MCRPC Treatment COE Articles

Articles

  • 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
  • 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 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
  • 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 three 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 study design:

    TROPIC study

    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 study design

    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 design:

    AFFIRM trial design.jpg

    Apalutamide


    Apalutamide, initially known as ARN-509, is a next-generation androgen receptor (AR) antagonist, shown to bind with high affinity to the ligand binding domain of the AR, inhibiting its transport to the nucleus and its DNA binding capacity.9 The advantages of apalutamide over enzalutamide include its greater antitumor activity at a lower dose, higher tumor/plasma ratio, and lower concentrations in the central nervous system, with a potentially lower risk of specific adverse events, namely, seizures.10 The first-in-human phase I study of apalutamide enrolled 30 patients with progressive mCRPC.11 Patients were assigned sequentially to escalating doses of apalutamide. The median duration of study participation was 9.5 months, with no medication discontinuation reported due to drug-related toxicity. Apalutamide was well-tolerated with the most common adverse events being fatigue (47%), all restricted to grade 1 or 2, and no grade 4 or 5 toxicities noted, and only four patients reporting grade 3 adverse events. Importantly, no seizures were reported. Across all cohorts, at 12 weeks from baseline PSA reduction of over 50% was observed in 46.7% of patients, suggesting significant clinical activity.11 Later, a phase II study was undertaken with three expansion cohorts: (1) patients with non-metastatic CRPC (2) abiraterone-naïve mCRPC patients and (3) mCRPC patients after treatment with abiraterone. The results of the two mCRPC cohorts were published and showed that patients in the post-abiraterone cohort and abiraterone-naïve cohort had a 12-week PSA decline of at least 50% of 88% and 22%, respectively.12 The median time to PSA progression was 18.2 months for abiraterone-naïve patients and 3.7 months for patients already treated with abiraterone.12 A total of 80% and 43% of patients in abiraterone-naïve and post-abiraterone cohorts, respectively, remained on treatment for at least 6 months. The safety profile of apalutamide in the two cohorts was consistent with the data reported in the phase I trial. These favorable results culminated in the design of future phase III trials (discussed below).

    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 design:

    ALSYMPCA trial design.jpg

    Figure 5 – ERA 223 study design:


    ERA 223 study design.jpg

    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 two 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.
    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
  • 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
    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
  • 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 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
    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
  • 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
  • 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.

    agents approved mCRPC.jpg


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


    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 design:

    figure 1 COU AA study.jpg

    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 design:

    PREVIAL study.jpg

    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 327 trial designs:

    SWOG TAX trials.jpg

    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 design:

    IMPACT trial.jpg

    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”).
    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
    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
  • 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
    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
  • 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
    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
  • The Five-Take Home Messages of the LATITUDE and STAMPEDE Studies

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 3
    LATITUDE was a phase III trial of men with high-volume metastatic prostate cancer (PC) that had not been previously treated with androgen deprivation therapy (ADT).1 The patients were randomized to receive standard ADT with placebos vs. ADT plus abiraterone and prednisone. The primary endpoint is overall survival (OS).
    Published November 22, 2017
  • The Impact of Visceral Metastasis in Prostate Cancer Patients

    Introduction and Epidemiology

    In 2018 in the United States, there will be an estimated 164,690 new cases of prostate cancer (19% of all male cancer incident cases, 1st) and an estimated 29,430 prostate cancer mortalities (9% of all male cancer deaths, 2nd only to lung/bronchus cancer).1 For the last 30 or more years, prostate cancer has been the most common noncutaneous malignancy among men in the United States, with 1 in 7 men being diagnosed with the disease.2 De-novo metastatic prostate cancer incidence seems to vary by geographical region and ranges from 4.4 to 9.9 per 100,000 men. A recent study found that over the last several decades, the incidence of de novo metastatic prostate cancer was decreasing in the United States (12.0 to 4.4 per 100,000 men) but increasing in Denmark (6.7 to 9.9 per 100,000 men).3 The exact mechanism for these epidemiologic differences is not clear, but likely related to varying uptake and utilization of PSA surveillance.

