The Prostate Cancer Working Group 3 (PCWG3) consensus for trials in castration-resistant prostate cancer (CRPC).

5000 Background: The availability of new agents for men with CRPC, recognition of new disease phenotypes, and an evolving regulatory environment have created the need for new CRPC clinical trial guidelines to succeed PCWG2, published in 2008. Methods: Eight face-to-face meetings were convened over 3 years to create the PCWG3 guidelines, with subcommittees meeting more frequently. PCWG2 criteria were updated or revised based on new evidence from clinical trial data and validation studies of PCWG2 recommendations Results: PCWG3 distinguishes between prostate adeno- and non-adenocarcinomas; considers the sequence and number of prior systemic therapies in lieu of the pre- and post-taxane distinctions in PCWG2; encourages detailed reporting of disease subtypes based on distribution patterns; and defines endpoints for patients transitioning between non-metastatic and metastatic disease. For non-cytotoxic therapies, outcomes are focused on establishing proof-of-mechanism and determining the optimal biologic dose. The strength of association between patient-reported outcomes, radiographic progression-free survival, circulating tumor cell enumeration, and time to clinical events is emphasized rather than alterations in individual biomarkers. Similarly, PCWG3 underscores the distinction between first evidence of progression based on one disease manifestation in contrast to terminating treatment because the patient is no longer benefitting. We emphasize the importance of documenting progression in existing lesions as distinct from the development of new lesions. The revised guidelines highlight the importance of serial biologic profiling of the disease from biopsies and/or blood to understand treatment resistance and identify predictive biomarkers of sensitivity for use in prospective trials. Conclusions: PCWG3 updates the PCWG2 consensus criteria based on available new treatments and disease manifestations, and data validating biomarkers that were proposed in PCWG2. The revised criteria define the endpoints for the M0 to M1 transition. These recommendations will guide clinical trial design and conduct for therapeutics being tested in both M0 and M1 CRPC patient populations.