiation oncologists, nurses, psychologists, and social workers.28 It is imperative to discuss palliation treatment options when considering additional systemic treatment, including management of pain, constipation, anorexia, nausea, depression, and fatigue.

    Another crucial point to consider when establishing the appropriate treatment sequence in this disease space is the associated cost. Using models that included additional lines of treatment before or after docetaxel, the mean cost of mCRPC treatment during a mean period of 28.1 months was approximately $48,000 per patient.29 This cost is quite high due to the fact that patients may receive multiple lines of therapy and incur ongoing medical services during the course of their disease.30

    Only two trials have demonstrated a marginal survival benefit for patients remaining on LHRH analogs instead of adding second- and third-line therapies.31,32 Studies have shown that CRPC is not resistant to ADT, but rather hypersensitive to it.10 Treatment-mediated selection pressure during ADT causes the AR to amplify, and ensure the situation does not escalate, ADT is continued to be administered in the mCRPC setting. Treatment-mediated selection pressure also continues throughout the entire lifespan of the tumor, intensifying the need to correctly sequence therapies. However, because prospective data are lacking, the minute potential benefit of continuing castration still outweighs the minimal risk of this treatment. In addition, all subsequently approved treatments have been studied in men with ongoing ADT, adding another reason why it should be continued.

    Before delving into the actual available treatment options, it is important to recognize that it is still unclear when to begin therapy in mCRPC patients who are completely asymptomatic. It is still unknown whether earlier treatment is superior, or if we should wait until the patient becomes symptomatic and develops pain. Before starting treatment, we should consider the patient’s existing comorbidities and expected adverse effects of starting therapy. Patients with early-stage mCRPC in the COU-AA-302 trial who received abiraterone typically survived almost one year longer than those who received placebo (median OS, 53.6 months vs. 41.8 months, respectively, HR, 0.61; 95% CI, 0.43 to 0.87; P = .006).33 Thus, early-stage mCRPC patients benefited from earlier start of abiraterone. In the same trial patients with asymptomatic or mildly symptomatic mCRPC, with baseline PSA < 15.6 ng/mL abiraterone also led to a faster rate and a greater degree of PSA decline than placebo.34 Although the currently available data is limited, it most likely suggests that starting treatment earlier rather than later is more advantageous.33,34

    Approved first-line treatment options for metastatic castrate-resistant prostate cancer

    Abiraterone

    Abiraterone is an antiandrogen which is an inhibitor of 17α-hydroxylase/C17,20-lyase (CYP17) enzyme. The COU-AA-302 phase III study evaluated abiraterone in 1,088 chemo-naïve, asymptomatic or mildly symptomatic mCRPC patients without visceral metastases. In this trial patients were randomized to abiraterone acetate or placebo, both combined with prednisone35 (Figure 1). Patients were stratified by either the Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 and by asymptomatic or mildly symptomatic disease.35 OS and radiographic progression-free survival (rPFS) was the co-primary end-points. The trial demonstrated that after a median follow-up of 22.2 months, there was a significant improvement of rPFS in the abiraterone arm (median 16.5 vs. 8.2 months, HR 0.52, p < 0.001). At the final analysis after a median follow-up of 49.2 months, the OS end-point was significantly positive (34.7 vs. 30.3 months, HR: 0.81, 95% CI: 0.70-0.93, p = 0.0033).36 It is important to remember that mCRPC spans a broad prognostic spectrum even when it is chemotherapy-naïve.37 In an analysis of the abiraterone arm of the COU-AA-302 study, patients who had no pain at baseline, normal alkaline phosphatase and LDH levels, and less than 10 bone metastases had a median OS of 42.6 months.37 However, patients with more risk factors for progression had significantly shorter median OS.37 When assessing the toxicity profile of abiraterone, it seemed to confer more adverse events related to mineralocorticoid excess and liver function abnormalities, but these were mostly graded 1-2 adverse effects. Lastly, abiraterone was also shown to be equally effective in the elderly population (> 75 years).38

    figure 1 COU AA 302 study

    Figure 1
    . COU-AA-302 study design

    Enzalutamide

    Enzalutamide is a nonsteroidal antiandrogen. The PREVAIL study which is a randomized phase III trial included 1,717 chemo-naïve mCRPC patients and patients with visceral metastases were eligible as well.39 This trial compared enzalutamide to placebo (Figure 2). The PREVAIL trial showed a significant improvement in enzalutamide-treated patients in both co-primary endpoints, which included rPFS (HR: 0.186; CI: 0.15-0.23, p < 0.0001), and OS (HR: 0.706; CI: 0.6-0.84, p < 0.001). Extended follow-up and final analysis confirmed a benefit in OS and rPFS for enzalutamide.40 In 78% of patients treated with enzalutamide a PSA decrease of more than 50% was reported. The most common clinically relevant adverse events were fatigue and hypertension. Enzalutamide was also equally effective and well-tolerated in older men (> 75 years)41 and in those with or without visceral metastases.42 However, for men with liver metastases, there seemed to be no discernible benefit.43 The TERRAIN trial compared enzalutamide with bicalutamide, an older antiandrogen, in a randomized double-blind phase II study, showing a significant improvement in PFS (15.7 months vs. 5.8 months, HR: 0.44, p < 0.0001) in favor of enzalutamide.44

