Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction.
Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509 In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs ODM-201 is currently in a phase 3 trial in CRPC
Scientific reports 2015 Jul 03*** epublish ***
Anu-Maarit Moilanen, Reetta Riikonen, Riikka Oksala, Laura Ravanti, Eija Aho, Gerd Wohlfahrt, Pirjo S Nykänen, Olli P Törmäkangas, Jorma J Palvimo, Pekka J Kallio
Orion Corporation, Orion Pharma, Finland , Orion Corporation, Orion Pharma, Finland , Orion Corporation, Orion Pharma, Finland , Orion Corporation, Orion Pharma, Finland , Orion Corporation, Orion Pharma, Finland , Orion Corporation, Orion Pharma, Finland , Orion Corporation, Orion Pharma, Finland , Orion Corporation, Orion Pharma, Finland , Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland , Orion Corporation, Orion Pharma, Finland