Antitumor activity of MDV3100 in a phase I/II study of castration-resistant prostate cancer (CRPC)

Abstract

5011 Background: MDV3100 is a novel AR antagonist selected for activity in prostate cancer model systems with overexpressed AR. In contrast to bicalutamide, MDV3100 blocks nuclear translocation of AR and DNA binding, and has no known agonist activity when AR is overexpressed. Antitumor activity of MDV3100 in a Phase I/II trial was assessed by prostate-specific antigen (PSA), soft tissue and osseous disease, circulating tumor cells (CTC), and time on treatment. Methods: Patients (pts) with progressive CRPC were enrolled in sequential cohorts of 3–6 pts at 30, 60, 150, 240, 360, 480 and 600 mg/day. Once the safety of a dose was established, enrollment was expanded at doses >60 mg/day to include 12 chemotherapy-naïve (naïve) and 12 post-chemotherapy pts per cohort. Results: 140 pts were enrolled. 114 pts at 30–360 mg/day have been followed for >12 weeks. PSA declines (>50% from baseline) were observed at week 12 in 57% (37/65) of naïve and 45% (22/49) of post-chemo pts. Data suggest a dose-response trend particularly in post-chemo pts where PSA responses were 32% at 60 and 150 mg/day and 58% at 240 and 360 mg/day. At 12 weeks, radiographic control (no progression) was observed in 35/47 pts (74%) with evaluable soft tissue lesions per PCWG2 guidelines and 50/81 pts (62%) with bone lesions. CTC counts on 101 of 114 pts showed 92% (56/61) with favorable (<5) counts pretreatment maintained favorable posttreatment counts, while 53% (21/40) converted from unfavorable to favorable posttreatment. For post-chemo pts, favorable retention was 100% (17/17) and unfavorable to favorable conversion at 240 and 360 mg/day was 60% (6/10). 87 pts at 30–240 mg/day have been followed for >24 weeks; 35 (40%) received treatment >24 weeks. At 600 mg/day, 2 of 3 pts had dose limiting toxicity (rash; seizure). Dose reductions due to fatigue were noted at 480 and 360 mg/day. Conclusions: MDV3100 is a promising candidate for the treatment of prostate cancer assessed by PSA, imaging, CTC, and time on treatment. The data suggest a dose-response trend and consistency across endpoints. Pt follow-up is continuing. The efficacy comparable to that at higher doses and the better adverse event profile, led to the selection of 240 mg/day as the recommended dose for a phase III trial in CRPC. [Table: see text]