    figure 2 PREVAIL study

    Figure 2
    . PREVAIL study design

    Docetaxel

    The landmark trial TAX 327 showed a significant improvement in median OS of 2-2.9 months in mCRPC patients treated with docetaxel-based chemotherapy when compared to patients who were treated with mitoxantrone plus prednisone therapy.22 The SWOG 9916 trial compared mitoxantrone to docetaxel and showed similar results23 (Figure 3). The standard first-line chemotherapy is docetaxel 75 mg/m2 in three-weekly doses combined with prednisone 5 mg twice a day, up to ten cycles. There are several important prognostic factors to consider when administering docetaxel: visceral metastases, pain, anemia (Hb < 13 g/dL), bone scan progression, and prior estramustine therapy. These prognostic factors may help to stratify response to docetaxel. Using these prognostic factors the disease can be categorized into low, intermediate and high risk, with significantly different corresponding median OS estimates of 25.7, 18.7 and 12.8 months, respectively.45 Although age by itself is not a contraindication to docetaxel therapy, patients must be fit enough to endure this type of treatment and comorbidities should be assessed prior to treatment initiation. In men who are thought to be unable to tolerate the standard dose and schedule of docetaxel, this can be decreased from 75 to 50 mg/m2 every two weeks, showing less grade 3-4 adverse events and a longer time to treatment failure.46

    figure 3 SWOG 9916 and TAX trials

    Figure 3
    . SWOG 9916 and TAX 327 trial designs

    Sipuleucel-T

    Sipuleucel-T, an autologous active cellular immunotherapy, was shown in a phase III trial (IMPACT trial) to confer a survival benefit in 512 asymptomatic or minimally symptomatic mCRPC patients when compared to placebo24 (Figure 4). After a median follow-up of 34 months, the median survival was significantly higher in the sipuleucel-T group (25.8 vs. 21.7 months, with an HR of 0.78,p = 0.03).24 Importantly, no PSA decline was observed during or after treatment and PFS was similar in both arms. The overall tolerance to sipuleucel-T was very good, with mostly grade 1-2 adverse events occurring. Currently, this treatment is only available in the US and is no longer available in Europe.

    figure 4 IMPACT trial

    Figure 4. IMPACT trial design

    Conclusions

    In the last 15 years, there has been considerable scientific progress and investment in drug development for patients with mCRPC. This has resulted in the FDA approval of several lines of systemic therapies on grounds of pain palliation, minimizing disease adverse effects, and OS prolongation. To date, the reported impact on OS in mCRPC patients from each of these individual agents is still modest, resulting in an addition of only a few months. It is necessary to enhance our understanding of the disease biology of mCRPC, integrate a comprehensive molecular understanding of castration resistance, and analyze mechanisms of resistance to current therapies to improve future treatment development. It is also crucial to invest and develop predictive biomarkers to assist in the personalization of therapy. Lastly, on a more practical note, more data is needed on the appropriate second and third-line therapies, and sequencing and combination of available medications, discussed in more detail in the next review article (“Beyond first line treatment of metastatic castrate-resistant prostate cancer”).

