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Updates and Insights on the Medical Science of Prostate Cancer

  • Authors: Charles Ryan, MD; Neal Shore, MD
  • CME / ABIM MOC Released: 5/25/2017
  • Valid for credit through: 5/25/2018, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for oncologists, urologists, and other healthcare professionals who treat patients with prostate cancer.

The goal of this activity is to advance the knowledge and competence of oncologists, urologists, and other healthcare professionals regarding the care of patients with metastatic prostate cancer and, in particular, interventions for patients with bone metastases, to improve patient outcomes and quality of life.

Upon completion of this activity, learners will demonstrate

  • Increased knowledge regarding the:
    • Disease process of bone metastases in advanced prostate cancer
    • Ongoing clinical trials in the management of advanced prostate cancer
  • Greater competence related to:
    • Implementing earlier interventions in advanced disease in order to improve patient outcomes and quality-of-life


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  • Charles Ryan, MD

    Professor of Medicine, Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California


    Disclosure: Charles Ryan, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Bayer HealthCare Pharmaceuticals; Ferring Pharmaceuticals; Xcell Biosciences
    Served as a speaker or a member of a speakers bureau for: Astellas Pharma, Inc.; Janssen Pharmaceuticals, Inc.
    Received grants for clinical research from: Karyopharm Therapeutics

    Dr Ryan does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Ryan does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


  • Neal Shore, MD

    Medical Director, Carolina Urologic Research Center, Myrtle Beach, South Carolina


    Disclosure: Neal Shore, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: AbbVie Inc.; Amgen Inc.; Astellas Pharma, Inc.; Bayer HealthCare Pharmaceuticals; Dendreon Corporation; Ferring Pharmaceuticals; Janssen Pharmaceuticals, Inc.; Medivation, Inc. ; Sanofi-Genzyme Corporation; Tolmar Pharmaceuticals, Inc.
    Received grants for clinical research from: AbbVie Inc.; Amgen Inc.; Astellas Pharma, Inc.; Bayer HealthCare Pharmaceuticals; Dendreon Corporation; Ferring Pharmaceuticals; Janssen Pharmaceuticals, Inc.; Medivation, Inc. ; Sanofi-Genzyme Corporation; Tolmar Pharmaceuticals, Inc.

    Dr Shore does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Shore does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


  • Roderick Smith, MS

    Scientific Director, Medscape, LLC


    Disclosure: Roderick Smith, MS, has disclosed no relevant financial relationships.

CME Reviewer

  • Robert Morris, PharmD

    Associate CME Clinical Director, Medscape, LLC


    Disclosure: Robert Morris, PharmD, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

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Updates and Insights on the Medical Science of Prostate Cancer


  • Biology of Bone Metastases in Prostate Cancer[4]

    • The homing of prostate cancer cells to bone is a complex process mediated by multiple pathways, ultimately resulting in the development of bone metastases

  • Slide 4.

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  • Prostate Cancer Cells Induce Bone Remodeling[5]

    • Many factors contribute to the process of bone remodeling in prostate cancer
    • Osteoclastic factors lead to the breakdown of laminar bone whereas osteoblastic factors lead to the laying down of newly woven bone
    • Although prostate cancer metastases are considered osteoblastic, the bone that is created by the metastatic interface is poor-quality

  • Slide 5.

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  • Selected Bone-Targeted Therapies in mCRPC[8]

    • Features of zoledronic acid:
      • It has many targets but generally acts by binding to bone mineral and disrupting the mevalonate pathway[9]
      • As an analog to pyrophosphate, it tends to stay in the bone for a long period of time, with a half-life of multiple years
      • It essentially disrupts the osteoclast, inhibiting the vicious cycle through which poorly woven bone is created
      • The nitrogen-containing ring makes it a little more powerful than non-nitrogen-containing bisphosphonates
    • Features of denosumab:
      • A fully human monoclonal antibody that blocks the RANKL ligand receptor
      • Similarly to zoledronic acid, it disrupts osteoclast function
    • The efficacy of these therapies validate the idea of the "seed and soil" hypothesis proposed more than 120 years ago by Stephen Paget[10]
    • Charles Ryan, MD: When we target the bone, we are not targeting the cancer; rather, we are making it a less hospitable environment for the cancer

  • Slide 7.

