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.
Highlights
castration-resistant prostate cancer (CRPC) typically arises through mechanisms involving androgen receptor (AR), as shown by studies demonstrating the role of autocrine synthesis of androgens and AR protein overexpression in CRPC11–13
ODM-201 and its pharmacologically active main metabolite ORM-15341 are structurally distinct from any known antiandrogens including the second-generation antiandrogens enzalutamide and ARN-509
It is understood that Prostate cancer (PC) is androgen-sensitive during the early stages of the disease but successful treatment with novel AR-targeting therapies indicates that CRPC remains androgen-sensitive[8,10,32]
Summary
CRPC typically arises through mechanisms involving AR, as shown by studies demonstrating the role of autocrine synthesis of androgens and AR protein overexpression in CRPC11–13. Amplification of the AR gene leading to AR protein overexpression[12] and mutations in the ligand binding domain (LBD) of AR can make the receptor more sensitive to growth-stimulating effects of low androgen concentrations[21] and turn antagonist responses to agonistic[22,23,24]. A F876L missense mutation in the LBD of the AR was identified to confer resistance to enzalutamide and ARN-509, an AR antagonist presently in a phase 3 study[27], by switching these antagonists to agonists[22,24]. ODM-201 exhibits negligible brain penetrance and does not increase serum testosterone levels in mice These findings have been translated to a promising antitumor activity in CRPC patients, as shown by significant PSA reductions. ODM-201 is currently being studied in a large, global phase 3 clinical trial in men with nonmetastatic CRPC (trial registration ID: NCT02200614)
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