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RecruitingInterventionalPhase 3

A Phase 3 Randomized, Open-label Study of MK-5684 Versus Alternative Abiraterone Acetate or Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) Previously Treated With Next-generation Hormonal Agent (NHA) and Taxane-based Chemotherapy (OMAHA-003)

NCT ID: NCT06136624Sponsor: Merck Sharp & Dohme LLCLast updated: 2026-05-05

Summary

This is a phase 3, randomized, open-label study of opevesostat compared to alternative abiraterone acetate or enzalutamide in participants with metastatic castration-resistant prostate cancer (mCRPC) with respect to overall survival (OS) in participants with mCRPC previously treated with next-generation hormonal agent (NHA) and taxane-based chemotherapy. It is hypothesized that opevesostat is superior with respect to OS in androgen receptor ligand binding domain (AR LBD) mutation-negative and -positive participants.

Arms & interventions

  • DrugOpevesostat

    Administered orally

  • DrugAbiraterone acetate

    Administered orally

  • DrugEnzalutamide

    Administered orally

  • DrugHydrocortisone

    Administered orally or IM as a rescue medication

  • DrugFludrocortisone acetate

    Administered orally

  • DrugPrednisone

    Administered orally

  • DrugDexamethasone

    Administered orally as rescue medication

Outcome measures

Primary

  • Overall Survival (OS) in Androgen Receptor Ligand Binding Domain (AR LBD) Mutation-Positive Participants

    OS is defined as time from randomization to death due to any cause. OS in AR LBD mutation-positive participants will be reported for each study arm.

    Time frame: Up to ~54 months

  • OS in AR LBD Mutation-Negative Participants

    OS is defined as time from randomization to death due to any cause. OS in AR LBD mutation-negative participants will be reported for each study arm.

    Time frame: Up to ~54 months

Secondary

  • Radiographic Progression-free Survival (rPFS) Per Prostate Cancer Working Group-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review in AR LBD Mutation-Positive Participants

    Time frame: Up to ~36 months

  • rPFS Per Prostate Cancer Working Group-modifiedRECIST 1.1 as Assessed by Blinded Independent Central Review in AR LBD Mutation-Negative Participants

    Time frame: Up to ~36 months

  • Time to Initiation of the First Subsequent Anti-Cancer Therapy or Death (TFST)

    Time frame: Up to ~54 months

  • Objective Response (OR)

    Time frame: Up to ~54 months

  • Duration of Response (DOR)

    Time frame: Up to ~54 months

  • Time to Pain Progression (TTPP)

    Time frame: Up to ~54 months

  • Time to Prostate-specific Antigen (PSA) Progression

    Time frame: Up to ~54 months

  • Time to First Symptomatic Skeletal-related Event (SSRE)

