ORLANDO, FL, USA (UroToday.com) - ARN-509 is a potent and selective antagonist of the androgen receptor (AR) that is being developed for the treatment of men with castration-resistant prostate cancer (CRPC).
ARN-509 binds directly to the ligand-binding domain of the androgen receptor, impairing nuclear translocation and DNA binding. A Phase I/II study was designed to assess the safety, pharmacokinetics, and antitumor activity of ARN-509 in men with CRPC. The first phase of the study was reported at ASCO 2012 by D. Rathkopf and showed that ARN-509 was safe and well tolerated in 30 patients with mCRPC who had progressed prior treatment. The dose for the phase II part of the study was chosen at 240 mg/day. The phase II study is evaluating ARN-509 in 3 patient populations of men with CRPC:
- high risk non-metastatic CRPC (M0),
- treatment-naïve mCRPC,
- post abiraterone acetate (AA) progressive mCRPC.
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Preliminary results from the group of patients in arm 1, i.e., high risk non-metastatic CRPC, are reported here.
Between Nov 2011 and Jun 2012, 47 patients were enrolled, and the cut-off for data was January, 10 2013. The included patients had no radiographic evidence of metastases but were all high-risk for disease progression based on PSA ≥8ng/ml within three months of enrollment, and/or PSA doubling time (PSADT) ≤10 months. The primary endpoint was PSA response at 12 weeks (PCWG2 criteria), and the secondary endpoints were time to PSA progression, one-year metastasis-free survival, and safety. All patients received ARN-509 at the dose of 240 mg/day on a 28-day dosing cycle. PSA assessments were collected every month, and tumor scans were performed every 4 months. The baseline data showed that the median age was 71 years, median PSA 10.7 ng/dl, ECOG status 0 (77%), Gleason score ≤7 (57%) and ≥8 (35%), and PSADT ≤10 months (55%). All patients received LHRH agonist treatment, with or without an anti-androgen. The median treatment time was 8.1 months.
The time to PSA progression was not reached at the median f-u at 8.1 months, but the proportion of patients free of PSA progression at 12 months was estimated to be 88.7%, and the PSA response was 91% (> 50ng/dl PSA decline) at 24 weeks. The safety profile was in line with the Ph I data. Most common treatment-related AEs were grade 1 and 2 fatigue, diarrhea, and nausea. There were no treatment-related SAEs, and 6 patients discontinued the study, but only 2 were due to treatment-related AEs.
In summary, treatment with ARN-509 is safe and well tolerated with promising preliminary activity based on high PSA-response rate in men with high-risk non-metastatic CRPC, and further development of ARN-509 is supported by this data.
Presented by Matthew R. Smith, MD, PhD at the 2013 Genitourinary Cancers Symposium - February 14 - 16, 2013 - Rosen Shingle Creek - Orlando, Florida USA
Massachusetts General Hospital and the Harvard Medical School, Boston, MA USA
Written by Anna Forsberg, medical reporter for UroToday.com
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