American Urological Association - Castration-Resistant Prostate Cancer

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Home Guidelines Clinical Guidelines Castration-Resistant Prostate Cancer (2013; Amended 2015)

Castration-Resistant Prostate Cancer

Published 2013; Amended 2015

Unabridged version of this Guideline [pdf]
Appendix A: ECOG Performance Status [pdf]
Appendix B: Summary Flowchart [pdf]

Note to the Reader:

On July 21, 2014, the FDA issued a recommendation that health care professionals should consider the alcohol content of docetaxel when prescribing or administering the drug to patients.

On July 26, 2013, the FDA issued a safety announcement related to the use of ketoconazole in the form of oral tablets. Side effects can include hepatotoxicity,adrenal insufficiency and dangerous drug interactions.

This document was amended in April 2014 and March 2015 to reflect literature that was released since the original publication of this guideline in May 2013. This document will continue to be periodically updated toreflect the growing body of literature related to this disease.

Panel Members

Michael S. Cookson, Bruce J. Roth, Philipp Dahm, Christine Engstrom, Stephen J. Freedland, Maha Hussain, Daniel W. Lin, William T. Lowrance, Mohammad Hassan Murad, William K. Oh, David F. Penson and Adam S. Kibel

Executive Summary

Note to the Reader:

On July 21, 2014, the FDA issued a recommendation that health care professionals should consider the alcohol content of docetaxel when prescribing or administering the drug to patients.

On July 26, 2013, the FDA issued a safety announcement related to the use of ketoconazole in the form of oral tablets. Side effects can include hepatotoxicity, adrenal insufficiency and dangerous drug interactions.

This document was amended in April 2014 and March 2015 to reflect literature that was released since the original publication of this guideline in May 2013. This document will continue to be periodically updated to reflect the growing body of literature related to this disease.

Purpose

As a direct result of the significant increase in multiple FDA-approved therapeutic agents for use in patients with metastatic castration-resistant prostate cancer (CRPC), clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision-making more complex. To assist in clinical decision-making, six index patients were developed representing the most common clinical scenarios that are encountered in clinical practice. With these patients in mind, guideline statements were developed to provide a rational basis for treatment based on currently available published data.

Methodology

A systematic review and meta-analysis of the published literature was conducted using controlled vocabulary supplemented with keywords relating to the relevant concepts of prostate cancer and castration resistance. The original search strategy was developed and executed by reference librarians and methodologists to create a final evidence report limited to English-language, peer-reviewed literature published between January 1996 and February 2013. This review yielded 303 articles, which were used to inform the statements presented in the guideline as Standards, Recommendations or Options. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate) or C (low). In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. In April 2014, the CRPC guideline underwent amendment based on an additional literature search, which retrieved additional studies published between February 2013 and February 2014. Thirty-seven studies from this search provided data relevant to the specific treatment modalities for CRPC. In March 2015, the CRPC guideline underwent a second amendment, which incorporated 10 additional studies into the evidence base published through February 2015.

Guideline Statements

Index Patient 1

1. Clinicians should recommend observation with continued androgen deprivation to patients with non-metastatic CRPC. (Recommendation; Evidence Level Grade C)

2. Clinicians may offer treatment with first- generation anti-androgens (flutamide, bicalutamide and nilutamide) or first generation androgen synthesis inhibitors (ketoconazole+steroid) to select patients with non-metastatic CRPC who are unwilling to accept observation. (Option; Evidence Level Grade C)

3. Clinicians should not offer systemic chemotherapy or immunotherapy to patients with non-metastatic CRPC outside the context of a clinical trial. (Recommendation; Evidence Level Grade C)

Index Patient 2

4. Clinicians should offer abiraterone + prednisone, enzalutamide, docetaxel, or sipuleucel-T to patients with asymptomatic or minimally symptomatic mCRPC with good performance status and no prior docetaxel chemotherapy. [Standard; Evidence Level Grade A (abiraterone + prednisone and enzalutamide)/B (docetaxel and sipuleucel-T)]

5. Clinicians may offer first- generation anti-androgen therapy, ketoconazole + steroid or observation to patients with asymptomatic or minimally symptomatic mCRPC with good performance status and no prior docetaxel chemotherapy who do not want or cannot have one of the standard therapies. (Option; Evidence Level Grade C)

