Establishing Guidelines for Castration Resistant Prostate Cancer Clinical Trials: A Collaborative Effort Led by PCCTC Investigators

Posted June 1, 2016
Howard Scher, M.D., Memorial Sloan Kettering Cancer Center

Dr. Howard Scher Prostate cancer is a heterogeneous disease with a clinical course that is highly variable with a range of molecular etiologies. Many tumors are slow-growing and progress over decades, while others metastasize early resulting in early mortality, making it difficult to assess baseline disease status. Standards for evaluating the clinical benefit of new agents are also lacking. Because of these challenges, new guidelines to design, implement and complete more informative clinical trials at discrete points in the illness are needed. To develop these guidelines, leading clinical prostate cancer investigators formed a collaborative initiative called the Prostate-Specific Antigen Working Group (PCWG1) in 1999. A key focus of PCWG1 was the development of standards for the use and interpretation of prostate-specific antigen (PSA) testing. Through the PCWG1 consensus recommendations, eligibility and outcome measures were also defined for use in phase II clinical trials in patients with castration-resistant disease who no longer respond to first line hormonal therapies.

The PCWG1 recommendations were well received by the scientific community, but were focused on a specific group of patients. In 2004, the US Food and Drug Administration (FDA) challenged the prostate cancer research community to update the eligibility and outcome measures of PCWG1 so that it could be applied broadly across the clinical spectrum of the disease. In response, investigators from the PCRP-funded Prostate Cancer Clinical Trials Consortium (PCCTC) rose to the challenge by forming the Prostate Cancer Working Group 2 (PCWG2), and issued recommendations for the design and end points for prostate cancer clinical trials for patients with metastatic castration-resistant prostate cancer (mCRPC). PCWG2 recognized that the standards used for trials in other tumor types did not apply to prostate cancer, a disease in which the two most common manifestations were a rising PSA and metastases to bone: manifestations that were not addressed by Response Evaluation Criteria in Solid Tumors (RECIST). Key PCWG2 recommendations were verification of the disease progression prior to beginning therapy; abandoning global response measures such as complete or partial response in favor of reporting changes in each disease manifestation separately using early outcomes that represent the control, relief or elimination of disease manifestations present at the start of therapy, and later time to event measures as the delay or prevention of future events; and stressed the importance of continuing treatment in spite of a rising PSA, until more meaningful evidence of disease progression was documented, e.g. radiographic progression. The latter was enabled in part by the "two plus two" rule defined by the Group that distinguishes bone scan "flare" from actual disease progression, particularly important in phase III trials. These recommendations have had a profound impact on clinical trial design, the evaluation of new therapies, and drug approvals.

When the PCWG2 recommendations were published in 2008, docetaxel was the only approved life prolonging therapy in mCRPC. Since then, five additional drugs have been approved, creating the need to update the recommendations and in particular, to better align clinical trial questions with clinical practice. As a result, 32 leading experts in prostate cancer drug development and trial design came together in 2012 to form Prostate Cancer Working Group 3 (PCWG3) in order to expand on the PCWG2 recommendations. Led by Dr. Howard Scher of Memorial Sloan Kettering Cancer Center, the PCWG3 formally convened eight times between June 2012 and February 2015 to develop the consensus recommendations, which included a revised disease states model, eligibility criteria, outcome criteria, and reporting methodology.

PCWG3 considered all aspects of the clinical trial process from discovery to validation in the context of biomarkers. The updated recommendations provide a framework for how best to use available agents in clinical practice, building on recent reports showing that mCRPC consists of several distinct biologic subtypes, creating the need to characterize the biology of an individual patient's tumor when a change in therapy is needed by direct biopsy of a metastatic site, circulated nucleic acid or circulating tumor cells in blood. The profiling is recommended at the initiation of the therapy, during the therapy and at progression. PCWG3 also advised that trial eligibility be based on prior therapies that the patient has received.

PCWG3 introduced an important new concept and trial endpoint of "no longer clinically benefitting (NLCB)" to ensure that a treatment that is controlling a patient's disease is not discontinued prematurely. For example, a patient with severe pain that has been relieved by a drug should not necessary have the drug stopped for a slow rise in PSA. Other times, progression may only occur in one site of disease of the 20 or more present in a patient, which can be treated with radiation while the drug controlling the other 19 lesions is continued.

The PCRP-funded infrastructure of the PCCTC has provided a multi-institutional network which has facilitated these important working group collaborations, the outcomes of which are making an enormous impact on the design, management, and outcomes of prostate cancer clinical trials. The latest recommendations from PCWG3 have already been implemented into many clinical trials supported by the PCCTC, and have led to the development of standardized templates that are available through the PCCTC to researchers and sponsors. Management of the trials by the PCCTC helps to ensure compliance with the recommendations in order to provide maximum clinical benefit to individuals with prostate cancer. These collaborative PCCTC initiatives to improve standards for the prostate cancer clinical trial process will keep the drug pipeline filled with novel agents and benefit patients by making promising therapies available sooner.

Figure from Dr. Scher

    1. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, Beer TM, Carducci MA, Chi KN, Corn PG, de Bono JS, Dreicer R, George DJ, Heath EI, Hussain M, Kelly WK, Liu G, Logothetis C, Nanus D, Stein MN, Rathkopf DE, Slovin SF, Ryan CJ, Sartor O, Small EJ, Smith MR, Sternberg CN, Taplin ME, Wilding G, Nelson PS, Schwartz LH, Halabi S, Kantoff PW, Armstrong AJ. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol.2016 Apr 20;34(12):1402-18.
    2. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol.2008 Mar 1;34(7):1148-59.
    3. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, Freidlin B, Halabi S, Hudes G, Hussain M, Kaplan R, Myers C, Oh W, Petrylak DP, Reed E, Roth B, Sartor O, Scher H, Simons J, Sinibaldi V, Small EJ, Smith MR, Trump DL, Wilding G, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol.1999 Nov;17(11):3461-7.


Public and Technical Abstracts: Coordinating Center Application for Prostate Cancer Research Program Clinical Consortium Award

Public and Technical Abstracts: Public and Technical Abstracts: The Prostate Cancer Clinical Trials Consortium: Application for Coordinating Center with Clinical Research Site Option

Top of Page