    Published Date: November 19th, 2019
    Written by: Hanan Goldberg, MD
    References:
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: A Cancer Journal for Clinicians. 2019;69(1):7-34.
    2. Moyer VA. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. Jul 17 2012;157(2):120-134.
    3. Fedewa SA, Ward EM, Brawley O, Jemal A. Recent Patterns of Prostate-Specific Antigen Testing for Prostate Cancer Screening in the United States. JAMA Intern Med. Jul 1 2017;177(7):1040-1042.
    4. Negoita S, Feuer EJ, Mariotto A, Cronin KA, Petkov VI, Hussey SK. Annual Report to the Nation on the Status of Cancer, part II: Recent changes in prostate cancer trends and disease characteristics. Jul 1 2018;124(13):2801-2814.
    5. Amling CL, Blute ML, Bergstralh EJ, Seay TM, Slezak J, Zincke H. Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years. J Urol. Jul 2000;164(1):101-105.
    6. Hotte SJ, Saad F. Current management of castrate-resistant prostate cancer. Curr Oncol. Sep 2010;17 Suppl 2:S72-79.
    7. Saad F, Hotte SJ. Guidelines for the management of castrate-resistant prostate cancer. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. 2010;4(6):380-384.
    8. Tangen CM, Hussain MH, Higano CS, et al. Improved overall survival trends of men with newly diagnosed M1 prostate cancer: a SWOG phase III trial experience (S8494, S8894 and S9346). J Urol. Oct 2012;188(4):1164-1169.
    9. Damodaran S, Lang JM, Jarrard DF. Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches. J Urol. May 2019;201(5):876-885.
    10. Mohler JL, Titus MA, Bai S, et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. Feb 15 2011;71(4):1486-1496.
    11. Sweeney CJ, Chen Y-H, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. New England Journal of Medicine. 2015;373(8):737-746.
    12. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. Mar 19 2016;387(10024):1163-1177.
    13. Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. May 2019;20(5):686-700.
    14. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. Jul 27 2017;377(4):338-351.
    15. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. Jul 22 2019:Jco1900799.
    16. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. New England Journal of Medicine. 2019;381(2):121-131.
    17. Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. Mar 15 2012;72(6):1494-1503.
    18. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. Jul 4 2019;381(1):13-24.
    19. Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. New England Journal of Medicine. 2018;378(15):1408-1418.
    20. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2018;378(26):2465-2474.
    21. Gartrell BA, Saad F. Managing bone metastases and reducing skeletal related events in prostate cancer. Nat Rev Clin Oncol. Jun 2014;11(6):335-345.
    22. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. New England Journal of Medicine. 2004;351(15):1502-1512.
    23. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. Oct 7 2004;351(15):1513-1520.
    24. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. Jul 29 2010;363(5):411-422.
    25. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. Oct 2 2010;376(9747):1147-1154.
    26. Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. New England Journal of Medicine. 2013;369(3):213-223.
    27. Crawford ED, Petrylak DP, Shore N, et al. The Role of Therapeutic Layering in Optimizing Treatment for Patients With Castration-resistant Prostate Cancer (Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II). Urology. Jun 2017;104:150-159.
    28. Esper PS, Pienta KJ. Supportive care in the patient with hormone refractory prostate cancer. Semin Urol Oncol. Feb 1997;15(1):56-64.
    29. Dragomir A, Dinea D, Vanhuyse M, Cury FL, Aprikian AG. Drug costs in the management of metastatic castration-resistant prostate cancer in Canada. BMC Health Serv Res. Jun 13 2014;14:252.
    30. Wen L, Valderrama A, Costantino ME, Simmons S. Real-World Treatment Patterns in Patients with Castrate-Resistant Prostate Cancer and Bone Metastases. Am Health Drug Benefits. May 2019;12(3):142-149.
    31. Hussain M, Wolf M, Marshall E, Crawford ED, Eisenberger M. Effects of continued androgen-deprivation therapy and other prognostic factors on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: a Southwest Oncology Group report. J Clin Oncol. Sep 1994;12(9):1868-1875.
    32. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol. Nov 1993;11(11):2167-2172.
    33. Miller K, Carles J, Gschwend JE, Van Poppel H, Diels J, Brookman-May SD. The Phase 3 COU-AA-302 Study of Abiraterone Acetate Plus Prednisone in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Stratified Analysis Based on Pain, Prostate-specific Antigen, and Gleason Score. Eur Urol. Jul 2018;74(1):17-23.
    34. Ryan CJ, Londhe A, Molina A, et al. Relationship of baseline PSA and degree of PSA decline to radiographic progression-free survival (rPFS) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302. Journal of Clinical Oncology. 2013;31(15_suppl):5010-5010.
    35. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. Jan 10 2013;368(2):138-148.
    36. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. Feb 2015;16(2):152-160.
    37. Ryan CJ, Kheoh T, Li J, et al. Prognostic Index Model for Progression-Free Survival in Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer Treated With Abiraterone Acetate Plus Prednisone. Clin Genitourin Cancer. Jul 25 2017.
    38. Roviello G, Cappelletti MR, Zanotti L, et al. Targeting the androgenic pathway in elderly patients with castration-resistant prostate cancer: A meta-analysis of randomized trials. Medicine (Baltimore). Oct 2016;95(43):e4636.
    39. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. Jul 31 2014;371(5):424-433.
    40. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol. Feb 2017;71(2):151-154.
    41. Graff JN, Baciarello G, Armstrong AJ, et al. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL. Ann Oncol. Feb 2016;27(2):286-294.
    42. Evans CP, Higano CS, Keane T, et al. The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer. Eur Urol. Oct 2016;70(4):675-683.
    43. Alumkal JJ, Chowdhury S, Loriot Y, et al. Effect of Visceral Disease Site on Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide in the PREVAIL Trial. Clin Genitourin Cancer. Oct 2017;15(5):610-617.e613.
    44. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. Feb 2016;17(2):153-163.
    45. Armstrong AJ, Garrett-Mayer E, de Wit R, Tannock I, Eisenberger M. Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer. Clin Cancer Res. Jan 1 2010;16(1):203-211.
    46. Kellokumpu-Lehtinen PL, Harmenberg U, Joensuu T, et al. 2-Weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol. Feb 2013;14(2):117-124.
    Published November 19, 2019
  • Genetic Evaluation of Hereditary Prostate Cancer

    Published in Everyday Urology - Oncology Insights: Volume 4, Issue 2
    Published Date: June 2019

    During much of the past 30 years, genetic tests for heritable disorders have assessed limited numbers of genes and have often employed serial testing algorithms in which the next test was determined by the results of the prior test.¹ The advent of next-generation (also known as massively parallel high-throughput) sequencing has transformed this picture by making it possible to sequence the entire human genome for less than $1,000.1,2
    Published November 11, 2019
  • Germline Testing for DNA Repair Mutations in Prostate Cancer: Who, When and How?

    Germline testing indications for prostate cancer (PCa) have rapidly expanded and have been catapulted by precision medicine and precision management.1,2 In particular, testing for mutations in DNA repair genes such as in BRCA2, BRCA1, ATM, and other DNA repair genes, has taken front-stage due to the clinical activity of poly (ADP-ribose) polymerase (PARP) inhibitors in metastatic, castration-resistant prostate cancer (mCRPC).3-7 Phase II trial data supported the U.S. Federal Drug Administration (FDA) designations for olaparib, rucaparib, and niraparib due to demonstrated response rates particularly among men with BRCA2mutations along with other DNA repair genes.5-7 Excitingly, the FDA has recently approved two PARP inhibitors for mCRPC. Rucaparib was granted accelerated approval for BRCA1/2-mutated mCRPC with prior treatment with androgen receptor-directed therapy and taxane-based chemotherapy based on TRITON2.5 Olaparib was FDA-approved for the treatment of mCRPC in men with deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutations who have progressed following prior treatment with enzalutamide or abiraterone based on PROfound.4 These approvals provide exciting therapeutic options for men with mCRPC and will increase the role of germline testing for DNA repair mutations. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines recommend germline testing for DNA repair mutations in all men with mCRPC, with additional testing criteria proposed.8,9 The international Philadelphia Prostate Cancer Consensus Conference 2019 has provided significant multidisciplinary guidance regarding germline testing for DNA repair mutations across the stage spectrum, along with strategies for implementation of genetic counseling and germline testing.1 Therefore, understanding the role of germline testing in PCa is now critical to urologic and oncology practice for this disease. Here, we will address who should be considered for germline testing, when germline testing may influence treatment and management, and how to implement germline testing involving provider practices and genetic counseling.

