Association of Progression by Prostate Cancer Working Group (PCWG)-2 Criteria and Survival in Metastatic Castration Resistant Prostate Cancer

ABSTRACT Background Intermediate endpoints to identify active agents for metastatic castration-resistant prostate cancer (mCRPC) are suboptimal. The Prostate Cancer Working Group (PCWG)-2 guidelines recommend time to clinical or radiographic event endpoints, and discouraged use of endpoints using PSA changes. We investigated the association of progression defined by PCWG-2 guidelines and overall survival (OS). Methods Two trials were analyzed: CS-205, a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone (DP) plus AT-101 or placebo, and SUN-1120 (n = 873), a phase III trial comparing prednisone plus sunitinib (SP) or placebo (PP) following docetaxel-based chemotherapy. Both trials continued therapy until progression defined by PCWG-2 criteria and OS was the primary endpoint. OS was derived by the Kaplan-Meier method. Cox proportional hazards regression models were used to estimate the effect of progression on OS. Landmark analyses at 2-month intervals compared patients with prior progression with those without progression. Sub-analyses compared patients removed from trial for progression vs. other reasons and examined the association of type of progression with OS. Results Patients who had previously progressed had an increased risk of death. In CS-205, the hazards ratio (HR) ranged from 2.31 to 3.43 between landmark times of 6 to 12 months and in SUN-1120 HR was 2.75 to 5.21 between landmark times from 2 to 8 months. Median OS was 5.5 versus 14.4 months in CS-205 beyond month 6 and 7.1 versus 16.1 months in SUN-1120 beyond month 2 for those with/without prior progression. The types of progression associated with OS varied between the trials. Patients removed from study due to progression (excluding death) had a significantly worse OS than those coming off for other reasons (HR: 1.90, 95% CI: 1.26-2.87 in CS-205 and HR: 1.23, 95% CI: 1.02-1.48 in SUN-1120). Conclusions Progression by PCWG-2 criteria was significantly associated with decreased OS in patients receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. Further validation will facilitate the employment of PCWG-2 defined progression as an intermediate endpoint. Disclosure G. Sonpavde: Research support to institution from Ascenta Therapeutics and Pfizer, Inc, B.A. Wood: Employee of Ascenta Therapeutics, S. Wang: Employee of Pfizer, Inc, J. Paolini: Employee of Pfizer, Inc, M. Lechuga: Employee of Pfizer, Inc, M.R. Smith: Research support to institution from Pfizer, Inc, M.D. Michaelson: Research support to institution from Pfizer, Inc, All other authors have declared no conflicts of interest.