Circulating tumor cells (CTC) and prostate specific antigen (PSA) as response indicator biomarkers in chemotherapy-naïve patients with progressive castration-resistant prostate cancer (CRPC) treated with MDV3100.

Abstract

4546 Background: The availability of reliable indicators of treatment efficacy is a critical unmet need in drug development for CRPC. MDV3100 is a second-generation oral androgen receptor antagonist that induces a prolonged apoptotic response in xenograft models and is active in men with progressive CRPC. We explored outcomes based on PSA and CTC number in relation to radiographic progression. Methods: 65 chemotherapy-naive patients with progressive CRPC were treated at doses of 30 to 360 mg/day. PSA levels were measured monthly, and CTC number at baseline, wks 4 and 12 using the CellSearch assay. A “PSA response” was defined as 3 consecutive declines within 12 wks of the start of treatment. Time to radiographic progression free survival (RPFS) was assessed by Prostate Cancer Working Group 2 criteria. The likelihood ratio test from the Cox proportional hazards model was used to determine the factors associated with RPFS, defined as being alive without progression. Results: The RPFS probability at 12 months was 0.56 (95% CI: 0.43, 0.73) with a median follow up of 13 months (2.4 to 26). 48 (74%) of the 65 pts were evaluable at the 12 wk landmark. CTC number, PSA, and PSA response, all assessed at 12 weeks, were all significant predictors of RPFS (p < 0.001). The joint model most predictive of RPFS time was CTC at 12 weeks and PSA response (3 consecutive declines). The concordance probability estimate (CPE) was used to measure the predictive accuracy of the model. The CPE for this joint model was 0.78, significantly higher than a model with each factor alone (CTC at 12 weeks – CPE= 0.63; PSA response- CPE=0.72). Conclusions: CTC at 12 weeks and PSA response provide independent predictive information for radiographic progression free survival time in chemotherapy-naive CRPC. Sustained PSA declines are consistent with the observed preclinical apoptotic response. Each biomarker may provide unique information. The results will be studied prospectively in an ongoing phase III randomized trial of MDV3100 with a survival endpoint. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Medivation Medivation Medivation Medivation Medivation, Veridex Medivation