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  • Comparison of Antiresorptive Therapies for Bone Metastases[11-12]

    • Zoledronic acid:
      • Administered intravenously; the dose that seems most safe to avoid renal toxicity is 4 mg every 3 to 4 weeks; this is about a 15- to 30-minute infusion
      • Monitoring for renal clearance is required
      • Osteonecrosis of the jaw occurs in a small percentage of patients; the effect can be cumulative
    • Denosumab:
      • Administered subcutaneously on a monthly basis
      • Subcutaneous administration is an advantage in terms of the clinic
    • Both agents:
      • Associated with a risk for hypocalcemia that requires monitoring. Patients receiving androgen-deprivation therapy (ADT) are augmented with calcium and vitamin D supplements to prevent bone demineralization; this can become more profound with zoledronic acid and denosumab
      • Both are associated with a small incidence of osteonecrosis of the jaw (ONJ); requires an inspection for oral hygiene and monitoring
      • If patients have not visited a dentist recently (≤6 months to a year), a formal dental inspection is recommended before starting therapy

  • Slide 8.

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  • Denosumab vs Zoledronic Acid for Bone Metastases in CRPC[13]

    • A head-to-head trial showed noninferiority of denosumab vs zoledronic acid for preventing skeletal-related events (SREs)
    • The study also met its secondary endpoint, showing a significant 3-month improvement in time to first SRE with denosumab vs zoledronic acid
    • Neither agent demonstrated a survival benefit or a significant effect on time to progression

  • Slide 9.

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  • Antiresorptive Therapies: Summary[11-12,14]

    • Bone-targeting agents are designed to delay SREs but have not shown a progression-free survival (PFS) or overall survival (OS) benefit
    • Both zoledronic acid and denosumab are associated with ONJ as a cumulative toxicity effect; thus, the optimal duration of therapy is unknown
    • It is important to supplement and monitor calcium and vitamin D
    • Consider not just SRE prevention but also patients’ overall performance status

  • Slide 10.

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  • Comparison of FDA-Approved AR Inhibitors[15,16]

    • Features and considerations for abiraterone:
      • CYP17 inhibitor administered with prednisone to mitigate potential adverse events from mineralocorticoid excess
      • Taken on an empty stomach
      • Requires monitoring of potassium levels and liver function
      • A small proportion of patients can develop adrenal corticoid insufficiency
    • Features and considerations for enzalutamide:
      • Androgen receptor (AR) is directly inhibited
      • Because the drug crosses the blood-brain barrier (BBB), there is a concern regarding seizures
      • Patients with any seizure history or predisposition to seizure were excluded from clinical trials
      • Posterior reversible encephalopathy syndrome (PRES) has been noted in a small number of patients; not completely clear why it evolves, but it has to do with BBB penetration of the drug

  • Slide 11.

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  • Selecting Abiraterone vs Enzalutamide

    • There are instances in which one AR inhibitor would be preferred over the other
    • Avoid enzalutamide in patients with neurologic issues, significant fatigue, and a history of falls. Seizures are on the far end of a spectrum of central nervous system (CNS) toxicities that can occur with enzalutamide
    • Avoid abiraterone in a patient with fluid overload syndromes such as congestive heart failure (CHF) and edema; mineralocorticoid excess can lead to fluid retention issues
    • Prednisone can be problematic in some patients, including patients with diabetes; lower doses of prednisone appear to be safe,[17] although patients do require monitoring

  • Slide 12.

