(UroToday.com) The 2026 ASCO GU Annual Symposium was host to a trials-in-progress prostate cancer poster session. Dr. Karim Fizazi presented OMAHA-004, an ongoing phase III trial of opevesostat, a CYP11A1 inhibitor, versus an androgen receptor pathway inhibitor (ARPI) switch in ARPI pre-treated men with metastatic castrate-resistant prostate cancer (mCRPC).
Activating androgen receptor (AR) somatic mutations are a common mechanism of resistance to AR-directed therapies in metastatic castration-resistant prostate cancer (mCRPC), and they may permit continued hormonal dependence.1-3 Upstream targeting of androgen biosynthesis may provide a therapeutic advantage over available AR antagonist therapies for mCRPC.
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 from cholesterol.4,5 Inhibition of CYP11A1 by opevesostat can potentially suppress the production of all steroid hormones and precursors that may promiscuously activate the AR signaling pathway.
In the phase 1/2 CYPIDES trial, opevesostat showed antitumor activity in participants with heavily pretreated mCRPC, especially in those with AR ligand-binding domain (AR-LBD) mutations.6
The randomized, open-label, phase 3 OMAHA-004 study (NCT06136650) will evaluate the efficacy and safety of opevesostat versus ARPI switch in participants with mCRPC after 1 prior ARPI. Eligible participants will be randomized 1:1 to:
- Arm 1: Opevesostat 5 mg PO BID + dexamethasone 1.5 mg QD + fludrocortisone 0.1 mg QD
- Arm 2 (ARPI switch): Abiraterone acetate 1,000 mg QD + prednisone 5 mg BID versus enzalutamide 160 mg QD
Randomization is stratified by:
- Presence versus absence of measurable disease
- AR-LBD mutation status
- Prior docetaxel exposure
Treatment continues until radiographic progression, unacceptable toxicity, or withdrawal of consent.
The key eligibility criteria are as follows:
Inclusion
- Disease progression after 1 prior ARPI in the mCRPC or mHSPC setting
Exclusion
- Prior taxane chemotherapy for mCRPC (docetaxel for mHSPC permitted)Prior treatment with CYP11A1 inhibitors
- Clinically significant cardiovascular disease
- Active CNS metastases
- Significant arrhythmias
The primary objective is radiographic progression-free survival (rPFS) per PCWG3-modified RECIST v1.1 by blinded independent central review (BICR), with a key secondary objective of overall survival (OS). Other secondary objectives include:
- Time to first subsequent therapy (TFST)
- Objective response rate (ORR) and duration of response (DOR)
- Time to pain progression (TTPP)
- Time to PSA progression
- PSA50 response rate
- Time to first symptomatic skeletal-related event (SSE)
- Safety and tolerability
Assessments and follow up are summarized below:
The statistical analytic plan is as follows:
- Efficacy analyses will be conducted in the intention-to-treat population. Between-arm comparisons for rPFS and OS will use stratified log-rank testing, with hazard ratios estimated using stratified Cox proportional hazards models
- ORR and PSA response rates will be evaluated using the Clopper–Pearson method, with between-arm differences assessed using the Miettinen and Nurminen method.
- Safety analyses will be conducted in the all-participants-as-treated population.
OMAHA-004 is actively enrolling globally, with participating sites across North America, South America, Europe, Asia, and Australia.
Presented by: Karim Fizazi, MD, PhD, Professor, Department of Medicine, Institut Gustave Roussy, Paris, France
Written by: Rashid K. Sayyid, MD, MSc, Assistant Professor, Urologic Oncologist, Department of Urology at The University of Arizona and Banner University Medical Center, Tucson, AZ – @rksayyid on X during the 2026 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA, between February 26th and 28th, 2026.
References:
- Tan MH, Li J, Xu HE, et al. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin. 2015;36:3-23.
- Bernard-Tessier A, Asselah J, Baciarello G, et al. Clinical activity of CYP11A1 inhibition in molecularly selected metastatic castration-resistant prostate cancer. J Clin Oncol. 2022;40(16_suppl):Abstract 5057.
- Yehya A, Ali M, Ibrahim M, et al. Mechanisms of resistance to androgen receptor-targeted therapies in metastatic castration-resistant prostate cancer. Cancer Drug Resist. 2022;5:667-690.
- Neunzig J, Bernhardt R, et al. Inhibition of CYP11A1 as a strategy to suppress steroid hormone biosynthesis in prostate cancer. PLoS One. 2014;9:e89727.
- McCarty KD, Smith R, Johnson T, et al. Structural and biochemical characterization of CYP11A1 inhibition and its impact on steroidogenesis. J Biol Chem. 2024;300:105495.
- Fizazi K, Smith MR, Tombal B, et al. Efficacy and safety of CYP11A1 inhibition with opevesostat in metastatic castration-resistant prostate cancer: results from the CYPIDES study. NEJM Evid. 2024;3:EVIDoa2300171.