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CRPC with Bone Metastases COE

  • A Review On The Development of Targeted Alpha Therapy in the Treatment of Cancer

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 2
    Focusing on The First and Only FDA Approved Targeted Alpha Therapy Radium-223 in the Treatment of mCRPC

    The Tenth Symposium on Targeted Alpha Therapy (TAT-10) opened on Wednesday, May 31, 2017 in Kanazawa Japan. The symposium was jointly organized by the Joint Research Centre (JRC) of the European Commission and Kanazawa University
    Published September 5, 2017
  • ASCO GU 2019: Hypocalcemia in Patients with Castration-Resistant Prostate Cancer Treated with Denosumab: The REDUSE Trial

    San Francisco, CA (UroToday.com) Silke Gillessen, MD presented a study comparing two different dosing frequencies of Denusomab in patients with castration-resistant prostate cancer, and evaluating the rate of hypocalcemia in these two treatment options.
    Published February 14, 2019
  • Chemotherapy following radium-223 dichloride treatment in ALSYMPCA.

    BACKGROUND - Radium-223 prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, regardless of prior docetaxel. Whether or not chemotherapy can be safely administered following radium-223 treatment is of clinical importance.

    Published March 29, 2016
  • Duke Researchers Awarded $1 Million For Prostate Cancer Research

    San Francisco, CA (UroToday.com) -- A team of researchers led by Duke Cancer Institute scientists Steven Patierno, Ph.D.; Daniel George, MD; Jennifer Freedman, Ph.D.; Jiaoti Huang, MD, Ph.D. and Amanda Hargrove, Ph.D. have been awarded a Movember Foundation-Prostate Cancer Foundation Challenge Award. The project includes a number of key co-investigators including Terry Hyslop, PhD (Biostatistics), Michael Kelley MD and Megan McNamara MD (key clinical oncology collaborators at the Durham Veterans Administration Hospital), James Abbruzzese, MD (DCI Associate Director for Clinical Research) and Hailiang Hu, PhD (senior scientist in Pathology). Muthana Al Abo, Ph.D., MD, joins the teams as a PCF Young Investigator. The $1 million award will support a two-year project investigating targeting RNA splicing for therapeutic application in race-related aggressive and lethal prostate cancer in African American and Caucasian patients, including Veterans.
    Published August 17, 2018
  • ESMO 2018: ERA 223 - A Phase 3 Trial of Ra-223 in Combination with Abiraterone Acetate & Prednisone for the Treatment of Asymptomatic or Mildly Symptomatic Chemotherapy-Naïve Patients with mCRPC

    Munich, Germany (UroToday.com) As has been the trend in management of advanced solid malignancies, there has been increasing interest in combining proven therapies to identify synergistic effect – survival benefit greater than any one drug alone could provide. This is particularly useful if the mechanism of action of these combined agents targets different pathways.
    Published October 19, 2018
  • ESMO 2018: Treatment of Asymptomatic or Mildly Symptomatic Chemotherapy-Naïve Patients with Bone-Predominant mCRPC

    Munich, Germany (UroToday.com) Radium-223 is an alpha emitter which selectively treats bone metastases with alpha radiation1. In a recent GU ASCO oral presentation, a radium-223 pharmacodynamic study demonstrated that higher gamma emission is found in deep tumor containing regions of bone biopsies, compared with superficial regions, supporting the presumed mechanism of radium-2232.

    Published October 19, 2018
  • EVERYDAY UROLOGY: Bone Metastases and Mortality in Prostate Cancer, Can We Be Doing More?- Full text article

    Published in Everyday Urology - Oncology Insights: Volume 3, Issue 3
    Prostate cancer is the most common malignancy among US men, with an estimated annual incidence of 180,890, accounting for one in five new cancer cases in men.1 The second-most common cause of cancer death in US men, prostate cancer is expected to claim the lives of 26,120 men in this country in 2016.1
    Published November 16, 2016
  • Evidence-Based Therapeutic Approaches for mCRPC

    Prostate cancer exhibits a wide spectrum of disease behavior. Despite the majority of cases presenting with relatively indolent biologic behavior, prostate cancer remains the second leading cause of cancer-related death in the United States, behind only lung cancer.1 With current treatment paradigms, nearly all patients who die of prostate cancer first receive androgen-deprivation therapy and then progress to castrate-resistant prostate cancer.