Index Patient 3

6. Clinicians should offer abiraterone + prednisone, enzalutamide or docetaxel to patients with symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy. [Standard; Evidence Level Grade A (abiraterone + prednisone and enzalutamide/ B (docetaxel)]

7. Clinicians may offer ketoconazole + steroid, mitoxantrone or radionuclide therapy to patients with symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy who do not want or cannot have one of the standard therapies. [Option; Evidence Level Grade C (ketoconazole) /B (mitoxantrone) / C (radionuclide therapy)]

8. Clinicians should offer radium-223 to patients with symptoms from bony metastases from mCRPC with good performance status and no prior docetaxel chemotherapy and without known visceral disease. (Standard; Evidence Level Grade B)

9. Clinicians should not offer treatment with either estramustine or sipuleucel-T to patients with symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy. (Recommendation; Evidence Level Grade C)

Index Patient 4

10. Clinicians may offer treatment with abiraterone + prednisone or enzalutamide to patients with symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy. (Option; Evidence Level Grade C)

11. Clinicians may offer treatment with ketoconazole+ steroid or radionuclide therapy to patients with symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy who are unable or unwilling to receive abiraterone + prednisone or enzalutamide. (Option; Evidence Level Grade C)

12. Clinicians may offer docetaxel or mitoxantrone chemotherapy to patients with symptomatic mCRPC with poor performance status and no prior docetaxel chemotherapy in select cases, specifically when the performance status is directly related to the cancer. (Expert Opinion)

13. Clinicians may offer radium-223 to patients with symptoms from bony metastases from mCRPC with poor performance status and no prior docetaxel chemotherapy and without known visceral disease in select cases, specifically when the performance status is directly related to symptoms related to bone metastases. (Expert Opinion)

14. Clinicians should not offer sipuleucel-T to patients with symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy. (Recommendation; Evidence Level Grade C)

Index Patient 5

15. Clinicians should offer treatment with abiraterone + prednisone, cabazitaxel or enzalutamide to patients with mCRPC with good performance status who received prior docetaxel chemotherapy. If the patient received abiraterone + prednisone prior to docetaxel chemotherapy, they should be offered cabazitaxel or enzalutamide. [Standard; Evidence Level Grade A (abiraterone) / B (cabazitaxel)/ A (enzalutamide)]

16. Clinicians may offer ketoconazole + steroid to patients with mCRPC with good performance status who received prior docetaxel if abiraterone + prednisone, cabazitaxel or enzalutamide is unavailable. (Option; Evidence Level Grade C)

17. Clinicians may offer retreatment with docetaxel to patients with mCRPC with good performance status who were benefitting at the time of discontinuation (due to reversible side effects) of docetaxel chemotherapy. (Option; Evidence Level Grade C)

18. Clinicians should offer radium-223 to patients with symptoms from bony metastases from mCRPC with good performance status who received prior docetaxel chemotherapy and without known visceral disease. (Standard; Evidence Level Grade B)

Index Patient 6

19. Clinicians should offer palliative care to patients with mCRPC with poor performance status who received prior docetaxel chemotherapy. Alternatively, for selected patients, clinicians may offer treatment with abiraterone + prednisone, enzalutamide, ketoconazole + steroid or radionuclide therapy. (Expert Opinion)

20. Clinicians should not offer systemic chemotherapy or immunotherapy to patients with mCRPC with poor performance status who received prior docetaxel chemotherapy. (Expert Opinion)

Bone Health

21. Clinicians should offer preventative treatment (e.g. supplemental calcium, vitamin D) for fractures and skeletal related events to CRPC patients. (Recommendation; Evidence Level Grade C)

22. Clinicians may choose either denosumab or zoledronic acid when selecting a preventative treatment for skeletal related events for mCRPC patients with bony metastases. (Option; Evidence Level Grade C)

Introduction

Incidence and Epidemiology

Prostate cancer is the most commonly diagnosed solid organ malignancy in the United States (US) and remains the second leading cause of cancer deaths among American men. Approximately 240,000 new diagnoses of prostate cancer and over 28,000 deaths were estimated in the US in 2012.1 Prostate cancer deaths are typically the result of metastatic castration-resistant prostate cancer (mCRPC), and historically the median survival for men with mCRPC has been less than two years. The recent availability of novel treatments for mCRPC has given a resurgence of hope for these men as studies now demonstrate improved survival with a variety of new agents. However, the unfortunate reality is that mCRPC remains an incurable disease, and it is against this backdrop that we look to the future with cautious optimism and new hope for scientific discovery.