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  • Phase 3 Trials of Abiraterone and Enzalutamide in Chemotherapy-Naive mCRPC[18-19]

    • The phase 3 COUGAR-302 and PREVAIL trials evaluated abiraterone and enzalutamide, respectively, in patients with chemotherapy-naive mCRPC. The investigators and study sites were very comparable, and these trials accrued rapidly because of the large unmet need
    • Both studies showed an approximately 4-month improvement in median OS, with hazard ratios of approximately 0.7 with the active treatment vs placebo
    • Dr Ryan: The pre-chemotherapy population represents a broad spectrum: from completely asymptomatic patients with a low burden of metastatic disease to symptomatic patients with a higher burden of metastatic disease. Although the OS and PFS benefits of both drugs persisted across that entire spectrum, if you look at the data in aggregate for both trials, it seems to suggest we should be giving these therapies in the chemotherapy-naive setting rather than waiting for patients to have more advanced disease

  • Slide 13.

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  • ODM-201 (Darolutamide): A Novel AR Inhibitor[20-22]

    • A novel AR inhibitor now in phase 3 trials for 2 populations not yet discussed: patients with newly diagnosed hormone-sensitive metastatic prostate cancer and patients with high-risk nonmetastatic CRPC
    • Has a markedly different chemical structure than enzalutamide or apalutamide
    • Preclinical models indicate a low penetration in the BBB; this may reduce the risk for neurocognitive impairment and seizures
      • Patients with a history of or predisposition to seizures were not excluded from the phase 1/2 study
      • Study found no evidence of seizure activity; fatigue and neurocognitive impairment may also be lower than with other AR inhibitors

  • Slide 14.

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  • ARADES: Phase 1/2 Study of ODM-201 in Progressive mCRPC[21]

    • The phase 1/2 trial showed significant PSA reductions
    • Responses were somewhat blunted in patients previously treated with taxane-based therapy or abiraterone/enzalutamide
    • Dr Ryan to Dr Shore: What are your thoughts about switching from enzalutamide to abiraterone, or vice versa, upon progression, rather than switching to a drug with another mechanism of action?
    • Dr Shore: Switching from abiraterone to enzalutamide, or vice versa, generally has a short-lived benefit.[23-24] For patients with progression after abiraterone or enzalutamide, I generally offer a therapy with a completely different mechanism of action, whether it is radium-223 or a taxane-based therapy.

  • Slide 15.

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  • ARADES: Phase 1/2 Study of ODM-201 in Progressive mCRPC -- Safety[21]

    • ODM-201 toxicities were primarily fatigue and asthenia and some mild to moderate gastrointestinal symptoms
    • There was not much of a hypertension signal in contrast with the arterial-type hypertension observed with enzalutamide and the hypertension seen with abiraterone in patients with heart failure and cardiovascular disease[18-19]
    • Head-to-head comparator trials with enzalutamide, abiraterone, and ODM-201 are needed to better understand this subjective symptomatology, particularly as it relates to fatigue and cognition

  • Slide 16.

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  • ARASENS: Randomized, Double-Blind, Phase 3 Trial of ODM-201 in Hormone-Sensitive mPC[22]

    • Evaluating the use of ODM-201 in patients with hormone-sensitive metastatic prostate cancer
    • Patients are randomly assigned 2:1 to ODM-201 or placebo in addition to ADT and 6 cycles of docetaxel
    • ADT and docetaxel was selected as the backbone based on the CHAARTED and STAMPEDE trials, which showed a dramatic survival benefit with the addition of 6 cycles of docetaxel to ADT, particularly in patients with high-volume disease (higher numbers of bone lesions and/or visceral metastases)[25,26]

  • Slide 17.