    There is a large spectrum of prostate cancer progression. For patients who are initially diagnosed with a clinically-localized disease, such a pathway is highlighted in the following diagram. For patients who present with de novo metastatic disease, they join this algorithm at “development of metastatic hormone-sensitive prostate cancer (mHSPC)”.

    diagram-evidence-based-theraputic-approaches-mCRPC@2x (1).jpg
     
    The clinical approach to patients with metastatic castrate-resistant prostate cancer (mCRPC) depends, in general terms, on three factors: whether the patient is symptomatic from their disease, the patient’s performance status, and previous therapies which the patient may have received. These factors have been used to guide treatment recommendations in the guidelines from many medical/urologic societies. The definition of “symptomatic” prostate cancer is somewhat imprecise. However, most consider that patients who require only acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) to be minimally symptomatic while those who require regular narcotic medications for pain that is attributable to documented metastasis are deemed symptomatic.

    Advanced androgen axis targeting agents (such as abiraterone and enzalutamide) and chemotherapeutics (such as docetaxel) are increasingly used earlier in the disease process, including in de novo metastatic castrate-sensitive prostate cancer and in non-metastatic castrate resistant prostate. While there is some evidence that re-challenge with docetaxel may provide benefit in patients who previously demonstrate docetaxel response, 2, 3 the use of advanced androgen axis targeting agents and docetaxel earlier in the disease trajectory may preclude their use at the development of mCRPC. Acknowledging the changes this utilization has on the treatment of mCRPC, this article will focus on guideline-recommended treatment options.

    As the androgen axis continues to be important in patients who have developed castration resistance, ongoing continuous treatment with androgen-deprivation therapy is recommended.4 Historically, a number of secondary hormonal maneuver have been employed. However, routine use of these preceded the availability of therapies with proven survival benefits. As no secondary hormonal maneuver has been shown to prolong survival, they are not widely recommended. However, there is evidence that, for patients who are currently receiving LHRH agonist or antagonist monotherapy, the addition of androgen receptor antagonists and resulting total androgen blockade is associated with short-term PSA-responses. Conversely, for patients who are currently receiving total androgen blockage, anti-androgen withdrawal is recommended as some patients may experience an antiandrogen withdrawal response.

    For patients who are asymptomatic or minimally-symptomatic, have good performance status, and have not yet received docetaxel chemotherapy, there are numerous treatment options. These include docetaxel, abiraterone plus prednisone, enzalutamide, and sipuleucel-T5. Docetaxel was the first agent shown to have a survival benefit in patients with mCRPC in 20046 and it quickly became standard of care for these patients as there were no alternatives with a demonstrated survival benefit. In 2012, COU-AA-302 was the first study to demonstrate a survival benefit for a non-cytotoxic agent in the treatment of mCRPC: patients treated with abiraterone plus prednisone demonstrated approximated 4 months longer overall survival (OS) than those receiving prednisone alone.7 Subsequently, in 2014, the PREVAIL study demonstrated similar benefits for enzalutamide in this patient population.8 Both abiraterone and enzalutamide target the androgen axis. In contrast, sipuleucel-T is an autologous active cellular immunotherapy. Published in 2010, the IMPACT study demonstrated that this approach was associated with approximately 20% improved overall survival.9 For patients who opt against these standard treatments, observation alone, first-generation anti-androgens, or ketoconazole accompanied by steroids may be offered.5 While not included in these guidelines, the FIRSTANA trial compared docetaxel and two doses of cabazitaxel in chemotherapy naïve patients with mCRPC. Overall, no large differences between the regimes were seen with respect to oncologic efficacy or tolerability.10

    For patients who have good performance status and have not yet received docetaxel but who are symptomatic (again, based on a definition requiring regular use of narcotic analgesics for the pain that is attributable to documented metastasis), there are again a number of treatment options. Abiraterone plus prednisone, enzalutamide, and docetaxel form the standard of care for these patients. In addition, the alpha-emitter radium-223 may be offered to patients who have symptoms attributable to bony metastatic disease in the absence of visceral disease on the basis of the results of the ALSYMPCA trial. This phase 3 trial demonstrated that treatment with radium-223 significantly improved overall survival as well as skeletal-related events.11  As with asymptomatic or minimally-symptomatic patients who have good performance status and are chemotherapy-naïve, symptomatic patients who decline standard treatments may be offered alternative therapies though these do not have proven survival benefit. In this patient population, these treatments include ketoconazole with steroids, mitoxantrone, or radionuclide therapy.5