The exact mechanism of transition from castration-sensitive prostate cancer to castration-resistant disease is still not fully understood, but with recent scientific breakthroughs in basic research, there is now a greater understanding. We now know that despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive prostate cancer progression.2, 3 This understanding has led to the development of novel agents aimed at further decreasing androgen production or blocking AR function. However, there are also many other biologic pathways that function independent of androgen signaling resulting in CRPC. With a greater understanding of the tumor biology, there is hope for continued development of innovative treatment options that improve survival for men with mCRPC.

The treatment of men with mCRPC has dramatically changed over the past decade. Prior to 2004, once patients failed primary androgen deprivation, treatments were administered solely for palliation. Landmark articles by Tannock et al.4 and Petrylak et al.5 demonstrated that docetaxel improved survival for these patients with mCRPC. Since the approval of docetaxel, five additional agents that show a survival benefit have been FDA-approved on the basis of randomized clinical trials. These have included enzalutamide and abiraterone, two agents designed specifically to affect the androgen axis;6, 7 sipuleucel-T, which stimulates the immune system;8 cabazitaxel, a chemotherapeutic agent;9 and radium-223, a radionuclide therapy.10 These agents have been tested in multiple "disease states" of CRPC to determine if or when patients might benefit from each treatment. Other treatments for men with mCRPC have been shown to improve outcomes, but remain to be approved by the FDA.11

Purpose

As a direct result of the significant increase in multiple FDA-approved therapeutic agents for use in patients with mCRPC, clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision-making more complex. These Guidelines were developed to provide a rational basis for treatment of patients with CRPC, based on currently available published data. To assist in clinical decision-making, six index patients were developed representing the most common clinical scenarios that are encountered in clinical practice. These index patients were created based on the presence or absence of metastatic disease, the degree of symptoms, the patients' performance status (as defined by the ECOG scale) and the prior treatment with docetaxel-based chemotherapy.

  1. Asymptomatic non-metastatic CRPC
  2. Asymptomatic or minimally-symptomatic, mCRPC without prior docetaxel chemotherapy
  3. Symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy
  4. Symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy
  5. Symptomatic, mCRPC with good performance status and prior docetaxel chemotherapy
  6. Symptomatic, mCRPC with poor performance status and prior docetaxel chemotherapy

Once index patients were developed, the literature was reviewed using the protocol described in the methodology section of this document.

The goal of this Guideline is to provide evidence based recommendations for the treatment of CRPC. Given that this is a rapidly evolving field, this guideline should be used in conjunction with recent systematic literature reviews and an understanding of the individual patient's treatment goals. In all cases, the patient's preferences and personal goals should be considered when choosing therapy. Although we are discussing castration-resistant disease, we support the standard of care to maintain castrate testosterone levels even in the face of castration-resistant disease. A flowchart summarizing the guideline statements of this document can be found in Appendix B.

Methodology

Process for Initial Literature Selection. Consistent with the AUA published guideline methodology framework,12 the process started by conducting a comprehensive systematic review. The AUA commissioned an independent group to conduct a systematic review and meta-analysis of the published literature on various therapies for CRPC. The protocol of the systematic review was developed a priori by the methodology team in conjunction with the expert panel. The search strategy was developed and executed by reference librarians and methodologists and spanned across multiple databases including Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials and Scopus. The evidence report was limited to English-language, peer-reviewed literature published between January 1996 and February 2013. Controlled vocabulary supplemented with keywords was used to search for the relevant concepts of prostate cancer and castration resistance (biochemical recurrence with a rising PSA and/or progression of disease by radiographic criteria despite a castrate testosterone level). An expert panel manually identified additional references to supplement the electronic search, which were required to meet the same criteria as the previously used studies.

