Building on Prostate Cancer Working Group 2 to Change the Paradigm from Palliation to Cure

Abstract

Developing systemic therapies for advanced prostate cancer has significant challenges, including the difficulty of assessing baseline disease status, disease heterogeneity, and the lack of standards for assessing treatment effects that reliably reflect clinical benefit. To address these issues, the Prostate Cancer Working Group (PCWG2) took three actions. First, the Group incorporated a prostate cancer clinical states model framework for patient management and drug development. Second was establishing a two-objective paradigm in which trials are designed to evaluate a drug's ability to either (a) control, relieve, or eliminate present disease manifestations or (b) prevent or delay future disease manifestations. Third was the development of consensus criteria for eligibility, outcomes, and reporting in prostate cancer clinical trials. Now that the molecular interrogation of prostate cancer has led to a more complex understanding of disease biology, drug development has transitioned from evaluating cytotoxic agents with activity in multiple tumor types to the rational development of therapies targeting different aspects of the malignant process. In addition, the current availability of multiple therapies for advanced prostate cancer that prolong life brings a new mandate: that we define, validate, and qualify predictive biomarkers of sensitivity to guide treatment selection and establish endpoints short of survival that can lead to drug approval. Optimization of outcomes in future trials will require revised guidance on how to align clinically relevant objectives and eligibility with an evolving disease framework.KEY POINTSThe Prostate Cancer Working Group (PCWG2) was convened to define consensus criteria for eligibility and outcome measures in trials evaluating systemic treatment for patients with castration-resistant prostate cancer (CRPC).Since PCWG2, drug development in prostate cancer has transitioned from the evaluation of cytotoxic agents with activity in multiple tumor types to the rational development of targeted approaches based on understanding mechanisms of tumor growth and treatment resistance.Clinical trials that limit enrollment to the patients most likely to respond are essential to minimize patient exposure to unnecessary toxicity from ineffective treatment, better enable drug approvals, and shorten drug development time lines.Achieving this requires the development of analytically valid assays for integral biomarkers, on the basis of which appropriate treatment can be selected.A coordinated effort to update the PCWG2 recommendations for clinical trial conduct in CRPC and in other disease states is currently underway.