    For symptomatic patients with poor performance status who have not previously received docetaxel, there is a relative paucity of direct evidence to inform treatment choices as most patients with poor performance status are excluded from clinical trials. However, guidelines typically extrapolate from studies in patients with better performance status to guide therapy in these patients.5 Aggressive prostate cancer treatment may especially be warranted where the functional impairments resulting in poor performance status are directly attributable to prostate cancer. In contrast, patients with poor performance status as a result of other medical conditions have less to gain from aggressive prostate cancer therapy. Considering these factors, individual, tailored therapy is warranted with a thorough discussion of potential risks and benefits of therapy. The AUA guidelines currently recommend either abiraterone plus prednisone or enzalutamide for these patients.5 For patients with poor performance status that is attributable to their disease burden, docetaxel or mitoxantrone may be offered whereas, when the poor performance status is related to bony metastatic disease, radium-223 is a recommended option. For patients unable or unwilling to receive standard therapies, ketoconazole with steroids or radionuclide therapy remain options though these have not demonstrated survival benefit5. In contrast, the CUA guidelines do not stratify by performance status and recommend docetaxel with abiraterone plus prednisone or enzalutamide as alternatives for patients who cannot receive or refuse docetaxel and radium-223 as an alternative for patients who have bony pain related to their metastases and no visceral disease.4 

    Among patients with mCRPC who have previously received docetaxel-based chemotherapy, treatment options may again be stratified by performance status. There are 4 agents with a proven survival benefit in this population: abiraterone plus prednisone; enzalutamide; cabazitaxel; and radium-223. Given that this is a relatively advanced disease state and these treatments remain non-curative and yet have a significant potential burden of toxicity, care should be taken to provide prostate cancer treatments which preserve these patients’ excellent quality of life. It is also at this time that sequencing of agents becomes particularly relevant as many patients will have received an advanced androgen axis targeting agent (abiraterone or enzalutamide) prior to receiving docetaxel and will now be on their third line of mCRPC treatment.

    In 2011, the COU-AA-301 trial demonstrated that abiraterone plus prednisone could improve overall survival approximately 4 months for patients with advanced mCRPC following docetaxel chemotherapy.12 Subsequently, in 2012, the AFFIRM trial demonstrated similar results for enzalutamide in this patient population.13 TROPIC tested cabazitaxel versus mitoxantrone, each with prednisone, in patients who had progressed following docetaxel for mCRPC and demonstrated an improvement of approximately 2.5 months overall survival for patients receiving cabazitaxel.14 As discussed previously among patients who had not yet received docetaxel, ALSYMPCA demonstrated an improvement in both survival and skeletal-related events for patients receiving radium-223.11 In addition to these agents, docetaxel re-challenge is suggested for patients who discontinued therapy due to reversible toxicity. The AUA guidelines again offer ketoconazole plus steroids for patients who are unable or unwilling to take other agents.

    In patients with advanced mCRPC who are symptomatic and have poor performance status following previous docetaxel chemotherapy, symptom management is strongly advocated in keeping with the American Society for Clinical Oncology’s guidance regarding the treatment of patients with advanced solid tumors. Aggressive treatment at this time may lead to unnecessary cost and toxicity, may delay access to the end of life care, and is unlikely to provide meaningful benefit. Therefore, palliative care is prioritized. Abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid or radionuclide therapy are offered within the AUA guidelines5 but there is no strong data to support the use of these agents in this patient population.

    Apart from specific mCRPC medication, bone health remains important in all patients with advanced prostate cancer due to a confluence of risk factors: age-related declines in bone mineral density, the deleterious effects of androgen-deprivation therapy on bones15 (even among patients with localized prostate cancer16), and the involvement of bony metastatic disease. Therefore, calcium and vitamin D are recommended for all patients with mCRPC. In addition, a bone-targeting agent, either denosumab or zoledronic acid, is recommended. These agents have been shown to decrease disease-related skeletal events though, unlike radium-223, they have not been found to improve survival. The timing of initiation of bone-targeted agents is somewhat unclear as there is evidence that the risk of significant toxicity (particularly, osteonecrosis of the jaw) increases substantially after 2 years of therapy17 and may patients with mCRPC will be expected to live longer than this.