    With improvements in the treatment of advanced prostate cancer over the last decade, men with advanced disease are living longer and developing non-lymph node visceral metastases.  In a single-institution Japanese study (from 2000-2014), among 1,038 prostate cancer patients, there were 144 (19.8 %) men with castration-resistant prostate cancer (CRPC) and 43 (33.1%) patients developing visceral metastases after CRPC progression.4 At diagnosis, the sites of visceral metastases included lung (89.5%), liver (5.3%), and adrenal glands (5.3%). After CRPC progression, new visceral metastases were found in the lung (47.3%), liver (43.6%), and adrenal gland (9.1%). Among 359 CRPC patients in the UK (June 2003 to December 2011), the frequency of radiologically detected visceral metastases before death was 32%; among the 92 patients with a CT scan performed within 3 months of death, 49% had visceral metastases, most commonly involving the liver (20%) and lung (13%).5 These findings confirm a large autopsy study that found among 1,500 prostate cancer patients, 25% of men had liver metastases and 46% had lung metastases.6 Of men participating in first-line studies for metastatic CRPC (mCRPC), ~20% of patients had non-lymph node soft tissue visceral metastases.7,8 As such, leaders in the field have suggested that men with visceral metastases have been an underestimated and understudied subgroup of patients with advanced and heavily treated mCRPC.9,10 The objective of this article is to discuss the biology of visceral metastases, assess the impact of visceral metastases on survival, highlight several large trials that have performed subgroup analyses of visceral metastases patients, and discuss emerging therapeutic regimens for these patients, specifically radioligand targeted therapy.

    The Biology of Visceral Metastases

    We are likely only beginning to understand the biology of visceral metastases, particularly as it differs from that of bone metastases. There are several interrelated factors leading to differing pathophysiology between visceral and bone metastases, namely intrinsic cellular factors, the tumor microenvironment, and systemic factors.

    1. Cellular Factors: Immunohistochemical analysis of tissue microarrays examining the antiapoptotic pathways expressed in visceral vs bone metastases found that soft-tissue metastases are more likely to express nuclear survivin, whereas bone lesions demonstrate relative overexpression of cytoplasmic survivin, B-cell lymphoma 2, and myeloid cell leukemia 1.11
    2. Tumor Microenvironment: microarray studies have found physiologically and clinically important differences between bone, liver, and lymph node metastases. Visceral lesions derived from liver and lymph nodes were found to express an angiogenic profile different from that of liver metastases alone, with significant relative overexpression of the proangiogenic factor angiopoietin-2.12
    3. Systemic Factors: serum cytokine levels are associated with prognosis as well as with the presence of liver metastases among prostate cancer patients.9,13 A number of studies have examined levels of TGF-β and interleukin-6 (IL-6) as prognostic markers, finding that the addition of TGF-β and soluble IL-6 receptor levels to a preoperative nomogram significantly improved the ability to predict biochemical progression of the disease.14

    Impact of Visceral Metastases on Survival

    Patients with visceral metastases invariably have a worse prognosis than patients with bone-only metastases, likely secondary to an overall increased disease burden.5,10,15-26 In a study including patients in the SEER database (2010-2013), patients with de-novo bone-metastases plus visceral metastases had significantly worse prostate cancer-specific mortality (vs bone only): bone + brain metastases HR 1.48, 95%CI 1.05-2.10; bone + liver metastases HR 2.18, 95%CI 1.79-2.65; bone + lung metastases HR 1.33, 95%CI 1.13-1.56.27

    Several large phase III randomized controlled trials (RCTs) have assessed the impact of visceral metastases on survival outcomes using post-hoc analysis of the trial data. The TAX 327 trial found that docetaxel plus prednisone improved OS, pain scores, PSA level, and quality of life compared to mitoxantrone plus prednisone among patients with mCRPC.8 A decade after this publication, Pond et al.25 performed a post-hoc analysis of this data stratified by metastasis site. They found that men with liver metastases with or without other metastases had a shorter median OS (10.0 months; 95%CI 5.4-11.5) than men with lung metastases with or without bone or nodal metastases (median OS: 14.4 months; 95%CI 11.5-22.4). The AFFIRM trial showed that treatment with the androgen receptor inhibitor enzalutamide led to significant improvements in outcomes for patients with mCRPC.28 A subsequent study assessed patients in the AFFIRM trial who had liver and/or lung metastases.20 In patients with liver metastases (n = 92), enzalutamide treatment was associated with a lower risk of radiographic progression (HR 0.645, 95%CI 0.413-1.008), improved 12-month OS (37.7% vs 20.6%) and radiographic progression-free survival (rPFS) (11.6% vs 3.0%) rates compared to those on placebo. Furthermore, patients treated with enzalutamide had higher PSA response rates (35.1% vs 4.8%) compared with placebo. Similarly, patients with lung metastases (n = 104) treated with enzalutamide also had an improved median OS (HR 0.848, 95%CI 0.510-1.410), reduced risk of radiographic progression (HR, 0.386, 95%CI 0.259-0.577), improved 12-month OS (65.1% vs 55.3%) and rPFS (30.9% vs 8.2%) rates, and a better PSA response rate (52.1% vs 4.9%) compared with those who received placebo. The PREVAIL clinical trial tested enzalutamide in men with mCRPC prior to chemotherapy, finding a decreased risk of radiographic progression and death among those taking enzalutamide compared to placebo.29 Of the 1,717 patients in PREVAIL, 12% had visceral metastases: 74 with liver-only or liver/lung metastases and 130 with lung only metastases.19 In patients with liver metastases, treatment with enzalutamide was associated with an improvement in rPFS (HR 0.44, 95%CI 0.22-0.90) but not OS. Among patients with lung metastases only, enzalutamide significantly improved rPFS (HR 0.14, 95%CI 0.06-0.36) and OS (HR 0.59, 95%CI 0.33-1.06). Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment.

