Abstract 674: ODM-201 - New generation androgen receptor inhibitor targeting resistance mechanisms to androgen signalling-directed prostate cancer therapies

Androgen receptor (AR) mutations have been described to emerge in response to prostate cancer treatment with first generation AR antagonists, resulting in broadened ligand specificity and AR antagonist-to-agonist switch. Second-generation AR antagonists enzalutamide and ARN-509 function as antagonists in the presence of AR overexpression. They express high clinical efficacy in castration resistant prostate cancer (CRPC) but eventually resistance will emerge. Recently, a F876L missense mutation in the ligand-binding domain of AR has been described that confers resistance to enzalutamide and ARN-509 in preclinical models of prostate cancer. AR F876L mutation has also been identified in plasma DNA from ARN-509-treated CRPC patients with rising PSA. ODM-201 is a new generation AR inhibitor with high anticancer activity in patients with CRPC and has unique properties compared to first and second generation antiandrogens. ODM-201 and its major metabolite bind to wt AR with excellent affinity (Ki 8 and 9 nM, respectively) and selectivity. In functional cell-based assays, ODM-201 functions as antagonist in highly AR overexpressing cells and does not induce AR T877A or W741L transcriptional activity. In contrast to enzalutamide and ARN-509, ODM-201 and its metabolite have been found to potently inhibit the activity of AR F876L while enzalutamide and ARN-509 were agonistic. ODM-201 is a promising new generation AR inhibitor for the treatment of advanced prostate cancer with superior antiandrogenic activity in preclinical models of AR function. Citation Format: Anu-Maarit Moilanen, Reetta Riikonen, Pekka J. Kallio. ODM-201 - New generation androgen receptor inhibitor targeting resistance mechanisms to androgen signalling-directed prostate cancer therapies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 674. doi:10.1158/1538-7445.AM2014-674