Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3

Abstract

Purpose Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups. Methods An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations. Results PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials. Conclusion PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

A prognostic model for stratifying clinical outcomes in chemotherapy-naive metastatic castration-resistant prostate cancer patients treated with abiraterone acetate

“…Our model was also predictive for time on treatment, a useful surrogate in the real-world setting for the duration of clinical benefit on treatment and an important endpoint, as highlighted in the updated recommendations on trial design and objectives from the Prostate Cancer Working Group 3. 16 These findings demonstrate that our model is predictive of outcomes on abiraterone and thus may be valuable in selecting patients likely to benefit from first-line abiraterone, and identifying those for whom alternate treatments could be considered, such as first-line chemotherapy or clinical trials. A key strength of the 6-factor prognostic index model is that it is a pragmatic tool for risk stratification utilising easily available (and inexpensive) clinical parameters.…”

Consequences of an Early PSA Response to Enzalutamide Treatment for Japanese Patients with Metastatic Castration-resistant Prostate Cancer

“…Although the cohort studied was small, Antonarakis et al (13) reported that the AR-V7 expression level in CTCs was prognostic of the outcomes of CRPC treatment. Further studies using liquid biopsies that include CTCs and cell-free DNA are warranted to establish robust biomarkers, which were cited in PCWG3 (24).…”

Heterogeneity of advanced prostate cancer: clinical implications of genomics

“…There are a number of recommendations within the new PCWG3 guidelines that reflect the increased understanding of prostate cancer heterogeneity. 19 • In recognition of the significant phenotypic heterogeneity of prostate cancer, it has been recommended that dedicated trials should be designed for different groups of prostate cancer patients, defined by their pattern of spread.…”