The search strategy focused on commonly used as well as experimental therapies including systemic chemotherapy (estramustine, mitoxantrone, docetaxel, cabazitaxel), immunotherapy (sipuleucel-T) and vaccine therapy, agents targeting the androgen signaling pathway (abiraterone, ketoconazole, corticosteroids, antiandrogens), radiotherapy and radiopharmaceuticals (Strontium-89 [Metastron®], Samarium- 153 [Quadramet®]), antiandrogen withdrawal, bone targeted therapies (zoledronic acid, denosumab), enzalutamide [androgen receptor inhibitor], palliative care and experimental therapy, (TAK700 [CYP-17 inhibitor], cabozantanib [cMET/VEGFR inhibitor], Radium-223 [Alpharadin®]).

The outcomes of interest were a priori determined by the panel based on their respective importance to patients, recognizing that some of these endpoints are surrogates for the patients and included overall survival (OS), progression-free survival (PFS), metastasis-free survival, PSA PFS, PSA decline, measurable disease response, adverse events/side-effects of treatment, quality of life (QOL), skeletal-related events (SREs), pain-free survival, and pain response.

The methodology team independently rated the methodological quality of the studies and provided an overall judgment of the whole body of evidence based on confidence in the available estimates of effect.

The methodology team summarized the data with explicit description of study characteristics, methodological quality, main findings and the quality of the evidence (confidence in the estimates). The methodology team attended panel meetings and facilitated incorporation of the evidence into the guideline.

Quality of Individual Studies and Determination of Evidence Strength. The systematic review included 303 eligible studies that addressed the pre-identified questions of interest. A large body of evidence evaluated established chemotherapy agents such as docetaxel [19 Randomized controlled trials (RCTs)], estramustine (5 RCTs) and mitoxantrone (5 RCTs). Randomized evidence was also available for various immunotherapies (8 RCTs), therapies targeting the androgen signaling pathway (12 RCTs), radiotherapy and radiopharmaceuticals (4 RCTs) and bone-targeting therapies (6 RCTs). The quality of these trials was acceptable overall and ranged from moderate to low risk of bias. All the remaining studies were otherwise non-randomized (observational) and considered to be at high risk of bias.

The quality of the evidence (confidence in the estimates) was limited in many studies by indirectness. Indirectness occurs when studies use surrogate endpoints that depend on laboratory or radiographic measurements (PSA free survival, PSA decline or PFS based on imaging).13 These outcomes usually are surrogates for other important patient outcomes more essential for decision making, such as mortality, pain and QOL. Imprecision (wide confidence intervals due to small number of events) was also common in most CRPC trials and can lower the confidence in the provided estimates.

Limitations of the Literature. The systematic review and guideline process identified clear gaps in the available evidence base. None of the therapies identified in this review were curative or resulted in long term remission. Therefore, primary research on new agents is clearly needed for this important and common condition. Future trials should also use and incorporate patient reported outcomes, such as QOL and pain control. The current evidence base suffers from imprecision that can be overcome by multi-site RCT collaboration or prospective (pre-planned) meta-analyses.

Guideline Amendment. In April 2014 and March 2015, the CRPC guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines in an effort to maintain currency. The amendments allowed for the incorporation of additional literature released since the initial publication of this guideline in 2013. Comprehensive searches of several databases from February 2013 to February 2014 (2014 amendment) and February 2014 to February 2015 (2015 amendment), English language, were conducted. The search strategy was designed and conducted by an experienced librarian with input from the study's principle investigator. Controlled vocabulary supplemented with keywords was used to search for studies on therapy for CRPC.

The 2014 search yielded 998 references, of which 662 were excluded after duplicate abstract and title review. Full text was retrieved for the 336 included studies. Eventually, 37 studies provided relevant data on the specific treatment modalities for CRPC. The resulting amendment focused on the incorporation of literature relevant to the use of radium-223 in the treatment of men with mCRPC.

The 2015 search yielded 1,150 references, of which 1,090 were excluded after duplicate abstract and title review. Full texts were retrieved for 60 included studies. Eventually, 10 studies (published in 14 manuscripts) provided relevant data on the specific treatment modalities for CRPC. The resulting amendment focused on the incorporation of additional information on the use of enzalutamide in chemo-naïve patients as well as the use of abiraterone + prednisone.

