ARN-509: A Novel Antiandrogen for Prostate Cancer Treatment

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.

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

“…Apalutamide (55, Figure 13) and darolutamide (56, OMD-201) are two molecules under evaluation in phase 3 clinical trials in patients with nonmetastatic CRPC (NCT01946204 and NCT02200614, respectively). Apalutamide shows high structural similarity to enzalutamide, but achieves the same therapeutic response as enzalutamide at a lower dose in a LNCaP xenograft mouse model and does not induce AR nuclear translocation or DNA binding [120] . Darolutamide is characterised by a different chemical scaffold from its cognate antagonists, and is able to antagonise AR mutants F876L, W741L and T877A [121] .…”

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

“…One such antagonist is ARN-509, a new-generation anti-androgen with similar structure and mechanism of action to enzalutamide but with potentially increased potency, better pharmacological characteristics and improved patient tolerability (Clegg et al 2012). Although the development of ARN-509 is ongoing, it must be noted that an AR mutation, F877L, that can confer resistance to this agent has already been reported (Joseph et al 2013, Korpal et al 2013.…”

Avances en el tratamiento de cáncer de próstata resistente a la castración: énfasis en nuevas terapias hormonales

“…Estudios preclínicos y clínicos iniciales sugieren mayor actividad e índice terapéutico, buen perfil de seguridad y tasas/duración de respuestas promisorias 41,42 . ARN-509 versus placebo en CPRC no metastásico (SPARTAN) 43 y el uso conjunto con AA en CPmRC 44 son estudios actualmente en curso.…”