    Written by: Veda N. Giri, MD
    References: 1. Giri, Veda N., Karen E. Knudsen, William K. Kelly, Heather H. Cheng, Kathleen A. Cooney, Michael S. Cookson, William Dahut et al. "Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019." Journal of Clinical Oncology (2020): JCO-20.
    2. Cheng, Heather H., Alexandra O. Sokolova, Edward M. Schaeffer, Eric J. Small, and Celestia S. Higano. "Germline and somatic mutations in prostate cancer for the clinician." Journal of the National Comprehensive Cancer Network 17, no. 5 (2019): 515-521.
    3. Mateo, Joaquin, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez, Daniel Nava Rodrigues et al. "DNA-repair defects and olaparib in metastatic prostate cancer." New England Journal of Medicine 373, no. 18 (2015): 1697-1708.
    4. de Bono, Johann, Joaquin Mateo, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi et al. "Olaparib for metastatic castration-resistant prostate cancer." New England Journal of Medicine 382, no. 22 (2020): 2091-2102.
    5. Abida, Wassim, David Campbell, Akash Patnaik, Jeremy D. Shapiro, Brieuc Sautois, Nicholas J. Vogelzang, Eric G. Voog et al. "Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: Analysis From the Phase II TRITON2 Study." Clinical Cancer Research 26, no. 11 (2020): 2487-2496.
    6. Mateo, Joaquin, Nuria Porta, Diletta Bianchini, Ursula McGovern, Tony Elliott, Robert Jones, Isabel Syndikus et al. "Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial." The Lancet Oncology 21, no. 1 (2020): 162-174.
    7. Smith, M. R., S. K. Sandhu, W. K. Kelly, H. I. Scher, E. Efstathiou, P. N. Lara, E. Y. Yu et al. "LBA50 Pre-specified interim analysis of GALAHAD: A phase II study of niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD)." Annals of Oncology 30, no. Supplement_5 (2019): mdz394-043.
    8. National Comprehensive Cancer Network Clinical Guidelines in Oncology (NCCN Guidelines®): Prostate Cancer (Version 4.2019). Accessed June 6, 2020. Available at NCCN.org.
    9. National Comprehensive Cancer Network Clinical Guidelines in Oncology (NCCN Guidelines®): Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 1.2020). Accessed June 6, 2020. Available at NCCN.org.
    10. Carter, H. Ballentine, Brian Helfand, Mufaddal Mamawala, Yishuo Wu, Patricia Landis, Hongjie Yu, Kathleen Wiley et al. "Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in men on active surveillance for prostate cancer." European urology 75, no. 5 (2019): 743-749.
    11. National Comprehensive Cancer Network Clinical Guidelines in Oncology (NCCN Guidelines®): Prostate Cancer Early Detection (Version 2.2019). Accessed June 6, 2020. Available at NCCN.org.
    12. National Cancer Institute Genetics of Prostate Cancer (PDQ®)–Health Professional Version. Accessed June 9, 2020. Available at: https://www.cancer.gov
    Published June 29, 2020
  • Local Cancer Survivor and Entrepreneur Donates $500,000 to Fund UMN Cancer Research Initiative

    San Francisco, CA USA (UroToday.com) --  Cancer mortality is higher among men than it is among women. It’s estimated that more than 174,000 new cases of prostate cancer, which is the most common cancer in American men, will be diagnosed in 2019 according to the American Cancer Society. Survival rates are improving as new cancer treatments are developed and become more effective.
    Published January 24, 2019
  • Low Incidence of Corticosteroid-associated Adverse Events on Long-term Exposure to Low-dose Prednisone Given with Abiraterone Acetate to Patients with Metastatic Castration-resistant Prostate Cancer.

    Abiraterone acetate (AA) is the prodrug of abiraterone, which inhibits CYP17A1 and testosterone synthesis and prolongs the survival of patients with metastatic castration-resistant prostate cancer (mCRPC).

    Published March 13, 2016
  • MDACC 2018: Local Therapy in Metastatic Prostate Cancer

    Houston, Texas (UroToday.com) The rationale for definitive treatment of the primary tumor in metastatic prostate cancer includes retrospective data suggesting improvement in overall survival, reduction of local symptomatic progression, the systemic biology may be altered, there may be molecularly lethal prostate cancer that persists in the primary and finally, a randomized trial is feasible and local treatment is safe.
    Published November 11, 2018
  • Optimizing Bone Health in Prostate Cancer

    Published in Everyday Urology - Oncology Insights: Volume 4, Issue 2
    Published Date: June 2019

    Protecting and improving bone health is critical when managing all stages of prostate cancer. Androgen deprivation therapy (ADT) accelerates bone resorption, which compromises bone mass and integrity starting early in treatment.1 Metastatic prostate cancer is associated with a marked increase in risk of skeletal events (fracture, spinal cord compression, and bone surgery or radiotherapy) associated with both bone metastases and treatment-induced bone loss.
    Published August 26, 2019
  • PARP Inhibitors - A Breakthrough in Targeted Therapies for Prostate Cancer