AUA Nomenclature: Linking Statement Type to Evidence Strength. The AUA nomenclature system explicitly links statement type to body of evidence strength and the Panel's judgment regarding the balance between benefits and risks/burdens (see Table 1).12 The framework of rating the quality of evidence is an adaptation and modification12 of the GRADE framework (Grading of Recommendations, Assessment, Development and Evaluation).13, 14 In this adaptation, the AUA rates the quality of evidence as high, moderate or low (A, B or C). Standards are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken based on Grade A or Grade B evidence. Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken based on Grade C evidence. Options are non-directive statements that leave the decision to take an action up to the individual clinician and patient because the balance between benefits and risks/burdens appears relatively equal or appears unclear; Options may be supported by Grade A, B or C evidence. It is important to note that grading (A, B or C) does not reflect the magnitude of a potential benefit or harm, but is instead related to the methodological review of the study. For some clinical issues, there was little or no evidence from which to construct evidence-based statements. Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinions with consensus achieved using a modified Delphi technique if differences of opinion existed among Panel members.15 A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge and judgment and for which there is no evidence. The completed evidence report may be requested through AUA.

Table 1: AUA Nomenclature
Linking Statement Type to Evidence Strength

Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A or B evidence
Recommendation: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade C evidence
Option: Non-directive statement that leaves the decision regarding an action up to the individual clinician and patient because the balance between benefits and risks/burdens appears equal or appears uncertain based on Grade A, B, or C evidence
Clinical Principle: a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature
Expert Opinion: a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence

Panel Selection and Peer Review Process. The Panel was created by the American Urological Association Education and Research, Inc. (AUA). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chair and Vice Chair who in turn appointed the additional panel members, all of whom have specific expertise with regard to the guideline subject to include both urologists and medical oncologists.

Once nominated, panel members are asked to record their conflict of interest (COI) statements, providing specific details on the AUA interactive web site. These details are first reviewed by the Guidelines Oversight Committee (GOC), a member sub-committee from the PGC consisting of the Vice Chair of the PGC and two other members. The GOC determines whether the individual has potential conflicts related to the guideline. If there are no conflicts, then the nominee's COI is reviewed and approved by the AUA Judicial and Ethics (J&E) committee. A majority of panel members may not have relationships relevant to the guideline topic.

The AUA conducted an extensive peer review process. The initial draft of this Guideline was distributed to 56 peer reviewers of varying backgrounds; 30 responded with comments. The panel reviewed and discussed all submitted comments and revised the draft as needed. Once finalized, the Guideline was submitted for approval to the PGC. It was then submitted to the AUA Board of Directors for final approval. Funding of the panel was provided by the AUA. Panel members received no remuneration for their work.

Index Patient 1: Asymptomatic non-metastatic CRPC

One of the first clinical presentations of CRPC occurs in a patient with a rising PSA despite medical or surgical castration. This is typically defined as a patient with a rising PSA and no radiologic evidence of metastatic prostate cancer. The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) defines PSA only failure as a rising PSA that is greater than 2ng/mL higher than the nadir; the rise has to be at least 25% over nadir and the rise has to be confirmed by a second PSA at least three weeks later. In addition, the patient is required to have castrate levels of testosterone (less than 50 ng/mL) and no radiographic evidence of metastatic disease.16 These patients represent a relatively common clinical presentation and the earliest clinical manifestation of castration resistance, but to date, there are no randomized trials showing an OS benefit in this patient population from a particular form of treatment.

Guideline Statement 1

Clinicians should recommend observation with continued androgen deprivation to patients with non-metastatic CRPC. (Recommendation; Evidence Level Grade C)

Discussion


Guideline Statement 2

Clinicians may offer treatment with first- generation anti-androgens (flutamide, bicalutamide and nilutamide) or first generation androgen synthesis inhibitors (ketoconazole+steroid) to select patients with non-metastatic CRPC who are unwilling to accept observation. (Option; Evidence Level Grade C)

Discussion


Guideline Statement 3

Clinicians should not offer systemic chemotherapy or immunotherapy to patients with non-metastatic CRPC outside the context of a clinical trial. (Recommendation; Evidence Level Grade C)

