2. Academic Validation
  3. ARN-509: a novel antiandrogen for prostate cancer treatment

ARN-509: a novel antiandrogen for prostate cancer treatment

  • Cancer Res. 2012 Mar 15;72(6):1494-503. doi: 10.1158/0008-5472.CAN-11-3948.
Nicola J Clegg 1,  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 Wasielewska,  Mark 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
Affiliations

Affiliation

  • 1 Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
PMID: 22266222 DOI: 10.1158/0008-5472.CAN-11-3948
Abstract

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.

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