    Results of post-hoc analyses of phase III RCTs showing poor outcomes among patients with visceral metastases have also been confirmed using population-level studies. Gandaglia et al.24 utilized the SEER-Medicare database (1991-2009) to assess outcomes of 3,857 patients presenting with metastatic prostate cancer. Among these patients, 80.2% had bone metastases, 10.9% had bone plus visceral metastases, 6.1% had visceral only metastases, and 2.8% had lymph node only metastases. Patients with bone plus visceral metastases had the worst cancer-specific survival (median 19 months), following by visceral only metastases (median 26 months), bone-only metastases (median 32 months) and lymph node only metastases (median 61 months). Patients with visceral metastases had a significantly higher risk of overall and cancer-specific mortality compared to those with exclusively lymph node metastases (p<0.001), and the unfavorable impact of visceral metastases persisted in the oligometastatic subgroup. Whitney et al.18 studied 494 men with M0 CRPC (diagnosed after 1999) from five Veterans Affairs hospitals in the Shared Equal Access Regional Cancer Hospital (SEARCH) database who later developed metastases. Among these patients, 236 men had a CT scan performed, of which 38 (16%) had visceral metastases, including 19 patients with liver metastases, 8 patients with lung metastases, and 16 patients with other locations of metastases. The authors found that visceral metastases were a predictor of OS on univariate analysis and after risk adjustment (HR 1.84, 95%CI 1.24-2.72).

    To further assess the impact of metastatic site on OS among men with mCRPC, a collaborative group performed an individual patient data meta-analysis of 8,820 men with mCRPC who received docetaxel chemotherapy in nine phase III RCTs.22 Site of metastases was categorized as lymph node only, bone with or without lymph node involvement (with no visceral metastases), and lung metastases (but no liver), and any liver metastases. 72.8% of patients had a bone with or without lymph node metastases, 20.8% had a visceral disease, and 6.4% had lymph node-only disease. Men with lymph node-only disease had the best survival with a median OS of 31.6 months, followed by men with non-visceral bone metastases (median OS 21.3 months), men lung metastases (median OS 19.4 months), and those with liver metastases (median OS 13.5 months).

    There are several take-home messages from these studies assessing survival outcomes among patients with visceral metastases:

    1. Patients with any degree of liver metastases typically have the worst survival outcomes compared to those with bone metastases or other sites of visceral metastases
    2. Patients with visceral metastases do have a response to enzalutamide (either in the pre- or post-chemotherapy setting), although their prognosis remains poor

    Radioligand Therapy for mCRPC Patients

    The recent uptake in the utilization of PSMA-PET/CT imaging has led to a new field of therapy among heavily pretreated mCRPC patients: radioligand directed therapy. The high PSMA expression in prostate cancer metastases makes it a promising approach to developing new tracers for targeted radionuclide therapies. Since 2015, several institutional studies have reported promising results for response rates and a favorable safety profile after radioligand therapy with 177Lu-PSMA-617 in patients with mCRPC,30-34, however, these studies have suffered from small sample sizes and thus poor generalizability. In an effort to overcome these issues, Rahbar and colleagues35 performed a multicenter German analysis among a cohort of patients treated with 177Lu-PSMA-617.  There were 145 patients with mCRPC treated with 177Lu-PSMA-617 at 12 centers undergoing 1-4 therapy cycles with an activity range of 2-8 GBq per cycle. Among these patients, 87% had bone, 77% lymph node, 20% liver, 14% lung, and 2% other sites of metastases. The study reported an overall biochemical response rate of 45% after all therapy cycles, including 40% of patients who responded after a single cycle. Notably, negative predictors of biochemical response include elevated alkaline phosphatase and the presence of visceral metastases.