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  • Ongoing Issues: Managing Nonmetastatic CRPC

    • There is currently no standard of care for patients who are receiving ADT and have a rising PSA
    • Dr Ryan to Neal Shore, MD: How you counsel these patients about their risk? Some will probably go on to die of prostate cancer and others may not
    • Dr Shore: M0 CRPC, or nonmetastatic CRPC, presents a challenge. If a patient is 85 years old and has significant comorbidities, it would probably be best just to monitor his PSA, as no one dies of a rising PSA. On the other hand, many of our patients are living a lot longer, and there is no approved therapy for this population
    • The increasing sensitivity of imaging studies is also a factor, as it is now possible to detect micrometastatic CRPC

  • Slide 18.

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  • Phase 3 Trial of Denosumab in Nonmetastatic CRPC[27]

    • This phase 3 trial that compared denosumab vs placebo in patients with M0 CRPC
    • Denosumab was associated with a significant improvement in metastasis-free survival, with a 33% improvement in time to symptomatic bone metastasis (hazard ratio [HR] = 0.67 [95% confidence interval (CI): 0.49, 0.92]; P = .01); there was no difference in PFS or OS, however, there was between denosumab and placebo

  • Slide 19.

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  • Phase 3 Trial of Denosumab in Nonmetastatic CRPC: Results by PSADT[28]

    • A subset analysis showed a greater benefit with denosumab in patients with a rapid PSA doubling time: a median delay in bone metastasis-free survival of approximately 7 months in patients with a PSA doubling time of up to 6 months
    • Although the primary endpoint was met, denosumab did not receive US Food and Drug Administration (FDA) approval for this indication because of the risk for ONJ and the lack of benefit in survival or progression

  • Slide 20.

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  • PROSPER: Randomized, Double-Blind, Phase 3 Trial of Enzalutamide in Nonmetastatic CRPC[29]

    • In contrast to denosumab, enzalutamide is an antitumor therapy; it is also being evaluated in patients with nonmetastatic CRPC
    • The phase 3 PROSPER trial has completed accrual, and results are awaited

  • Slide 21.

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  • SPARTAN: Randomized, Double-Blind, Phase 3 Trial of Apalutamide in Nonmetastatic CRPC[30]

    • Apalutamide is a novel AR antagonist that has demonstrated safety and efficacy in nonmetastatic CRPC[31]
    • The phase 3 SPARTAN trial is evaluating apalutamide in the nonmetastatic CRPC setting and is still accruing

  • Slide 22.

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  • ARAMIS: Randomized, Double-Blind, Phase 3 Trial of ODM-201 in High-Risk Nonmetastatic CRPC[32]

    • The global phase 3 ARAMIS trial is evaluating ODM-201 vs placebo in a 2:1 randomization in 1500 patients with M0 CRPC

  • Slide 23.

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  • Radium-223: A Novel Radioisotope[33]

    • Radium-223 is the most recent therapy to receive approval in mCRPC based on an OS benefit
    • Radiotherapy has been used in the treatment of CRPC for decades; radium-223 differs from other radiopharmaceuticals in that it emits α particles
    • Prior radiopharmaceuticals including β and γ particles never showed a survival benefit in phase 3 trials; moreover, they caused more myelosuppression because their smaller particle size allowed them to penetrate the bone marrow
    • Alpha particles are larger but have a more shallow depth of penetration into the cortical bone, creating an apoptotic effect on metastatic cancer cells and disrupting the bone milieu

  • Slide 24.

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  • ALSYMPCA: Randomized, Phase 3 Trial of Radium-223 in Symptomatic mCRPC[34]

    • The phase 3 ALSYMPCA trial compared radium-223 to placebo in a CRPC population that included patients both before and after they were treated with chemotherapy
    • Patients were symptomatic but represented a wide continuum of symptomatology: from patients receiving only acetaminophen to patients requiring morphine patches
    • Radium-223 was associated with a 3.6-month median OS benefit
    • Dr Ryan to Dr Shore: Do you think we should continue zoledronic acid if we are using radium-223? What do you think about using antiresorptive therapies in patients who have already received abiraterone or enzalutamide?
    • Dr Shore: Denosumab was not approved while the ALSYPMCA trial was being conducted; however, zoledronic acid was available, and patients were stratified based on zoledronic acid use. There were no untoward safety signals seen with the combination, and actually there was a signal that the patients receiving the combination therapy had a delay in symptomatic skeletal events

  • Slide 25.