Discussion


Index Patient 2: Asymptomatic or minimally symptomatic, mCRPC without prior docetaxel chemotherapy

This patient represents a common clinical presentation seen in the CRPC setting today. These patients are characterized as having a rising PSA in the setting of castrate levels of testosterone, documented metastatic disease on radiographic imaging and no prior treatment with docetaxel chemotherapy for CRPC. The key distinction between this patient and Index Patients 3 and 4 is symptom status. Specifically, this patient is defined as having no symptoms or mild symptoms attributable to his prostate cancer. However, one must then consider whether the patient requires regular opioid pain medications for symptoms thought to be attributable to documented metastases to achieve this level of pain control. In general, if patients require regular narcotic medications for pain relief, they are not included in this category. Acknowledging these important definitions, the panel makes the following guidelines statements:

Guideline Statement 4

Clinicians should offer abiraterone + prednisone, enzalutamide, docetaxel, or sipuleucel-T to patients with asymptomatic or minimally symptomatic mCRPC with good performance status and no prior docetaxel chemotherapy. [Standard; Evidence Level Grade A (abiraterone + prednisone and enzalutamide)/B (docetaxel and sipuleucel-T)]

Discussion


Guideline Statement 5

Clinicians may offer first- generation anti-androgen therapy, ketoconazole + steroid or observation to patients with asymptomatic or minimally symptomatic mCRPC with good performance status and no prior docetaxel chemotherapy who do not want or cannot have one of the standard therapies. (Option; Evidence Level Grade C)

Discussion


Index Patient 3: Symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy

These patients have a rising PSA in the setting of castrate levels of testosterone, documented symptomatic metastatic disease on radiographic imaging and no prior history of docetaxel chemotherapy for prostate cancer. The definition of symptomatic disease warrants additional explanation to contrast with Index Patient 2. First, the patient must have symptoms that are clearly attributable to the metastatic disease burden, not any other medical condition. Second, if having pain, the patient should require regular opiate pain medications for symptoms attributable to documented metastases in order to achieve an acceptable level of pain control. If patients require regular narcotic medications for pain relief, then they are symptomatic from their prostate cancer and should be included in this category.

Guideline Statement 6

Clinicians should offer abiraterone + prednisone, enzalutamide or docetaxel to patients with symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy. [Standard; Evidence Level Grade A (abiraterone + prednisone and enzalutamide)/ B (docetaxel)]

Discussion


Guideline Statement 7

Clinicians may offer ketoconazole + steroid, mitoxantrone or radionuclide therapy to patients with symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy who do not want or cannot have one of the standard therapies. [Option; Evidence Level Grade C (ketoconazole) /B (mitoxantrone) / C (radionuclide therapy)]

Discussion


Guideline Statement 8

Clinicians should offer radium-223 to patients with symptoms from bony metastases from mCRPC with good performance status and no prior docetaxel chemotherapy and without known visceral disease. (Standard; Evidence Level Grade B)

Discussion


Guideline Statement 9

Clinicians should not offer treatment with either estramustine or sipuleucel-T to patients with symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy. (Recommendation; Evidence Level Grade C)

Discussion


Index Patient 4: Symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy

Clinical trials have generally excluded patients with a poor performance status (ECOG 3-4) from participation. Thus, most data regarding management of such patients is extrapolated from randomized trials of eligible patients who had a better performance status, as well as from some smaller trials and registries. Even a phase III clinical trial that was presumptively designed for a population considered "unfit" for docetaxel (ALSYMPCA to evaluate radium-223) still only allowed a performance status of ECOG 0-1. However, treatments with acceptable safety profiles do exist and should be considered, even in poor performance status patients. This is especially true in those patients in whom the poor performance status may be considered to be directly related to the cancer itself and thus whose status might improve with effective treatment. Treatments must be individually tailored in these patients after a careful discussion of risks and benefits with particular attention to patient QOL.