    A study published last month reported on 100 consecutive patients at a single institution receiving 177Lu-PSMA-I&T, treated with a median of two cycles of therapy (range 1-6).36 Among these 100 patients, 57 had received ≥3 prior treatment regimens for mCRPC. There were 87 patients that had lymph metastases and 35 with visceral metastases, including 18 with liver, 11 with lung and 8 with adrenal metastases. A PSA decline of ≥50% was achieved in 38 patients, the median clinical progression-free survival was 4.1 months, and median OS was 12.9 months.  The presence of visceral metastasis was the only variable associated with a poor PSA response (p = 0.049), as only nine of 35 (26%) patients with visceral metastasis achieved a maximum PSA decline of ≥50%. The authors concluded that the presence of visceral metastases and rising LDH were associated with worse treatment outcome.

    Although 177Lu-PSMA-617 is the most well-studied radioligand to date, there are several other compounds in development and undergoing initial testing. These compounds include: 177Lu-J591, 90Y-J591, 131I-MIP 1095, 177Lu-PSMA-I&T, and 225Ac-PSMA-617.37

    Conclusions  

    Secondary to the improved treatment options available for patients with mCRPC, these men are living longer and thus increasing the prevalence of mCRPC patients with visceral metastases. Although post-hoc studies of enzalutamide trials in the pre- and post-chemotherapy mCRPC setting demonstrate a degree of response, visceral metastases are associated with poor survival outcomes. Initial radioligand therapy studies, primarily with 177Lu-PSMA-617, show promise for heavily treated mCRPC patients, although subgroup analyses of these studies also demonstrate worse survival among patients with visceral metastases. For the future design of phase II and phase III clinical trials among men with mCRPC, patients should be stratified by metastasis site to preclude patients with visceral metastases being inadvertently randomized to an unbalanced trial arm. Further efficacious treatment options for these patients are in dire need. The treatment of visceral metastases is one of the new therapeutic frontiers for prolonging not only quantity but also the quality of life.