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  • Phase 3b Expanded Access Trial of Radium-223[35]

    • Information about the combination of radium-223 and denosumab comes from the radium-223 expanded access program, although this was a retrospective analysis
    • Showed a potential survival benefit and a delay in symptomatic skeletal events with combination therapy; prospective trials are needed
    • No untoward safety signals with these combinations
    • Dr Ryan: The data suggest that radium-223 can safely be combined with denosumab, zoledronic acid, abiraterone, and enzalutamide
      • There has been some concern regarding the combination of radium-223 and docetaxel; however, a phase 1/2 trial showed that radium-223 and docetaxel could be effectively combined at a lower docetaxel dose of 60 mg/m2 rather than the standard 75 mg/m2.[36] This will require more prospective study

  • Slide 26.

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  • ALSYMPCA Subgroup Analysis According to Prior Docetaxel[37]

    • Early after its FDA approval, radium-223 was typically used in patients post-docetaxel; today, in contrast, most patients receiving radium-223 are docetaxel-naive
    • In a post-hoc analysis of the ALSYMPCA trial, there was a median OS benefit of 4.6 months with the use of radium-223 before docetaxel and a 3.1-month benefit pre-docetaxel
    • Dr Shore: It is important that patients receive the full courses of both radium-223 and docetaxel (5-6 infusions); a key aspect of treatment planning is to find the window of opportunity to ensure the patient is fit for chemotherapy and that they first receive a full course of radium-223 for bone-predominant disease

  • Slide 27.

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  • CA184-043: Phase 3 Trial of Ipilimumab After Docetaxel in mCRPC[38]

    • Dr Ryan: There is great interest in immunotherapies in prostate cancer; many of my patients are asking about them
    • There is one immunotherapy used in the treatment of mCRPC, sipuleucel-T, which received FDA approval in 2010, making it the first immunotherapy to be approved in any metastatic solid tumor[39]
    • With regard to the checkpoint inhibitors, ipilimumab has been evaluated in several trials, but these have not met their primary endpoints[40]
      • It is possible that the ipilimumab dosage was too high for this setting as there was substantially more toxicity

  • Slide 28.

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  • Phase 1 Trial of Tremelimumab + Short-Term ADT in PSA-Recurrent Prostate Cancer[41]

    • Another cytoxic T lymphocyte-associated protein 4 (CTLA-4) blocker, tremelimumab, is also being evaluated and early evidence suggests it may have a better safety profile than ipilimumab

  • Slide 29.

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  • Phase 2 Trial of Pembrolizumab in mCRPC Post-Enzalutamide[42]

    • A small phase 2 study evaluated the checkpoint inhibitor pembrolizumab in patients with mCRPC who had disease progression on enzalutamide
    • Responses to pembrolizumab were observed in a small number of patients with heavily mutated cancers; these may represent only a small fraction of the CRPC population (1%-3%)

  • Slide 30.

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  • Phase 2 Study of Olaparib in mCRPC[43]

    • Olaparib is a PARP inhibitor FDA-approved for treatment of patients with BRCA-mutated advanced ovarian cancer who have previously received 3 or more chemotherapy regimens[44]
    • Evaluated in a phase 2 study in patients with mCRPC
    • In patients with heavily pretreated mCRPC, defects in certain DNA repair mechanism genes, including BRCA2, were associated with exquisite sensitivity to PARP inhibition
    • Other PARP inhibitors (ie, rucaparib, niraparib) are also being evaluated in mCRPC[45-46]

  • Slide 31.

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  • This content has been condensed for improved clarity.


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