OMAHA-003: Phase 3 trial of CYP11A1 inhibitor opevesostat versus androgen receptor pathway inhibitor (ARPI) switch in participants (pts) with metastatic castration-resistant prostate cancer (mCRPC) after ARPI and taxane-based chemotherapy.

TPS298 Background: The androgen receptor (AR) plays a pivotal role in prostate cancer pathogenesis, even after progression on AR-directed therapies. In patients with mCRPC, activation of AR ligand binding domain somatic point mutations (AR-LBDm) is a common mechanism of resistance to AR-directed therapies. 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 can suppress the production of all steroid hormones and their precursors that may promiscuously activate the AR signaling pathway, especially in populations with AR-LBDm. In the phase 1/2 CYPIDES trial, opevesostat showed antitumor activity in pts with heavily pretreated mCRPC, and in those with AR-LBDm. The randomized, open-label, phase 3 OMAHA-003 trial (NCT06136624) is evaluating the efficacy and safety of opevesostat versus ARPI switch in pts with mCRPC after ARPI and taxane-based chemotherapy. Methods: Eligible pts have mCRPC that progressed on androgen deprivation therapy ≤6 mo of screening and during or after treatment with 1 ARPI or 1-2 taxane-based chemotherapies. Pts will be randomly assigned 1:1 to receive opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg + 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) until radiographic disease progression, unacceptable toxicity, investigator’s decision, or consent withdrawal. Stratification factors are measurable disease (yes vs no), AR-LBDm status (positive vs negative), and prior cabazitaxel treatment (yes vs no). The protocol was amended to use overall survival as the primary end point in pts with AR-LBDm-positive and -negative disease, separately, and radiographic progression-free survival per Prostate Cancer Clinical Trials Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR) as a secondary end point. Other secondary end points include objective response rate, and duration of response per PCWG3-modified RECIST v1.1 by BICR, time to initiation of first subsequent anticancer therapy or death, time to pain progression, time to PSA progression, time to first symptomatic skeletal-related event, and safety. AEs will be monitored throughout the study and graded per NCI CTCAE v5.0. Planned enrollment was amended to approximately 1310 pts (460 AR-LBDm-positive and 850 AR-LBDm-negative). The predefined eligibility cap for pts with AR-LBDm-negative status has been reached, and the study is currently only enrolling pts with AR-LBDm-positive status. Clinical trial information: NCT06136624 .