    PARP inhibition has become a key therapeutic option for a genomically-defined subset of patients with metastatic prostate cancer. Further clinical trial work may expand both the number and setting of PARP inhibitor therapies. In this review, we will summarize the current indications for PARP inhibitor monotherapies and combination(s), review data from clinical trials in prostate cancer, discuss management of commonly encountered side effects, and highlight exciting clinical research on expanding the role of PARP inhibitors in prostate cancer.
    Written by: Arpit Rao, MBBS and Charles Ryan, MD
    References: 1. Clark, J. B., G. M. Ferris, and S. Pinder. "Inhibition of nuclear NAD nucleosidase and poly ADP-ribose polymerase activity from rat liver by nicotinamide and 5′-methyl nicotinamide." Biochimica et Biophysica Acta (BBA)-Nucleic Acids and Protein Synthesis 238, no. 1 (1971): 82-85.
    2. Tentori, Lucio, Ilaria Portarena, and Grazia Graziani. "Potential clinical applications of poly (ADP-ribose) polymerase (PARP) inhibitors." Pharmacological research 45, no. 2 (2002): 73-85.
    3. Farmer, H., N. McCabe, C. J. Lord, and A. N. Tutt. "Johnso n DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC and Ashworth A. Targeting the DN A repair defect in BRCA mutant cells as a therapeutic strategy." Nature 434 (2005): 917-921.
    4. Bryant, Helen E., Niklas Schultz, Huw D. Thomas, Kayan M. Parker, Dan Flower, Elena Lopez, Suzanne Kyle, Mark Meuth, Nicola J. Curtin, and Thomas Helleday. "Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase." Nature 434, no. 7035 (2005): 913-917.
    5. “Drugs@FDA: FDA-Approved Drugs.” Accessed June 14, 2020. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=reportsSearch.process.
    6. U.S. Food and Drug Administration - Full prescribing information for Lynparza (olaparib). U.S. Food and Drug Administration - Full prescribing information for Lynparza (olaparib). Accessed June 14, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s013lbl.pdf
    7. U.S. Food and Drug Administration - Full prescribing information for Rubraca (rucaparib). U.S. Food and Drug Administration - Full prescribing information for Rubraca (rucaparib). Accessed June 14, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s004lbl.pdf
    8. U.S. Food and Drug Administration - Full prescribing information for Zejula (niraparib). U.S. Food and Drug Administration - Full prescribing information for Zejula (niraparib). Accessed June 14, 2020.https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf
    9. U.S. Food and Drug Administration - Full prescribing information for Talzenna (talazoparib). U.S. Food and Drug Administration - Full prescribing information for Talzenna (talazoparib). Accessed June 14, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211651s005lbl.pdf
    10. Mateo, Joaquin, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez, Daniel Nava Rodrigues et al. "DNA-repair defects and olaparib in metastatic prostate cancer." New England Journal of Medicine 373, no. 18 (2015): 1697-1708.
    11. Mateo, Joaquin, Nuria Porta, Diletta Bianchini, Ursula McGovern, Tony Elliott, Robert Jones, Isabel Syndikus et al. "Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial." The Lancet Oncology 21, no. 1 (2020): 162-174.
    12. de Bono, Johann, Joaquin Mateo, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi et al. "Olaparib for metastatic castration-resistant prostate cancer." New England Journal of Medicine 382, no. 22 (2020): 2091-2102.
    13. Abida, W., D. Campbell, A. Patnaik, B. Sautois, J. Shapiro, N. J. Vogelzang, A. H. Bryce et al. "Preliminary results from the TRITON2 study of rucaparib in patients (pts) with DNA damage repair (DDR)-deficient metastatic castration-resistant prostate cancer (mCRPC): Updated analyses." Annals of Oncology 30 (2019): v327-v328.
    14. Smith, Matthew Raymond, Shahneen Kaur Sandhu, William Kevin Kelly, Howard I. Scher, Eleni Efstathiou, Primo Lara, Evan Y. Yu et al. "Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): preliminary results of GALAHAD." (2019): 202-202.
    15. De Bono, Johann S., Niven Mehra, Celestia S. Higano, Fred Saad, Consuelo Buttigliero, Marielena Mata, Hsiang-Chun Chen et al. "TALAPRO-1: A phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration-resistant prostate cancer (mCRPC)—First interim analysis (IA)." (2020): 119-119.
    16. LaFargue, Christopher J., Graziela Z. Dal Molin, Anil K. Sood, and Robert L. Coleman. "Exploring and comparing adverse events between PARP inhibitors." The Lancet Oncology 20, no. 1 (2019): e15-e28.
    17. Sandhu, Shahneen K., William R. Schelman, George Wilding, Victor Moreno, Richard D. Baird, Susana Miranda, Lucy Hylands et al. "The poly (ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial." The lancet oncology 14, no. 9 (2013): 882-892.
    18. Francica, Paola, and Sven Rottenberg. "Mechanisms of PARP inhibitor resistance in cancer and insights into the DNA damage response." Genome medicine 10, no. 1 (2018): 1-3.
    19. Brenner, J. Chad, Bushra Ateeq, Yong Li, Anastasia K. Yocum, Qi Cao, Irfan A. Asangani, Sonam Patel et al. "Mechanistic rationale for inhibition of poly (ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer." Cancer cell 19, no. 5 (2011): 664-678.
    20. Asim, Mohammad, Firas Tarish, Heather I. Zecchini, Kumar Sanjiv, Eleni Gelali, Charles E. Massie, Ajoeb Baridi et al. "Synthetic lethality between androgen receptor signaling and the PARP pathway in prostate cancer." Nature communications 8, no. 1 (2017): 1-10.
    21. Clarke, Noel, Pawel Wiechno, Boris Alekseev, Nuria Sala, Robert Jones, Ivo Kocak, Vincenzo Emanuele Chiuri et al. "Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial." The Lancet Oncology 19, no. 7 (2018): 975-986.
    Published June 29, 2020
  • PARP Inhibitors in Prostate Cancer: PROfound and Beyond