    Additionally, the symptomatic benefit of palliative radiotherapy should not be underestimated, and this should be offered where it is deemed clinically appropriate.

    Special considerations should be undertaken for some patients as these may guide treatment choices. In heavily pre-treated patients with mCRPC, Mateo et al. found that mutations or deletions in DNA-repair genes could be found in 33% of patients.18 These patients demonstrated a notably strong response to treatment with the PARP inhibitor olaparib. A biomarker suite including BRCA 1 and 2, ATM, Fanconi’s anemia genes, and CHECK2 had a specificity of 94% for identifying treatment response. Thus, identification of these defects in DNA-repair may guide treatment choice. More recently, a phase 2 trial demonstrated that olaparib added to abiraterone plus prednisone improved overall survival compared to abiraterone plus prednisone alone in a population of patients who had previously received docetaxel but were not enriched for DNA-repair defects.19

    Recently, the phase 3 trial of PROSTVAC, viral vector-based immunotherapy, in chemotherapy naïve patients with asymptomatic or minimally symptomatic mCRPC were reported. Despite promising results in a phase 2 trial where median OS was improved by 8.5 months, this phase 3 trial was unfortunately negative with a non-significant median difference in overall survival of approximately 1 month.20

    Despite the survival benefits of many agents in metastatic castrate-resistant prostate cancer, these treatments remain non-curative. Therefore, consideration for enrollment in ongoing clinical trials should be considered for all eligible patients.
    Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
    References:
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68(1):7-30.
    2. Thomas C, Brandt MP, Baldauf S, et al. Docetaxel-rechallenge in castration-resistant prostate cancer: defining clinical factors for successful treatment response and improvement in overall survival. Int Urol Nephrol 2018; 50(10):1821-1827.
    3. Oudard S, Kramer G, Caffo O, et al. Docetaxel rechallenge after an initial good response in patients with metastatic castration-resistant prostate cancer. BJU Int 2015; 115(5):744-52.
    4. Saad F, Chi KN, Finelli A, et al. The 2015 CUA-CUOG Guidelines for the management of castration-resistant prostate cancer (CRPC). Can Urol Assoc J 2015; 9(3-4):90-6.
    5. Lowrance WT, Murad MH, Oh WK, et al. Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2018. J Urol 2018; 200(6):1264-1272.
    6. 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):1502-12.
    7. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368(2):138-48.
    8. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371(5):424-33.
    9. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363(5):411-22.
    10. 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 2017:JCO2016721068.
    11. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369(3):213-23.
    12. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364(21):1995-2005.
    13. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367(13):1187-97.
    14. 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 2010; 376(9747):1147-54.
    15. Shahinian VB, Kuo YF, Freeman JL, et al. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352(2):154-64.
    16. Wallis CJ, Mahar AL, Satkunasivam R, et al. Cardiovascular and Skeletal-Related Events Following Localised Prostate Cancer Treatment: Role of Surgery, Radiotherapy and Androgen-Deprivation. Urology 2016; 97:145-152.
    17. Barasch A, Cunha-Cruz J, Curro FA, et al. Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR dental PBRN. J Dent Res 2011; 90(4):439-44.
    18. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015; 373(18):1697-708.
    19. 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 2018; 19(7):975-986.
    20. Gulley JL, Borre M, Vogelzang NJ, et al. Phase III Trial of PROSTVAC in Asymptomatic or Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 2019:JCO1802031.
    Published April 16, 2019
  • From the Desk of the Associate Editor: Radium-223 Radiographic Response

    Radium-223 is a novel alpha emitting radiopharmaceutical with bone tropism, now FDA approved for men with symptomatic bone-metastatic castration-resistant prostate cancer.  Approval was based on the survival benefit observed in the phase 3 ALSYMPCA trial over best supportive care, which included oral steroids or hormonal therapies, bone anti-resorptive therapy, and palliative radiation.
    Published June 1, 2017
  • Health Economics and Radium-223 (Xofigo®) in the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Case History and a Systematic Review of the Literature.

    OBJECTIVE - Prostate cancer (PC) is the most common cancer in Western countries. Recent advances in the treatment of metastatic castration resistant prostate cancer (mCRPC) have caused significant pressure on health care budgets.

    Published November 24, 2015
  • Imaging Response During Therapy with Radium-223 For Castration-Resistant Prostate Cancer With Bone Metastases—Analysis Of An International Multicenter Database

    BACKGROUND: The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment.

