ARN-509: A novel antiandrogen for prostate cancer treatment

Nicola J. Clegg, John Wongvipat, James D. Joseph, Chris Tran, Samedy Ouk, Anna Dilhas, Yu Chen, Kate Grillot, Eric D. Bischoff, Ling Cai, Anna Aparicio, Steven Dorow, Vivek Arora, Gang Shao, Jing Qian, Hong Zhao, Guangbin Yang, Chunyan Cao, John Sensintaffar, Teresa WasielewskaMark R. Herbert, Celine Bonnefous, Beatrice Darimont, Howard I. Scher, Peter Smith-Jones, Mark Klang, Nicholas D. Smith, Elisa De Stanchina, Nian Wu, Ouathek Ouerfelli, Peter J. Rix, Richard A. Heyman, Michael E. Jung, Charles L. Sawyers, Jeffrey H. Hager

Research output: Contribution to journalArticlepeer-review

460 Scopus citations


Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.

Original languageEnglish
Pages (from-to)1494-1503
Number of pages10
JournalCancer research
Issue number6
StatePublished - Mar 15 2012


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