    Background

    Prostate cancer is a clinically heterogeneous disease with many patients having an indolent course requiring no interventions and others who either present with or progress to metastasis. While underlying dominant driving mutations are not widespread, there have been a number of key genomic mutations that have been consistently identified in prostate cancer patients, across the disease spectrum including gene fusion/chromosomal rearrangements (TMPRSS2-ERG), androgen receptor (AR) amplification, inactivation of tumor suppressor genes (PTEN/PI3-K/AKT/mTOR, TP53, Rb1) and oncogene activation (c-MYC, RAS-RAF).1 More significantly, defects in DNA repair appear to be central in increasing one’s susceptibility to malignant transformation. Because cellular DNA is continually subject to damage, there are coordinated pathways designated for repairing DNA, maintaining genomic integrity, and ensuring cell survival. This process of DNA repair requires excision of the damaged DNA followed by repair via mechanisms including include homologous recombination repair (HRR), base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR). Repair itself may occur via two mechanisms, single (SSBR) or double stranded break repair (DSBR). While the details of these repair pathways are beyond the scope of this manuscript, it is valuable to understand that poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzyme and BRCA 1/2 (BReast CAncer gene 1 and 2) and ATM (Ataxia-Telangiesctasia Mutated) gene products play important roles in this process.2

    Examining patients with advanced prostate cancer, Pritchard and colleagues were among the first to demonstrate the value of assessing inherited genetic changes. Among 692 patients with metastatic prostate cancer, they identified mutations in 20 DNA-repair genes in 82 men (11.8%),3 with significant geographic heterogeneity, even among these recognized cancer centers with a prevalence of 8.8% in patients treated at the University of Washington and 18.5% in patients treated at Memorial Sloan Kettering, potentially reflecting referral biases. In a similar study of patients with metastatic castrate resistance prostate cancer, Castro et al. found a prevalence of germline DNA damage repair gene mutations of 16.2%.4 In an analysis which spanned the disease spectrum, Nicolosi and colleagues found germline variants in 620 of 3607 patients (17.2%), of which BRCA1/2 comprised only a small proportion.5

    In patients with metastatic castrate-resistant prostate cancer in the PROREPAIR-B cohort, Castro et al. found that germline BRCA2 mutations specifically were associated with significantly worse prostate cancer specific mortality (17 months compared with 33 months, hazard ratio 2.11, p-value = 0.033), though an aggregate assessment of ATM, BRCA1, BRCA2, or PALB2 was not associated with prostate cancer-specific survival (different in survival 10 months, p=0.264).4 However, while these mutations are associated with poor prognosis, they also offer potential therapeutic options.

    Over the past decade, treatment of men with advanced prostate cancer has been revolutionized with numerous new treatment options for men with castration-sensitive metastatic prostate cancer, non-metastatic castrate-resistant prostate cancer, and metastatic castrate-resistant prostate cancer. Leading this process has been changes in therapeutic options for men with metastatic castrate-resistant prostate cancer. Coupled with these new therapeutic options is an increasing understanding of the heterogeneity in response between patients, with the potential to tailor therapy for patients most likely to benefit. Perhaps the strongest example of such tailed therapy in patients with metastatic castrate-resistant prostate cancer is the use of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors.

    Pathophysiology

    The PARPs are a family of enzymes (most abundantly PARP1) that excise bases, playing a key role in repair of DNA single strand breaks.6 PARP inhibition leads to an accumulation of DNA single strand breaks, leading to DNA double-strand breaks at replication forks that are normally repaired by the homologous recombination double stranded DNA repair pathway.7 Key components of this specific pathway are the tumor-suppressor proteins BRCA1 and BRCA 2.8 When cells carrying heterozygous loss-of-function BRCA mutations lose the remaining wild-type allele, there is deficient homologous-recombination DNA repair leading to carcinogenesis. These tumors carrying specific DNA-repair defects can be exploited using PARP inhibitors to induce selective tumor cytotoxicity and spare normal cells. PAPR inhibition in these homologous-recombination repair deficient cells leads to unrepaired DNA single-strand breaks, causing accumulation of DNA double-strand breaks.9,10 This has lead researchers to suggest the term “synthetic lethality” when there is a lethal synergy between two otherwise nonlethal events: a PARP inhibitor inducing a DNA lesion and a genetic loss of function for the homologous recombination DNA repair pathway required to fix it.10 In vitro studies have shown that BRCA1/2 deficient cells were 1000-fold more sensitive to PARP inhibition than wild-type cells.9

    Early data for Olaparib

    The first phase I trial utilizing the PARP inhibitor olaparib was performed more than a decade ago among a population of cancer patients enriched with carriers of a BRCA1 or BRCA2 mutation.11 Among 60 patients, 22 were BRCA1 or BRCA2 mutation carriers and one patient had a strong family history of BRCA-associated cancers. The olaparib dose and schedule were increased from 10 mg daily for two of every three weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily and two of five patients receiving 600 mg twice daily. Subsequently, another cohort was enrolled consisting only of carriers of a BRCA1 or BRCA2 mutation to receive olaparib at a dose of 200 mg twice daily. This phase I trial found objective antitumor activity was reported only in mutation carriers, all of whom had ovarian, breast, or prostate cancer and had received multiple treatment regimens. Subsequently, the TOPARP-A Trial demonstrated that treatment with the PARP inhibitor olaparib was associated with improvements in radiographic progression-free survival and overall survival, specifically among patients with extensively pre-treated mCRPC who had DNA-repair defects:12 16 of 49 patients (33%) had a response to olaparib, with 12 patients remaining on treatment for >6 months. TOPARP-B, was a phase II trial for patients with mCRPC preselected for putatively pathogenic DNA damage repair alterations.13  Because TOPARP-A used a 400 mg olaparib dose and patients with breast cancer typically use a 300 mg dose, patients in TOPARP-B were randomized 1:1 to 400mg or 300mg of olaparib BID, aiming to exclude ≤30% response rate using radiographic (RECIST 1.1), PSA (50% decrease) or CTC conversion criteria. A response was seen in 54% (95%CI 39-69%) of patients in the 400 mg cohort and 39% (95%CI 24-54%) in the 300 mg cohort. Over a median follow-up of 17.6 months, the overall median PFS (mPFS) was 5.4 months. Notably, response rates and mPFS were higher in patients with BRCA1/2 of 83% (mPFS 8.1 months) and PALB2 57% (mPFS 5.3 months).

