Introduction:

The androgen receptor (AR) plays a pivotal role in prostate cancer pathogenesis, even after progression on androgen-directed therapies (ADT). In patients with metastatic castration-resistant prostate cancer (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. The randomized, open-label, phase 3 MK-5684-003 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 have mCRPC (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 end points are radiographic PFS per PCWG3-modified RECIST v1.1 by BICR and OS in patients with AR-LBD mutation-positive and -negative disease, separately. Secondary end points include time to initiation of first subsequent anticancer therapy or death; ORR and DOR per PCWG3-modified RECIST v1.1 by BICR; and safety. Enrollment is ongoing.

© 2024 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was previously presented at the 2024 ASCO Annual Meeting. All rights reserved.

Results:

Conclusion:

Funding: This study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Orion Corporation, who are codeveloping MK-5684 (ODM-208).