    Time frame: Up to ~54 months

  • Number of Participants Who Experience an Adverse Event

    Time frame: Up to ~54 months

  • Number of Participants Who Discontinue Study Treatment Due to an Adverse Event

    Time frame: Up to ~54 months

Eligibility criteria

Sex: AllAge: All agesHealthy volunteers: No
Inclusion Criteria: * Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology. * Has prostate cancer progression while on androgen deprivation therapy (or post bilateral orchiectomy) within 6 months before Screening * Has current evidence of distant metastatic disease (M1 disease) documented by either bone lesions on bone scan and/or soft tissue disease by computed tomography/magnetic resonance imaging (CT/MRI). * Has disease that progressed during or after treatment with 1 novel hormonal agent (NHA) * Has received 1 but no more than 2 taxane-based chemotherapy regimens for metastatic castration-resistant prostate cancer (mCRPC) and has had progressive disease (PD) during or after treatment * Has ongoing androgen deprivation with serum testosterone \<50 ng/dL (\<1.7 nM) * Has provided tumor tissue from a fresh core or excisional biopsy from soft tissue not previously irradiated * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization * Has had prior treatment with PARPi or were deemed ineligible to receive treatment by the investigator or have refused PARPi treatment * Has received prior 177Lu-PSMA-617 or were deemed ineligible to receive 177Lu-PSMA-617 treatment by the investigator or refused 177Lu-PSMA-617 treatment * Participants who have not received cabazitaxel can be enrolled if they are ineligible for cabazitaxel treatment as determined by the investigator or have refused treatment * If participant received first generation anti-androgen therapy before screening, the participant has evidence of disease progression \>4 weeks since the last flutamide treatment and \>6 weeks since the last bicalutamide or nilutamide treatment * Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses for ≥ 4 weeks before the date of randomization * Participants with human immunodeficiency virus (HIV) infection must have well controlled HIV on antiretroviral therapy (ART) * Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load before randomization * Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at Screening. * Participants who can produce sperm must agree to the following during the study treatment period and for at least 7 days after the last dose of opevesostat, for at least 30 days after the last dose of abiraterone acetate, and for at least 3 months after the last dose of enzalutamide: EITHER be abstinent OR must agree to use male condom Exclusion Criteria: * Has a gastrointestinal disorder that might affect absorption * Has a history of pituitary dysfunction * Has poorly controlled diabetes mellitus * Has clinically significant abnormal serum potassium or sodium level * Has a history of active or unstable cardio/cerebro-vascular disease, including thromboembolic events * Has a history of seizure within 6 months of providing documented informed consent or any condition that may predispose to seizures within 12 months before the date of randomization * Has a history of clinically significant ventricular arrhythmias * Has received an anticancer monoclonal antibody (mAb) within 4 weeks before the date of randomization, or has not recovered from adverse events (AEs) due to mAbs administered more than 4 weeks before the date of randomization * Has undergone major surgery, including local prostate intervention (except prostate biopsy), within 28 days before the date of randomization, and has not recovered from the toxicities and/or complications * Participants who have not adequately recovered from major surgery or have ongoing surgical complications * Has used herbal or medicinal products that may have hormonal anti-prostate cancer activity and/or are known to decrease prostate-specific Antigen (PSA) (eg, saw palmetto, megesterol acetate, citrus pectin polysaccharide) within 4 weeks before the date of randomization * Has received radium-223 or lutetium-177 within 4 weeks before the date of randomization, or has not recovered to Grade ≤1 or baseline from AEs due to radium-223 or lutetium-177 administered more than 4 weeks before the date of randomization * Has received treatment with 5-αreductase inhibitors (eg, finasteride or dutasteride), estrogens, or cyproterone within 4 weeks before the date of randomization * Has received colony-stimulating factors within 28 days before the date of randomization * Has received a whole blood transfusion in the last 120 days before the date of randomization. Packed red blood cells and platelet transfusions are acceptable if not given within 28 days of the date of randomization * Has received prior targeted small molecule therapy or NHA treatment within 4 weeks before the first dose of study intervention as follows: enzalutamide or apalutamide within 3 weeks or abiraterone acetate + prednisone or darolutamide within 2 weeks * Has a "superscan" bone scan * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis * Has an active autoimmune disease that has required systemic treatment in past 2 years * Has an active infection requiring systemic therapy * Has concurrent active HBV or known active HCV infection * Has a history of long QTc syndrome * Has any of the following at Screening Visit: hypotension (systolic BP \<110 mm Hg) or uncontrolled hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥90 mm Hg, in 2 out of 3 recordings with optimized antihypertensive therapy) * Is unable to swallow capsules/tablets * Is currently being treated with cytochrome 450-inducing antiepileptic drugs for seizures * Participants on an unstable dose of thyroid hormone therapy within 6 months before the start of the study intervention * Received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention * Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids * Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention * Systemic use of the following medications within 2 weeks before the first dose of study intervention: strong CYP3A4 inducers (eg, avasimibe, carbamazepine, lumacaftor, phenobarbital, rifampicin, rifapentine, or St John's Wort); P-gp inhibitors (eg, erythromycin, clarithromycin, rifampicin, ketoconazole, itraconazole, posaconazole, artesunate-pyronaridine, ritonavir, indinavir, nelfinavir, atazanavir, glecaprevir-pibrentasvir, simeprevir, ledipasvir-sofosbuvir, verapamil, diltiazem, dronedarone, propafenone, quinidine, cyclosporine, valspodar, or milk thistle \[Silybum marianum\]) * Use of aldosterone antagonist (eg, spironolactone, eplerenone) and phenytoin within 4 weeks before the start of the study intervention

Study locations (44)

University of California, Irvine (UCI) Health - UC Irvine Medical Center ( Site 0040)

Orange, California, 92868

Active Not Recruiting

Stanford Cancer Center ( Site 0036)

Palo Alto, California, 94304

Recruiting
Study Coordinator · Contact

Kaiser Permanente Riverside Medical Center ( Site 0099)

Riverside, California, 92505

Recruiting
Study Coordinator · Contact

Anschutz Cancer Pavilion ( Site 0046)

Aurora, Colorado, 80045

Recruiting
Study Coordinator · Contact

University of Colorado Health - Highlands Ranch Hospital ( Site 0111)

Highlands Ranch, Colorado, 80129

Recruiting
Study Coordinator · Contact

Colorado Clinical Research ( Site 0067)

Lakewood, Colorado, 80228

Active Not Recruiting

University of Colorado Health - Lone Tree Medical Center ( Site 0112)

Lone Tree, Colorado, 80124

Recruiting
Study Coordinator · Contact

Yale-New Haven Hospital-Yale Cancer Center ( Site 0064)

New Haven, Connecticut, 06510

Recruiting
Study Coordinator · Contact

Florida Cancer Specialists - South ( Site 7003)

Fort Myers, Florida, 33901

Recruiting
Study Coordinator · Contact

Bruce W. Carter Veterans Affairs Medical Center ( Site 0082)

Miami, Florida, 33125

Active Not Recruiting

University of Miami Hospital and Clinics, Sylvester Cancer Center ( Site 0051)

Miami, Florida, 33136

Recruiting
Study Coordinator · Contact

University of Illinois at Chicago ( Site 0105)

Chicago, Illinois, 60612

Recruiting
Study Coordinator · Contact

University of Chicago Medical Center ( Site 0045)