    PROfound: phase III data for Olaparib in mCRPC

    On the basis of the above data, the PROfound study recruited men with metastatic castrate-resistant prostate cancer who had progressed on previous abiraterone acetate or enzalutamide administered at the time of non-metastatic castrate-resistant prostate cancer or at the time of metastatic castrate-sensitive prostate cancer14. Patients with prior taxane exposure were allowed. The investigators then used an investigational assay based on the FoundationOne CDx to identify alterations in one of 15 pre-specified genes involved in homologous recombination repair (BRCA 1/2, ATM, BRIP1, BARD1, CDK12, CHEK 1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L).

    The authors then used biomarker driven stratification to derive two study cohorts: Cohort A had alterations in BRCA1, BRCA2, or ATM while Cohort B had alterations in any of the other 15 included genes. In both cohorts, patients were randomized 2:1 to olaparib vs. abiraterone or enzalutamide. Within each biomarker strata, randomization was stratified based on prior taxane use and measurable disease burden (according to RESIST 1.1 criteria).

    Primary analysis was based on imaging-based progression free survival (soft-tissue according toe RESIST 1.1 and bony according to PCCTWG3 criteria) among patients in Cohort A. Secondary outcomes including PFS in the combined Cohort A+B, objective response rates, time to pain progression, overall survival, reduction in PSA >50%, CTC conversion rate, and safety/toxicity outcomes.

    The authors utilized a hierarchical analysis strategy with sequential analysis of each endpoint on the basis of preceding outcomes.

    Among 4425 patients who were screened, 4047 had sufficient tissue available for genetic testing of which 2972 had appropriate biomarker testing. 778 patients were identified as having at least one mutation in one of the 15 eligible genes. 387 of these patients met the remainder of eligibility criteria and were randomized.

    In assessment of the primary outcome, the authors found significantly improved progression-free survival in patients with mutations of BRCA1, BRCA2, or ATM (hazard ratio 0.34, 95% confidence interval 0.25 to 0.47). Similar results were seen in the combined cohort (hazard ratio 0.49, 95% confidence interval 0.38 to 0.63). Subgroup analysis showed similar results when stratified according to prior taxane use, measurable disease at baseline, location of metastasis (bone only, visceral, or other), performance status, age at randomization, region, and baseline PSA (dichotomized around the median).

    While data is immature (data maturity 38%), there is suggestion of improved overall survival in Cohort A (hazard ratio 0.64, 95% confidence interval 0.43 to 0.97, p=0.02 with an alpha significance threshold of 0.01 based on alpha-spending function).

    Adverse events were common in both patients on olaparib (any = 95%, grade ≥ 3 = 51%) and in the control group (any = 88%, grade ≥ 3 = 38%).

    While these results support the phase I/II data demonstrating the activity of olaparib in patients with mCRPC, particularly among patients with qualifying gene mutations, some have questioned these results, particularly as patients to be eligible must have progressed on abiraterone or enzalutamide (with approximately 20% having received both prior to randomization) and those who were randomized to the control arm received abiraterone or enzalutamide. Given the results of the CARD trial, patients progression following docetaxel and one androgen-axis inhibitor (abiraterone or enzalutamide) are likely to derive significantly greater benefit from cabazitaxel than a switch to a different androgen-axis inhibitor15.

    On May 19, 2020, as a result of the data from the PROfound trial, the U.S. Food and Drug Administration approved olaparib for the treatment of patients with germline or somatic homologous recombination repair gene-mutated metastatic castrate resistant prostate cancer (mCRPC) who progressed following treatment with enzalutamide or abiraterone acetate.

    Combination therapy with Olaparib:

    Based on the initial success with PARP inhibitor monotherapy, there has been recent interest in combination therapy trials. The androgen receptor promotes DNA damage repair, whereas ADT upregulates PARP-mediated repair pathways with synthetic lethality between ADT and PARP inhibition. Furthermore, PARP1 also regulates AR-mediated transcriptional activation. As a result, there is a biologic rationale for combinations of androgen-axis targeting agents and PARP inhibitors. In 2018, results of phase 2 trial assessing olaparib with abiraterone were published in Lancet Oncology.16 There were 142 patients randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The median rPFS was 13.8 months (95% CI 10.8-20.4) with olaparib and abiraterone and 8.2 months (5.5-9.7) with placebo and abiraterone (HR 0.65, 95% CI 0.44-0.97, p = 0.034). One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group. Based on the results of this phase 2 study, the ongoing PROpel phase 3 trial will evaluate olaparib + abiraterone in the first line mCRPC setting. Goal enrolment for PROpel is 720 patients, with an estimated trial completion of 2022.

    Other PARP inhibitors in mCRPC:

    In addition to olaparib, there are a number of other PARP inhibitors being assessed in patients with advanced prostate cancer. The TRITON2 trial assessed rucaparib 600 mg BID in patients with mCRPC associated homologous recombination repair gene alterations, initially presented at ESMO 2018.17 For the patients with BRCA1/2 alteration, there was a 44% confirmed overall response rate and 51% confirmed PSA response rate while patients harboring an ATM and CDK12 alteration did not receive significant benefit. On the basis of the data from TRITON2, on May 15, 2020, the US Food and Drug Administration (FDA) approved rucaparib for patients with mCRPC and BRCA mutations (germline or somatic) who had progressed following treatment with androgen-axis targeted treatment and taxane-based chemotherapy. The TRITON3 trial, discussed below, is set to serve as the confirmatory trial for this indication.

