OMAHA-003: A phase 3 study of CYP11A1 inhibitor opevesostat versus next-generation hormonal agent (NHA) switch in metastatic castration-resistant prostate cancer (mCRPC) after NHA and taxane-based chemotherapy.

TPS286 Background: The androgen receptor (AR) plays a pivotal role in prostate cancer pathogenesis, even after progression on androgen-directed therapies (ADT). In patients with mCRPC, activation of AR ligand binding domain (AR-LBD) somatic point mutations is a common mechanism of resistance to ADTs. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), which catalyzes the first and rate-limiting step of steroid biosynthesis. By inhibiting CYP11A1, opevesostat suppresses the production of all steroid hormones and their precursors that may promiscuously activate the AR signaling pathway. Opevesostat showed antitumor activity in patients with heavily pretreated mCRPC, and in those with AR-LBD mutations, in the phase 1/2 CYPIDES trial (Fizazi et al. NEJM Evid. 2024). The randomized, open-label, phase 3 OMAHA-003 study (NCT06136624) is evaluating the efficacy and safety of opevesostat versus NHA switch in patients with mCRPC who received NHA and taxane-based chemotherapy. Methods: Eligible patients havemCRPC (unselected for AR-LBD mutations) that progressed on ADT ≤6 months of screening and during/after treatment with 1 NHA or 1-2 taxane-based chemotherapies. Approximately 1200 patients (300 with, 900 without AR-LBD mutations) will be randomly assigned 1:1 to opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg QD) or enzalutamide 160 mg PO QD (if prior abiraterone) or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide). Primary endpoints are radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR) and overall survival in patients with AR-LBD mutation-positive and -negative disease, separately. Secondary endpoints include time to initiation of first subsequent anticancer therapy or death; objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR; and safety. Enrollment is ongoing. Clinical trial information: NCT06136624 .