Chicago, Illinois, 60637

Recruiting
Study Coordinator · Contact

University of Iowa ( Site 0047)

Iowa City, Iowa, 52242

Recruiting
Study Coordinator · Contact

University of Kentucky Chandler Medical Center ( Site 0048)

Lexington, Kentucky, 40536

Active Not Recruiting

Ochsner Clinic Foundation ( Site 0108)

New Orleans, Louisiana, 70121

Active Not Recruiting

Baltimore Veterans Affairs Medical Center ( Site 0069)

Baltimore, Maryland, 21201

Recruiting
Study Coordinator · Contact

Greenebaum Comprehensive Cancer Center ( Site 0049)

Baltimore, Maryland, 21201

Recruiting
Study Coordinator · Contact

Henry Ford Hospital ( Site 0015)

Detroit, Michigan, 48202

Active Not Recruiting

M Health Fairview Clinics and Surgery Center ( Site 0019)

Minneapolis, Minnesota, 55455

Recruiting
Study Coordinator · Contact

Metro-Minnesota Community Clinical Oncology ( Site 0014)

Saint Louis Park, Minnesota, 55416

Recruiting
Study Coordinator · Contact

Washington University School of Medicine-Internal Medicine/Oncology ( Site 0062)

St Louis, Missouri, 63110

Active Not Recruiting

University Of Nebraska Medical Center-Oncology/Hematology ( Site 0095)

Omaha, Nebraska, 68105

Recruiting
Study Coordinator · Contact

Comprehensive Cancer Centers of Nevada ( Site 0010)

Las Vegas, Nevada, 89148

Recruiting
Study Coordinator · Contact

Atlantic Health System Morristown Medical Center ( Site 0115)

Morristown, New Jersey, 07960

Recruiting
Study Coordinator · Contact

Rutgers Cancer Institute of New Jersey ( Site 0033)

New Brunswick, New Jersey, 08901

Active Not Recruiting

James J. Peters VA Medical Center ( Site 0088)

The Bronx, New York, 10468

Recruiting
Study Coordinator · Contact

University Hospitals Cleveland Medical Center ( Site 0043)

Cleveland, Ohio, 44106

Recruiting
Study Coordinator · Contact

Oregon Health and Science University ( Site 0028)

Portland, Oregon, 97239

Active Not Recruiting

VA Portland Health Care System ( Site 0058)

Portland, Oregon, 97239

Recruiting
Study Coordinator · Contact

AHN Allegheny General Hospital ( Site 0001)

Pittsburgh, Pennsylvania, 15212

Active Not Recruiting

Ralph H. Johnson VA Health Care System (RHJVAHCS)-Urology ( Site 0083)

Charleston, South Carolina, 29401

Active Not Recruiting

Avera Cancer Institute - Pierre ( Site 0118)

Pierre, South Dakota, 57501

Recruiting
Study Coordinator · Contact

Avera Cancer Institute- Research ( Site 0094)

Sioux Falls, South Dakota, 57105

Recruiting
Study Coordinator · Contact

Avera Cancer Institute - Yankton ( Site 0117)

Yankton, South Dakota, 57078

Recruiting
Study Coordinator · Contact

SCRI Oncology Partners ( Site 7000)

Nashville, Tennessee, 37203

Recruiting
Study Coordinator · Contact

Texas Oncology - Central/South Texas ( Site 8003)

Austin, Texas, 78731

Recruiting
Study Coordinator · Contact

Texas Oncology - DFW ( Site 8001)

Dallas, Texas, 75246

Active Not Recruiting

Texas Oncology - Gulf Coast ( Site 8002)

The Woodlands, Texas, 77380

Recruiting
Study Coordinator · Contact

University of Virginia Health System ( Site 0054)

Charlottesville, Virginia, 22908

Recruiting
Study Coordinator · Contact

VCU Health Adult Outpatient Pavillion ( Site 0061)

Richmond, Virginia, 23219

Active Not Recruiting

Blue Ridge Cancer Care ( Site 0004)

Roanoke, Virginia, 24014

Recruiting
Study Coordinator · Contact

Fred Hutchinson Cancer Center ( Site 0013)

Seattle, Washington, 98109

Recruiting
Study Coordinator · Contact

MEDICAL COLLEGE OF WISCONSIN ( Site 0020)

Milwaukee, Wisconsin, 53226

Recruiting
Study Coordinator · Contact

References

  • Yu EY, Gratzke C, Burotto M, Zhang AY, Levesque E, Ortega F, Peer A, Vile D, Chen ZH, Song Y, Schloss C, Todoric J, Garratt C, Poehlein C, Antonarakis ES, Fizazi K. Steroidogenesis inhibitor opevesostat (MK-5684) for metastatic castration-resistant prostate cancer: OMAHA-003 and OMAHA-004 trial designs. Future Oncol. 2026 Mar;22(7):765-772. doi: 10.1080/14796694.2025.2595914. Epub 2026 Feb 23.(PubMed)
Study of Opevesostat (MK-5684) Versus Alternative NHA in mCRPC (MK-5684-003) | Cancerify