Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer.
Abstract PURPOSE： ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and， unlike bicalutamide， does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety， tolerability， pharmacokinetics， pharmacodynamics， and antitumor activity of ARN-509 in men with metastatic CRPC. PATIENTS AND METHODS： Thirty patients with progressive CRPC received continuous daily oral ARN-509 at doses between 30 and 480 mg， preceded by administration of a single dose followed by a 1-week observation period with pharmacokinetic sampling. Positron emission tomography/computed tomography imaging was conducted to monitor [(18)F]fluoro-α-dihydrotestosterone (FDHT) binding to AR in tumors before and during treatment. Primary objective was to determine pharmacokinetics， safety， and recommended phase II dose. RESULTS： Pharmacokinetics were linear and dose proportional. Prostate-specific antigen declines at 12 weeks (≥ 50% reduction from baseline) were observed in 46.7% of patients. Reduction in FDHT uptake was observed at all doses， with a plateau in response at ≥ 120-mg dose， consistent with saturation of AR binding. The most frequently reported adverse event was grade 1/2 fatigue (47%). One dose-limiting toxicity event (grade 3 abdominal pain) occurred at the 300-mg dose. Dose escalation to 480 mg did not identify a maximum-tolerated dose. CONCLUSION： ARN-509 was safe and well tolerated， displayed dose-proportional pharmacokinetics， and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data.