Guideline Statement 10

Clinicians may offer treatment with abiraterone + prednisone or enzalutamide to patients with symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy. (Option; Evidence Level Grade C)

Discussion


Guideline Statement 11

Clinicians may offer treatment with ketoconazole+ steroid or radionuclide therapy to patients with symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy who are unable or unwilling to receive abiraterone + prednisone or enzalutamide. (Option; Evidence Level Grade C)

Discussion


Guideline Statement 12

Clinicians may offer docetaxel or mitoxantrone chemotherapy to patients with symptomatic mCRPC with poor performance status and no prior docetaxel chemotherapy in select cases, specifically when the performance status is directly related to the cancer. (Expert Opinion)

Discussion


Guideline Statement 13

Clinicians may offer radium-223 to patients with symptoms from bony metastases from mCRPC with poor performance status and no prior docetaxel chemotherapy and without known visceral disease in select cases, specifically when the performance status is directly related to symptoms related to bone metastases. (Expert Opinion)

Discussion


Guideline Statement 14

Clinicians should not offer sipuleucel-T to patients with symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy. (Recommendation; Evidence Level Grade C)

Discussion


Index Patient 5: Symptomatic, mCRPC with good performance status and prior docetaxel chemotherapy

As patients with prostate cancer receive hormonal therapy earlier in the course of the disease (frequently for non-metastatic disease), they may actually develop castration-resistant disease (based on serologic progression) with non-metastatic or asymptomatic metastatic disease. Thus, additional agents, including docetaxel chemotherapy may be administered earlier in the course of metastatic disease. These trends have resulted in a population of mCRPC patients who have completed docetaxel and may continue to be asymptomatic or minimally-symptomatic with an excellent performance status. While such patients may be healthy enough to receive a number of subsequent therapies, a focus of therapy should also be to maintain their excellent performance status without significant toxicity from additional therapy. It is in this context that providers should choose from a number of additional therapies to offer to this patient population.

Guideline Statement 15

Clinicians should offer treatment with abiraterone + prednisone, cabazitaxel or enzalutamide to patients with mCRPC with good performance status who received prior docetaxel chemotherapy. If the patient received abiraterone + prednisone prior to docetaxel chemotherapy, they should be offered cabazitaxel or enzalutamide. [Standard; Evidence Level Grade A (abiraterone) / B (cabazitaxel)/ A (enzalutamide)]

Discussion


Guideline Statement 16

Clinicians may offer ketoconazole + steroid to patients with mCRPC with good performance status who received prior docetaxel if abiraterone + prednisone, cabazitaxel or enzalutamide is unavailable. (Option; Evidence Level Grade C)

Discussion


Guideline Statement 17

Clinicians may offer retreatment with docetaxel to patients with mCRPC with good performance status who were benefitting at the time of discontinuation (due to reversible side effects) of docetaxel chemotherapy. (Option; Evidence Level Grade C)

Discussion


Guideline Statement 18

Clinicians should offer radium-223 to patients with symptoms from bony metastases from mCRPC with good performance status who received prior docetaxel chemotherapy and without known visceral disease. (Standard; Evidence Level Grade B)

Discussion


Index Patient 6: Symptomatic, mCRPC with poor performance status and prior docetaxel chemotherapy

The American Society of Clinical Oncology (ASCO) has posted recommendations regarding treatment for patients with advanced solid tumors; particularly in the last months of life. ASCO advocates for an increasing emphasis on a patient's QOL and concentrates on symptom management. Treatment given in the last months of life may delay access to end of life care, increase costs and add unnecessary symptom management. Patients with poor performance status (ECOG 3 or 4) should not be offered further treatment.

Guideline Statement 19

Clinicians should offer palliative care to patients with mCRPC with poor performance status who received prior docetaxel chemotherapy. Alternatively, for selected patients, clinicians may offer treatment with abiraterone + prednisone, enzalutamide, ketoconazole + steroid or radionuclide therapy. (Expert Opinion)

Discussion


Guideline Statement 20

Clinicians should not offer systemic chemotherapy or immunotherapy to patients with mCRPC with poor performance status who received prior docetaxel chemotherapy. (Expert Opinion)

Discussion


Guideline Statements on Bone Health (not specific to any one index patient)

Several factors conspire to place the average patient with metastatic prostate cancer at a higher risk of bone complications. First, the median age of onset of the disease is in the late 60s, meaning that the average patient with metastatic disease may be in the 70s (or beyond), clearly a population at risk of physiologic, age-related decreases in bone mineral density. Secondly, a primary therapeutic intervention in patients with recurrent disease, ADT, is associated with progressive loss of bone mineral density, not infrequently to the point of measurable osteopenia or frank osteoporosis, increasing the patient's fracture risk, even in patients with non-metastatic disease.63,64 Finally, in patients with advanced disease, bones are the most common site of metastatic disease, with as many as 70% of patients at some point in their course demonstrating evidence of disease in this site.