    Written by: Zachary Klaassen, MD
    References:
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
    2. Brawley OW. Trends in prostate cancer in the United States. J Natl Cancer Inst Monogr. 2012;2012(45):152-156.
    3. Helgstrand JT, Roder M, Klemann N, et al. Incidence and survival trends of de-novo metastatic prostate cancer - A population-based analysis of the national cohorts from USA and Denmark. Eur Urol Suppl. 2018;17(2):e383.
    4. Iwamoto H, Izumi K, Kadono Y, Mizokami A. Incidences of visceral metastases from prostate cancer increase after progression of castrion-resistant status. J Clin Oncol. 2018;36(6_Suppl):291.
    5. Pezaro C, Omlin A, Lorente D, et al. Visceral disease in castration-resistant prostate cancer. Eur Urol. 2014;65(2):270-273.
    6. Bubendorf L, Schopfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31(5):578-583.
    7. 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. 2004;351(15):1513-1520.
    8. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512.
    9. Drake CG. Visceral metastases and prostate cancer treatment: 'die hard,' 'tough neighborhoods,' or 'evil humors'? Oncology (Williston Park). 2014;28(11):974-980.
    10. Bourlon MT, Flaig TW. Visceral metastases in prostate cancer: an underestimated and understudied subgroup. Oncology (Williston Park). 2014;28(11):980-986.
    11. Akfirat C, Zhang X, Ventura A, et al. Tumour cell survival mechanisms in lethal metastatic prostate cancer differ between bone and soft tissue metastases. J Pathol. 2013;230(3):291-297.
    12. Morrissey C, True LD, Roudier MP, et al. Differential expression of angiogenesis associated genes in prostate cancer bone, liver and lymph node metastases. Clin Exp Metastasis. 2008;25(4):377-388.
    13. Steuber T, O'Brien MF, Lilja H. Serum markers for prostate cancer: a rational approach to the literature. Eur Urol. 2008;54(1):31-40.
    14. Kattan MW, Shariat SF, Andrews B, et al. The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer. J Clin Oncol. 2003;21(19):3573-3579.
    15. Buelens S, De Bleser E, Dhondt B, et al. Importance of metastatic volume in prognostic models to predict survival in newly diagnosed metastatic prostate cancer. World J Urol. 2018.
    16. Mazzone E, Preisser F, Nazzani S, et al. Location of Metastases in Contemporary Prostate Cancer Patients Affects Cancer-Specific Mortality. Clin Genitourin Cancer. 2018;16(5):376-384 e371.
    17. Shou J, Zhang Q, Wang S, Zhang D. The prognosis of different distant metastases pattern in prostate cancer: A population based retrospective study. Prostate. 2018;78(7):491-497.
    18. Whitney CA, Howard LE, Posadas EM, et al. In Men with Castration-Resistant Prostate Cancer, Visceral Metastases Predict Shorter Overall Survival: What Predicts Visceral Metastases? Results from the SEARCH Database. Eur Urol Focus. 2017;3(4-5):480-486.
    19. 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. 2017;15(5):610-617 e613.
    20. Loriot Y, Fizazi K, de Bono JS, Forer D, Hirmand M, Scher HI. Enzalutamide in castration-resistant prostate cancer patients with visceral disease in the liver and/or lung: Outcomes from the randomized controlled phase 3 AFFIRM trial. Cancer. 2017;123(2):253-262.
    21. Badrising SK, van der Noort V, Hamberg P, et al. Enzalutamide as a Fourth- or Fifth-Line Treatment Option for Metastatic Castration-Resistant Prostate Cancer. Oncology. 2016;91(5):267-273.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. 2016;34(14):1652-1659.
    22. Conteduca V, Caffo O, Fratino L, et al. Impact of visceral metastases on outcome to abiraterone after docetaxel in castration-resistant prostate cancer patients. Future Oncol. 2015;11(21):2881-2891.
    23. Gandaglia G, Karakiewicz PI, Briganti A, et al. Impact of the Site of Metastases on Survival in Patients with Metastatic Prostate Cancer. Eur Urol. 2015;68(2):325-334.
    24. Pond GR, Sonpavde G, de Wit R, Eisenberger MA, Tannock IF, Armstrong AJ. The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer. Eur Urol. 2014;65(1):3-6.
    25. Vinjamoori AH, Jagannathan JP, Shinagare AB, et al. Atypical metastases from prostate cancer: 10-year experience at a single institution. AJR Am J Roentgenol. 2012;199(2):367-372.
    26. Klaassen Z, Chandrasekar T, Goldberg H, Hamilton R, Fleshner N, Kulkarni G. Predictors of Early Disease Specific Mortality Among Patients with Prostate Adenocarcinoma Bone Metastasis at Diagnosis. J Urol. 2017;197(4S_Suppl):e170.
    27. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197.
    28. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424-433.
    29. Ahmadzadehfar H, Rahbar K, Kurpig S, et al. Early side effects and first results of radioligand therapy with (177)Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-centre study. EJNMMI Res. 2015;5(1):114.
    30. 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. 2016;7(11):12477-12488.
    31. 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. 2016;57(8):1170-1176.
    32. 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. 2016;57(9):1334-1338.
    33. Rahbar K, Bode A, Weckesser M, et al. Radioligand Therapy With 177Lu-PSMA-617 as A Novel Therapeutic Option in Patients With Metastatic Castration Resistant Prostate Cancer. Clin Nucl Med. 2016;41(7):522-528.
    34. 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. 2017;58(1):85-90.
    35. Heck MM, Tauber R, Schwaiger S, et al. Treatment Outcome, Toxicity, and Predictive Factors for Radioligand Therapy with (177)Lu-PSMA-I&T in Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2018.
    36. Awang ZH, Essler M, Ahmadzadehfar H. Radioligand therapy of metastatic castration-resistant prostate cancer: current approaches. Radiat Oncol. 2018;13(1):98.
    Published April 16, 2019
  • The Importance of Clinical Trials for Genitourinary Malignancies

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 4
    As we counsel our patients about the importance of clinical research, there are two key messages to send. The first is that without clinical trials, we would not have access to the large number of life-prolonging therapies that we have for genitourinary cancers and others. That translates into more family trips, birthday parties, time spent with grandchildren and graduations attended.
    Published February 28, 2018
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