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.

• Authors: Dana E Rathkopf, Michael J Morris, Josef J Fox, Daniel C Danila, Susan F Slovin, Jeffrey H Hager, Peter J Rix, Edna Chow Maneval, Isan Chen, Mithat Gönen, Martin Fleisher, Steven M Larson, Charles L Sawyers, Howard I Scher
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 31 Issue 28 Pg. 3525-30 (Oct 01 2013) ISSN: 1527-7755 [Electronic] United States
• PMID: 24002508 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Androgen Antagonists
• Androgen Receptor Antagonists
• Thiohydantoins
• apalutamide
• Prostate-Specific Antigen

Topics

• Aged
• Aged, 80 and over
• Androgen Antagonists (pharmacokinetics, therapeutic use)
• Androgen Receptor Antagonists (pharmacokinetics, therapeutic use)
• Bone Neoplasms (drug therapy, secondary)
• Castration
• Diagnostic Imaging
• Follow-Up Studies
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Grading
• Neoplastic Cells, Circulating (pathology)
• Prognosis
• Prostate-Specific Antigen (blood)
• Prostatic Neoplasms (drug therapy, pathology)
• Thiohydantoins (pharmacokinetics, therapeutic use)
• Tissue Distribution