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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Percent change in 16β-[18F]fluoro-α-dihydrotestosterone standard uptake value (SUVmax-avg) after 4 weeks of treatment in 16 patients receiving ARN-509 30 to 390 mg daily. Total numbers of lesions and patients at each dose level are shown below each bar.

Fig 2.

Prostate-specific antigen (PSA) kinetics (with prior chemotherapy in gold). (A) Maximum PSA decline during study (n = 30); (B) PSA levels at 12 weeks (n = 30).

Fig 3.

Steady-state ARN-509 plasma trough concentrations in patients and in murine model of castration-resistant prostate cancer (CRPC). Mean predose ARN-509 concentrations for patients in each dose cohort (error bars indicate standard deviation) and steady-state trough concentrations associated with efficacy in clinically validated LNCaP/androgen receptor model of CRPC.

Fig A1.

16β-[18F]fluoro-α-dihydrotestosterone (FDHT) response to ARN-509. Left hemipelvis at (A) baseline and (B) 4 weeks. Arrows indicate representative bone metastases that have increased uptake of FDHT prior to treatment, and decreased uptake after treatment due to displaced tracer by ARN-509.