Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer Journal Article


Authors: Rathkopf, D. E.; Morris, M. J.; Fox, J. J.; Danila, D. C.; Slovin, S. F.; Hager, J. H.; Rix, P. J.; Chow-Maneval, E.; Chen, I.; Gonen, M.; Fleisher, M.; Larson, S. M.; Sawyers, C. L.; Scher, H. I.
Article Title: Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer
Abstract: 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. 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. 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. 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.
Keywords: aged; aged, 80 and over; bone neoplasms; middle aged; bone tumor; follow up; follow-up studies; cancer grading; prostate specific antigen; metastasis; pathology; diagnostic imaging; prostate-specific antigen; prostatic neoplasms; blood; tissue distribution; neoplastic cells, circulating; prostate tumor; androgen antagonists; maximum tolerated dose; phase 1 clinical trial; antiandrogen; castration; tumor embolism; thiohydantoin derivative; androgen receptor antagonist; thiohydantoins; androgen receptor antagonists; neoplasm grading; arn 509; arn-509; very elderly; humans; prognosis; human; male; article
Journal Title: Journal of Clinical Oncology
Volume: 31
Issue: 28
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2013-10-01
Start Page: 3525
End Page: 3530
Language: English
PUBMED: 24002508
PROVIDER: scopus
PMCID: PMC3782148
DOI: 10.1200/jco.2013.50.1684
DOI/URL:
Notes: Export Date: 3 February 2014 -- Source: Scopus
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MSK Authors
  1. Charles L Sawyers
    153 Sawyers
  2. Josef J Fox
    44 Fox
  3. Susan Slovin
    184 Slovin
  4. Michael Morris
    274 Morris
  5. Mithat Gonen
    701 Gonen
  6. Dana Elizabeth Rathkopf
    142 Rathkopf
  7. Steven M Larson
    764 Larson
  8. Martin Fleisher
    237 Fleisher
  9. Howard Scher
    817 Scher
  10. Daniel C Danila
    82 Danila