    METHODS: We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate cancer (CRPC) patients treated with radium-223, in eight centers in three countries.
    Published June 1, 2017
  • Microscopic Imaging Pierces the “Black Box” of Cancer Bone Metastasis

    San Francisco, CA (UroToday.com) MD Anderson researchers develop a model for spying on prostate cancer and bone dynamics

    Scientists at The University of Texas MD Anderson Cancer Center have engineered a system allowing microscopic monitoring and imaging of cancer that has spread to the bone in mice so they can better understand and develop treatment for bone metastasis in humans.
    Published August 1, 2018
  • Patient-reported quality of life analysis of radium-223 dichloride from the phase 3 ALSYMPCA study.

    BACKGROUND - Radium-223 dichloride (radium-223), a first-in-class alpha-emitting radiopharmaceutical, is recommended in both pre- and post-docetaxel settings in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases based on overall survival benefit demonstrated in the phase 3 ALSYMPCA study.

    Published February 29, 2016
  • Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial.

    In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo.

    Published August 1, 2016
  • Radium-223 dichloride: illustrating the benefits of a multidisciplinary approach for patients with metastatic castration-resistant prostate cancer

    Improving options for patients with metastatic castration-resistant prostate cancer (mCRPC) provide latitude in designing treatment plans that meet patients' medical needs and personal goals.

    Published August 28, 2015
  • Radium-223 for primary bone metastases in patients with hormone-sensitive prostate cancer after radical prostatectomy.

    Radium-223 dichloride (Ra-223) is the first bone-targeting agent showing improvement in overall survival in patients with castration-resistant prostate cancer (CRPC) and bone metastases. We aimed to assess feasibility of Ra-223 treatment in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
    Published September 6, 2017
  • Radium-223 in Heavily Pretreated Metastatic Castrate-Resistant Prostate Cancer.

    BACKGROUND - Radium-223 is a bone-targeting radiopharmaceutical that extends survival in mCRPC. Postapproval data are limited, and the value of biochemical and radiologic monitoring during radium therapy is unknown.

    Published April 11, 2016
  • Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer-Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT: Beyond the Abstract

    This article [1] is a comprehensive analysis of 10 prostate cancer patients who received Ra-223-treatments. These patients were imaged with multiple quantitative PET methods according to our own algorithm [2], including fluoro-18-choline-PET and sodium fluoride-18 PET. These patients were additionally treated with multidisciplinary methods, including other radiation therapies. We recently reported an overall survival of 8.4 years in 46 patients of high-risk T3-4NXM1 primarily metastatic prostate cancer [2].
    Published April 7, 2017
  • Radium-223:The Only Approved Targeted Alpha Therapy (TAT) in mCRPC- Outcomes, Opportunities and Lessons Learned

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 1
    More than 90% of patients with metastatic castration-resistant prostate cancer (mCRPC) develop bone metastases which leads to a significant increase in morbidity and mortality.1,2 Patients with metastatic prostate cancer and bone involvement have only a 3% five-year survival, whereas the five-year survival of patients without bone metastases is 56%.
    Published June 9, 2017
  • Targeted Alpha Therapy, an Emerging Class of Cancer Agents - A Review

    IMPORTANCE: Targeted alpha therapy attempts to deliver systemic radiation selectively to cancer cells while minimizing systemic toxic effects and may lead to additional treatment options for many cancer types.
    Published September 21, 2018
  • Treatment landscape of metastatic prostate cancer: the role of radium-223.

    The landscape of metastatic prostate cancer has changed recently with the availability of six new molecules showing an overall survival benefit. The development of compounds able to decrease the rate of complications from bone metastasis has also led to improvements in overall morbidity associated with this disease.

    Published July 11, 2016
  • When Men With Advanced Prostate Cancer Aren’t Speaking, Clinicians Must Encourage Talk About Emerging Symptoms - A Conversation with Neal Shore

    Even when symptoms, such as pain, impose significant impacts on their daily lives, many men with advanced prostate cancer do not report the symptoms to their doctors, according to an international survey of both patients and their caregivers to explore this issue. Symptoms may go unrecognized as being associated with cancer, or men deliberately choose not to speak about them with their doctors. As a result, they may not receive interventions that could ease the discomfort.

    Published April 20, 2016
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