Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.
Bottom Line: Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR.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.
Affiliation: Orion Corporation, Orion Pharma, Finland.
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.
No MeSH data available.
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Mentions: Emergence of mutations in AR has been suggested to drive resistance to antiandrogen therapies. The effects of antiandrogens on mutant AR(F876L), AR(W741L), and AR(T877A) were studied in transactivation assays in human U2-OS osteosarcoma cells transiently transfected with expression vectors encoding the corresponding mutant AR and an androgen-responsive luciferase reporter gene construct. The F876L substitution in AR switched enzalutamide and ARN-509 from antagonists to agonists, whereas bicalutamide was agonistic for AR(W741L) mutation (Fig. 2A, Supplementary Fig. S1), as previously reported2223242629. Of the tested antiandrogens, only ODM-201 and its main metabolite ORM-15341 functioned as full antagonists for all tested mutant ARs (Fig. 2B). Data on antagonism of the tested antiandrogens with wtAR and mutated ARs are summarized in Table 1.
No MeSH data available.