Guideline Statement 21

Clinicians should offer preventative treatment (e.g. supplemental calcium, vitamin D) for fractures and skeletal related events to CRPC patients. (Recommendation; Evidence Level Grade C)

Discussion


Guideline Statement 22

Clinicians may choose either denosumab or zoledronic acid when selecting a preventative treatment for skeletal related events for mCRPC patients with bony metastases. (Option; Evidence Level Grade C)

Discussion


Future Directions

Over the past 15 years there has been un-paralleled scientific progress and investment in drug development for patients with mCRPC. As a direct result of these studies, several lines of systemic therapies have been FDA approved for use in mCRPC on grounds of pain palliation, minimizing disease adverse effects and prolonging survival.

Ongoing Research. In addition to agents discussed above, several other drugs are in the pipeline:

Ongoing Phase III trials as of guideline publication:

Tasquinomod: Tasquinomod is an orally active quinoline-3-carboxamide. It has anti-angiogenic and anti-tumor properties and is currently in ongoing phase III testing to assess men with bone-metastatic disease to assess its impact on survival (NCT01234311).

Immunotherapy: Novel vaccine strategies to harness the immune system are being tested, such as PROSTVAC in asymptomatic, chemotherapy-naïve men with mCRPC in a phase III study randomizing participants to PROSTVAC with or without GM-CSF or to placebo (NCT01322490). Other immune based strategies include inhibition of immune check points using Ipilimumab, which is a monoclonal anti-CTLA4 antibody that binds to the CTLA-4 receptor on T cells, blocking CTLA4 and, in turn, activating T-cell anti-tumor activity. A phase III study comparing ipilimumab to placebo is ongoing (NCT01057810).

Custirsen: Custirsen inhibits the production of clusterin, a protein associated with treatment resistance in a number of cancers, including prostate cancer. Adding agents with novel or different mechanisms of action to a docetaxel-backbone remains an area of significant interest. Results are pending from the phase III trials combining docetaxel + prednisone with custirsen, (NCT01188187), and another phase III trial was recently activated comparing cabazitaxel + prednisone with or without custirsen (NCT01578655).

Future Research. The impact on survival in mCRPC from each of these individual agents thus far continues to be modest, being measured only in months. To further impact outcomes therapy, development in this stage of disease must focus on the totality of disease biology integrating a comprehensive molecular understanding of castration resistance and investigating mechanisms of resistance to current therapies so as to better guide future treatment development. Continued investments in discovery, investigation and validation of important new candidate targets is needed.

One of the glaring deficiencies in prostate cancer drug development, by comparison to several other solid tumors, has been the lack of predictive biomarkers to help better personalize therapy. This is especially important if we are to optimize risk/benefit, particularly given that a significant percentage of patients do not benefit or have small benefits from current FDA approved agents.

In addition to the continued investigation of new agents in the mCRPC population, it is critical that we prospectively define the optimal sequence of approved treatments in order to guide proper use taking into account efficacy and cost-effectiveness, particularly for agents that target similar pathways. Furthermore, maximizing the antitumor effect by investigating scientifically rational combinations should be an area of high priority.

Over the past decade there have been considerable advances in our biologic understanding of mCRPC that have led to an explosion of novel treatments. Unfortunately, mCRPC remains a fatal disease. Hence, research to maximize the efficacy of ADT with the use of even more effective agents and investigating alternative combination strategies in well-designed and supported clinical trials is critical.

Tools and Resources

Educational Resources

Castration-Resistant Prostate Cancer Webcast

Castration-Resistant Prostate Cancer – Clinical Problem Solving (CPS) Protocol

Webcast: Castration-Resistant Prostate Cancer: Care through the Continuum

For Patients

Know Your Stats about Prostate Cancer

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