Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. Academic Article uri icon

Overview

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.

publication date

  • September 3, 2013

Research

keywords

  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • Bone Neoplasms
  • Castration
  • Prostatic Neoplasms
  • Thiohydantoins

Identity

PubMed Central ID

  • PMC3782148

Scopus Document Identifier

  • 84891538656

Digital Object Identifier (DOI)

  • 10.1200/JCO.2013.50.1684

PubMed ID

  • 24002508

Additional Document Info

volume

  • 31

issue

  • 28