    The GALAHAD trial was a phase II study of niraparib in patients with mCRPC and biallelic DNA-repair gene defects, initially presented at ASCO 2019.18 For this study, a patient’s plasma sample was evaluated to identify DNA repair defects, including mutations in BRCA1/2, ATM, FANCA, PALB2, CHEK2, BRIP1 or HDAC2. The composite response rate was 18/29 (62%) in the BRCA1/2 patients, and non-BRCA 5/21 (23.8%). Finally, veliparib has also been assessed among patients with previously treated mCRPC in a biomarker-stratified phase II trial: patients were randomized to abiraterone + veliparib versus abiraterone alone. The authors found no difference in terms of PSA response rate, objective response rate, or progression-free survival.19 Veliparib was also assessed in combination with temozolomide in a small pilot study among men with mCRPC.20

    Ongoing trials of PARP inhibitors in mCRPC

    As may be expected given the recent promising results of PARP inhibitor treatment in both monotherapy and combination therapy in patients with advanced prostate cancer.

    • Olaparib: The PROpel trial is randomizing patients with mCRPC to first line treatment with Olaparib + abiraterone vs abiraterone alone, without biomarker selection. Further, KEYNOTE-365 Cohort A is testing pembrolizumab + Olaparib,21 while KEYLYNK-010 is randomizing 780 patients to pembrolizumab + olaparib versus abiraterone or enzalutamide in patients with mCRPC.
    • Talazoparib: The TALAPRO-1 trial will assess talazoprabib in patients with progressive disease following both taxane and androgen axis inhibitor treatment (and biomarker selection for DDR mutations likely to sensitize to PARP inhibitor) while TALAPRO-2 will assess talazopraib + enzalutamide versus enzalutamide alone in first-line treatment of mCRPC without biomarker selection.
    • Rucarparib: the TRITON3 trial is randomizing patients with mCRPC and mutations in BRCA1, BRCA2, or ATM to rucaparib or abiraterone/enzalutamide/docetaxel following progression on an androgen axis inhibitor.
    • Niraparib: The MAGNITUDE trial is recruiting patients with mCRPC to first-line therapy with niraparib + abiraterone or abiraterone alone. Analysis is stratified by the presence (cohort A) or absence (cohort B) of DDR mutations.

    Conclusions

    Germline mutations in DNA-repair genes are relatively uncommon in patients with prostate cancer, though the prevalence increases among patients with advanced disease and somatic changes are also common in this disease. While such mutations are associated with a worse prognosis, they open the possibility of targeted therapy using PARP inhibitors. Phase I, II, and III data have now demonstrated benefit to the use of PARP inhibitors in patients with alterations in DNA repair genes, especially BRCA2. In the past week, two PARP inhibitors (olaparib and rucarparib) have received FDA approval for patients with advanced prostate cancer. Numerous ongoing studies will continue to refine the role of these agents, both alone and in combination, for patients with advanced prostate cancer.

    Written by: Christopher J.D. Wallis, MD, PhD, Vanderbilt University Medical Center, Nashville, TN, and Zachary Klaassen, MD, MSc, Medical College of George, Augusta, GA 

    Published June 29, 2020
    Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
    References:
    Published June 17, 2020
  • PARP Inhibitors, Prostate Cancer and a Promise Fulfilled

    June 26, 2020, marked the 20th anniversary of the publication of the first working draft from the Human Genome Project. At a special White House event to commemorate the results of this 10-year public effort (it was really more like 50 years since the discovery of DNA, but I digress), then-President Bill Clinton called the project “the most wondrous map ever created by humankind”, and touted its promise to detect, prevent, and treat disease.  Obtaining that first sequence from one human cost about $2B and resulted from a massive global public/private partnership.

    Written by: Charles Ryan, MD
    References: 1. McKie, Robin. ‘The wondrous map’: how unlocking human DNA changed the course of science. The Guardian. June 21, 2020. Retrieved from: https://www.theguardian.com/science/2020/jun/21/human-genome-project-unlocking-dna-covid-19-cystic-fibrosis-molecular-scientists
    Published June 30, 2020
  • Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer.

    The availability of multiple new treatments for metastatic castration-resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an intermediate endpoint for overall survival (OS).

    Published March 13, 2016
  • Sequencing and Combining CRPC Therapies - What Does the Future Hold?

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 4
    Published Date: December 2017

    The European Association of Urology defines castration-resistant prostate cancer (CRPC) as serum testosterone < 50 ng/dL or < 1.7 nmol/L plus either biochemical progression (three consecutive rises in prostate-specific antigen [PSA] one week apart, resulting in two 50% increases over the nadir, and PSA > 2 ng/mL) or radiologic progression
    Published February 28, 2018
  • SUO 2019: PARP Inhibitors for Prostate Cancer

    Washington, DC (UroToday.com) To conclude the Society of Urologic Oncology (SUO) 2019 advanced prostate cancer session, Dr. Joaquin Mateo provided an overview of PARP inhibitors in prostate cancer. Metastatic prostate cancer remains a lethal disease, however, abiraterone, enzalutamide, and radium-223 have prolonged survival. Currently, the one-size-fits-all approach remains the standard of care in metastatic castration-resistant prostate cancer (mCRPC). As we learn more about mCRPC, Dr. Mateo notes that we identify potential additional targets for tailored treatment.

    Published December 7, 2019
  • SUO 2019: Poly ADP Ribose Polymerase (PARP) Inhibitors for Prostate Cancer

    Washington, DC (UroToday.com)  At the Advanced Prostate Cancer session at the 2019 Annual Meeting of the Society for Urologic Oncology, Dr. Joaquin Mateo presented an overview of the use of poly ADP ribose polymerase (PARP) inhibitors in the treatment of metastatic prostate cancer, from their biological rationale, to the preliminary data suggesting their efficacy, and finally to a review of the recent PROfound randomized phase III trial.  
    Published December 7, 2019

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