ARN-509: A Novel Antiandrogen for Prostate Cancer Treatment
Nicola J. Clegg,John Wongvipat,James Joseph,Chris Tran,Samedy Ouk,Anna Dilhas,Yu Chen,Kate Grillot,Eric D. Bischoff,Ling Cai,Anna Aparicio,Steven Dorow,Vivek K. Arora,Gang Shao,Jing Qian,Hong Zhao,Guangbin Yang,Chunyan Cao,John Sensintaffar,Teresa Wasielewska,Herbert Mark R,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 +34 more
TLDR
ARS-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists, and offers preclinical proof of principle for ARN-509 as a promising therapeutic in bothCastration-sensitive and castration-resistant forms of prostate cancer.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 this 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/day of ARN-509, whereas the same response required 100 mg/kg/day 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.read more
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Journal ArticleDOI
Emerging Mechanisms of Resistance to Androgen Receptor Inhibitors in Prostate Cancer
TL;DR: This Review highlights emerging mechanisms of acquired resistance to contemporary therapies targeting the AR pathway, which fall into the three broad categories of restored AR signalling, AR bypass signalling and complete AR independence.
Journal ArticleDOI
Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer
Matthew R. Smith,Fred Saad,Simon Chowdhury,Stéphane Oudard,Boris Hadaschik,Julie N. Graff,David Olmos,Paul N. Mainwaring,Ji Youl Lee,Hiroji Uemura,Angela Lopez-Gitlitz,Geralyn Carol Trudel,Byron M. Espina,Youyi Shu,Youn C. Park,Wayne R. Rackoff,Margaret K. Yu,Eric J. Small,Spartan Investigators +18 more
TL;DR: Among men with nonmetastatic castration‐resistant prostate cancer, metastasis‐free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo.
Journal ArticleDOI
Glucocorticoid Receptor Confers Resistance to Antiandrogens by Bypassing Androgen Receptor Blockade
Vivek K. Arora,Emily Schenkein,Rajmohan Murali,Sumit K. Subudhi,John Wongvipat,Minna D. Balbas,Neel Shah,Ling Cai,Eleni Efstathiou,Chris Logothetis,Deyou Zheng,Charles L. Sawyers,Charles L. Sawyers +12 more
TL;DR: This work identifies induction of glucocorticoid receptor (GR) expression as a common feature of drug-resistant tumors in a credentialed preclinical model and establishes a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.
Journal ArticleDOI
Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer.
Kim N. Chi,Neeraj Agarwal,Anders Bjartell,Byung Ha Chung,Andrea J. Pereira de Santana Gomes,Robert Given,Álvaro Juárez Soto,Axel S. Merseburger,Mustafa Ozguroglu,Hirotsugu Uemura,Dingwei Ye,Kris Deprince,V. Naini,Jinhui Li,Shinta Cheng,Margaret K. Yu,Ke Zhang,Julie S. Larsen,Sharon Anne McCarthy,Simon Chowdhury +19 more
TL;DR: Overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups.
Journal ArticleDOI
Androgen receptor: structure, role in prostate cancer and drug discovery
TL;DR: An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided are provided.
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