Opevesostat

Overview

Opevesostat (MK-5684; formerly ODM‑208) is an oral, non‑steroidal, selective inhibitor of CYP11A1 (cholesterol side‑chain cleavage enzyme) being developed for hormone‑dependent cancers, primarily metastatic castration‑resistant prostate cancer (mCRPC). Early‑phase data show suppression of steroidogenesis with antitumor activity, particularly in tumors harboring activating androgen receptor ligand‑binding‑domain (AR‑LBD) mutations. Two Phase 3 trials in mCRPC are ongoing. (evidence.nejm.org)

Mechanism of action

CYP11A1 catalyzes conversion of cholesterol to pregnenolone, the first and rate‑limiting step in biosynthesis of all steroid hormones (glucocorticoids, mineralocorticoids, and sex steroids). By inhibiting CYP11A1, opevesostat suppresses production of steroids and precursors that can activate AR signaling, including in tumors with AR‑LBD mutations that broaden ligand sensitivity. Because systemic steroid synthesis is blocked, therapy is co‑administered with glucocorticoid/mineralocorticoid replacement (e.g., dexamethasone and fludrocortisone). (evidence.nejm.org)

Efficacy

• Phase I (CYPIDES, ASCO‑GU 2022): In heavily pretreated mCRPC (n=41 treated in dose‑finding; 36 evaluable for PSA), ≥50% PSA decline (PSA50) occurred in 33% overall. PSA50 was enriched in AR‑LBD–mutant tumors: 67% (10/15) vs 8% (2/24) without AR‑LBD mutation. Serum testosterone and other measured steroids became undetectable in most patients within 4 weeks. (ascopubs.org)

• Phase I/IIa interim publication (NEJM Evidence, posted Dec 26, 2023; in issue Jan 1, 2024): In the first part of CYPIDES (n=92 treated with 5 mg BID plus hormone replacement), investigators reported potent, pan‑steroid suppression with antitumor activity, especially in AR‑LBD–mutant mCRPC. (Full study details—including protocol and appendix—are available in the publication.) (evidence.nejm.org)

• Phase II expansion (ASCO‑GU 2024 poster; data cutoff July 17, 2023): At the recommended 5 mg BID dose with replacement therapy, PSA50 occurred in 55.6% of AR‑LBD–mutant vs 16.7% of AR‑LBD–wild‑type patients; objective responses (RECIST) were observed in 8 patients, all AR‑LBD–mutant (ORR 20.5% in that subgroup). (ascopubs.org)

• Updated Phase II results (ESMO Congress 2024): Among 66 AR‑LBD–mutant and 68 AR‑LBD–wild‑type patients, PSA50 rates were 53.0% vs 14.7%, respectively; RECIST responses in 10 patients (8 with AR‑LBD mutations; ORR 18.6% in AR‑LBD–mutant subgroup). (oncologypro.esmo.org)

Note: All reported patients were heavily pretreated (prior novel hormonal agent[s] and taxane[s]). Phase 3 studies are designed to determine whether these signals translate into improvements in radiographic progression‑free survival (rPFS) and overall survival (OS). (yalemedicine.org)

Safety

Across studies, on‑target adrenal suppression/adrenal‑insufficiency–like events are the principal risk and are mitigated with glucocorticoid/mineralocorticoid replacement. In Phase I dose‑finding (higher/earlier doses), grade 3 adrenal insufficiency occurred in 37% (15/41). At the 5 mg BID Phase II dose, hospitalization for adrenal‑insufficiency–like events was substantially lower (reported ~3–7% across data cuts). Other common effects reflect steroid suppression. (ascopubs.org)

Clinical development status (as of Oct 7, 2025)

• OMAHA1 (NCT06136624; MK‑5684‑003): Phase 3, randomized, open‑label opevesostat + hormone replacement vs alternative abiraterone or enzalutamide in later‑line mCRPC previously treated with ≥1 NHA and taxane(s); coprimary endpoints OS and rPFS. Ongoing. (merck.com)

• OMAHA2a/OMAHA‑004 (NCT06136650; MK‑5684‑004): Phase 3 in mCRPC after one prior NHA; coprimary endpoints rPFS and OS. Ongoing. (stanfordhealthcare.org)

Merck (MSD) holds exclusive global rights following exercise of an option with Orion (July 1, 2024). (merck.com)

Further reading

• Targeted Inhibition of CYP11A1 in Castration‑Resistant Prostate Cancer (NEJM Evidence; interim CYPIDES Phase I/IIa results) https://evidence.nejm.org/doi/10.1056/EVIDoa2300171 (evidence.nejm.org)
• ASCO‑GU 2024 abstract: MK‑5684 (ODM‑208), a CYP11A1 inhibitor, in mCRPC with and without AR‑LBD mutations (CYPIDES Phase 2) https://ascopubs.org/doi/10.1200/JCO.2024.42.4_suppl.159 (ascopubs.org)
• ASCO‑GU 2022 Phase I results (CYPIDES) https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.6_suppl.018 (ascopubs.org)
• ESMO Congress 2024 updated Phase II results (OncologyPRO) https://oncologypro.esmo.org/meeting-resources/esmo-congress-2024/opevesostat-mk-5684-odm-208-an-oral-cyp11a1-inhibitor-in-metastatic-castration-resistant-prostate-cancer-mcrpc-updated-cypides-phase-ii-results (oncologypro.esmo.org)
• Phase 3 OMAHA1 (NCT06136624) overview (e.g., CDEK, UChicago) https://cdek.pharmacy.purdue.edu/trial/NCT06136624/; https://www.uchicagomedicine.org/find-a-clinical-trial/clinical-trial/irb240166 (cdek.pharmacy.purdue.edu)
• Phase 3 OMAHA‑004 (NCT06136650) overview (e.g., Stanford) https://stanfordhealthcare.org/trials/a/NCT06136650.html (stanfordhealthcare.org)
• Merck–Orion licensing announcement (July 1, 2024) https://www.merck.com/news/merck-and-orion-announce-mutual-exercise-of-option-providing-merck-global-exclusive-rights-to-opevesostat-an-investigational-cyp11a1-inhibitor-for-the-treatment-of-metastatic-castration-resistant-pr/ (merck.com)

Notes and limitations: Reported efficacy comes from early‑phase, predominantly single‑arm cohorts in heavily pretreated mCRPC; responses are enriched in AR‑LBD–mutant disease. Definitive benefit on rPFS/OS awaits results from ongoing Phase 3 trials. (ascopubs.org)

Last updated: Oct 2025