Abstract
The next-generation AR inhibitor ODM-201 is tolerable and induces PSA responses in metastatic CRPC.
Major finding: The next-generation AR inhibitor ODM-201 is tolerable and induces PSA responses in metastatic CRPC.
Concept: ODM-201 binds AR with higher affinity than other AR inhibitors and blocks AR nuclear translocation.
Impact: Further clinical development of ODM-201 in metastatic CRPC is warranted.
Despite initial treatment with androgen deprivation therapy, most patients with advanced prostate cancer develop metastatic castration-resistant prostate cancer (CRPC) due to sustained androgen receptor (AR) signaling. Next-generation AR inhibitors have shown improved survival in patients with metastatic CRPC, demonstrating that AR inhibition can be an effective treatment strategy in this disease. Fizazi and colleagues report findings from an open-label, multicenter, combined phase 1 dose-escalation and randomized phase 2 dose-expansion study of ODM-201, a structurally distinct next-generation AR inhibitor that prevents AR nuclear translocation and binds AR with higher affinity than other AR inhibitors such as bicalutamide, enzalutamide, and ARN-509. In contrast to other next-generation AR inhibitors, preclinical studies have also indicated that ODM-201 does not cross the blood–brain barrier, suggesting there may be a lower risk of seizures. The primary objective of the phase 1 trial was to assess safety and tolerability, and the primary objective of the phase 2 trial was to determine the prostate-specific antigen (PSA) response. The maximum-tolerated dose of ODM-201 was not reached, and few serious adverse events were reported; the most common adverse events were fatigue and weakness, and no seizures were reported. Based on PSA response as well as RECIST response and circulating tumor cell counts, ODM-201 had antitumor activity at all doses tested. Patients who had not previously received chemotherapy or CYP17 inhibitors had the best responses, a finding consistent with previous reports of cross-resistance to sequential treatment with AR and CYP17 inhibitors in metastatic CRPC. Collectively, these findings suggest that ODM-201 is a safe and tolerable addition to the armamentarium of next-generation AR inhibitors and support further evaluation of ODM-201 in larger randomized controlled trials in patients with progressive metastatic CRPC.
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