title: Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.
abstract: 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.
authors.affiliation: Orion Corporation, Orion Pharma, Finland.
authors.forename: Anu-Maarit
authors.initials: AM
authors.lastname: Moilanen
authors.affiliation: Orion Corporation, Orion Pharma, Finland.
authors.forename: Reetta
authors.initials: R
authors.lastname: Riikonen
authors.affiliation: Orion Corporation, Orion Pharma, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Oksala
authors.affiliation: Orion Corporation, Orion Pharma, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Ravanti
authors.affiliation: Orion Corporation, Orion Pharma, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Aho
authors.affiliation: Orion Corporation, Orion Pharma, Finland.
authors.forename: Gerd
authors.initials: G
authors.lastname: Wohlfahrt
authors.affiliation: Orion Corporation, Orion Pharma, Finland.
authors.forename: Pirjo S
authors.initials: PS
authors.lastname: Nykänen
authors.affiliation: Orion Corporation, Orion Pharma, Finland.
authors.forename: Olli P
authors.initials: OP
authors.lastname: Törmäkangas
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jorma J
authors.initials: JJ
authors.lastname: Palvimo
authors.affiliation: Orion Corporation, Orion Pharma, Finland.
authors.forename: Pekka J
authors.initials: PJ
authors.lastname: Kallio
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D000970:Antineoplastic Agents; D011720:Pyrazoles; D011944:Receptors, Androgen; C000607739:darolutamide