Recruiting
Phase 3

Opevesostat vs. NHA

Sponsor:

Merck Sharp & Dohme LLC

Code:

NCT06136624

Conditions

Prostate Cancer Metastatic

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Opevesostat

Abiraterone acetate

Enzalutamide

Hydrocortisone

Fludrocortisone acetate

Study Details

Brief 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.

Conditions

Prostate Cancer Metastatic

Study ID

NCT06136624

Start date

Dec 31, 2023

Status verified date

Oct, 2026

Completion date

Feb 15, 2030

Anticipated

Primary completion date

Aug 2, 2028

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

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 Design

Enrollment

1310 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Opevesostat

Participants receive opevesostat 5 mg by oral tablets twice daily (bid) plus dexamethasone 1.5 mg by oral tablets once daily (qd) and 0.1 mg fludrocortisone acetate by oral tablet qd until progression. Hydrocortisone 100 mg (oral or intramuscular \[IM\]) dose will also be provided to participants for use as rescue medication. Prior to study protocol amendment 9, prednisone was provided as a rescue medication during adrenal recovery, titrated at 5mg daily maintenance dose and then titrated to discontinuation.

active comparator: Abiraterone Acetate or Enzalutamide

Participants receive abiraterone 1000 mg qd by oral tablets plus prednisone 5 mg bid by oral tablets or enzalutamide 160 mg qd by oral tablets.

Interventions

Opevesostat

Administered orally

Abiraterone acetate

Administered orally

Enzalutamide

Administered orally

Hydrocortisone

Administered orally or IM as a rescue medication

Fludrocortisone acetate

Administered orally

Prednisone

Administered orally as a rescue medication

Dexamethasone

Administered orally as rescue medication

Primary outcome measure

  • Overall Survival (OS) in Androgen Receptor Ligand Binding Domain (AR LBD) Mutation-Positive Participants [ Time Frame: Up to ~54 months ]
  • OS in AR LBD Mutation-Negative Participants [ Time Frame: Up to ~54 months ]

Central Contacts and Locations

Central contacts

Toll Free Number

1-888-577-8839Trialsites@msd.com

Locations

Stanford Cancer Center ( Site 0036)

Recruiting

Palo Alto, California, United States, 94304

Contacts

Study Coordinator

650-725-2078

Kaiser Permanente Riverside Medical Center ( Site 0099)

Recruiting

Riverside, California, United States, 92505

Contacts

Study Coordinator

951-809-8361

Anschutz Cancer Pavilion ( Site 0046)

Recruiting

Aurora, Colorado, United States, 80045

Contacts

Study Coordinator

302-290-3598

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

Recruiting

Highlands Ranch, Colorado, United States, 80129

Contacts

Study Coordinator

302-290-3598

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

Recruiting

Lone Tree, Colorado, United States, 80124

Contacts

Study Coordinator

720-848-5146

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

Recruiting

New Haven, Connecticut, United States, 06510

Contacts

Study Coordinator

203-737-8076

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

Recruiting

Miami, Florida, United States, 33136

Contacts

Study Coordinator

305-243-1543

University of Illinois at Chicago ( Site 0105)

Recruiting

Chicago, Illinois, United States, 60612

Contacts

Study Coordinator

973-330-2391

University of Chicago Medical Center ( Site 0045)

Recruiting

Chicago, Illinois, United States, 60637

Contacts

Study Coordinator

773-702-7609

Baltimore Veterans Affairs Medical Center ( Site 0069)

Recruiting

Baltimore, Maryland, United States, 21201

Contacts

Study Coordinator

410-707-4011

Greenebaum Comprehensive Cancer Center ( Site 0049)

Recruiting

Baltimore, Maryland, United States, 21201

Contacts

Study Coordinator

410-707-4011

Avera Cancer Institute - Marshall ( Site 0122)

Recruiting

Marshall, Minnesota, United States, 56258

Contacts

Study Coordinator

605-601-1830

M Health Fairview Clinics and Surgery Center ( Site 0019)

Recruiting

Minneapolis, Minnesota, United States, 55455

Contacts

Study Coordinator

612-626-1422

Hattiesburg Clinic Hematology/Oncology ( Site 0120)

Recruiting

Hattiesburg, Mississippi, United States, 39401

Contacts

Study Coordinator

601-261-1700

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

Recruiting

St Louis, Missouri, United States, 63110

Contacts

Study Coordinator

314-286-2341

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

Recruiting

Omaha, Nebraska, United States, 68105

Contacts

Study Coordinator

402-559-8500

Comprehensive Cancer Centers of Nevada ( Site 0010)

Recruiting

Las Vegas, Nevada, United States, 89148

Contacts

Study Coordinator

702-952-1251

Atlantic Health System Morristown Medical Center ( Site 0115)

Recruiting

Morristown, New Jersey, United States, 07960

Contacts

Study Coordinator

973-971-7960

James J. Peters VA Medical Center ( Site 0088)

Recruiting

The Bronx, New York, United States, 10468

Contacts

Study Coordinator

718-584-9000

University Hospitals Cleveland Medical Center ( Site 0043)

Recruiting

Cleveland, Ohio, United States, 44106

Contacts

Study Coordinator

216-844-3951

VA Portland Health Care System ( Site 0058)

Recruiting

Portland, Oregon, United States, 97239

Contacts

Study Coordinator

503-220-8262

Avera Cancer Institute - Aberdeen ( Site 0123)

Recruiting

Aberdeen, South Dakota, United States, 57401

Contacts

Study Coordinator

605-601-1830

Avera Cancer Institute - Mitchell ( Site 0121)

Recruiting

Mitchell, South Dakota, United States, 57301

Contacts

Study Coordinator

605-601-1830

Avera Cancer Institute - Pierre ( Site 0118)

Recruiting

Pierre, South Dakota, United States, 57501

Contacts

Study Coordinator

605-224-3370

Avera Cancer Institute- Research ( Site 0094)

Recruiting

Sioux Falls, South Dakota, United States, 57105

Contacts

Study Coordinator

605-322-6900

Avera Cancer Institute - Yankton ( Site 0117)

Recruiting

Yankton, South Dakota, United States, 57078

Contacts

Study Coordinator

605-655-1800

SCRI Oncology Partners ( Site 7000)

Recruiting

Nashville, Tennessee, United States, 37203

Contacts

Study Coordinator

615-218-4647

Texas Oncology - Central/South Texas ( Site 8003)

Recruiting

Austin, Texas, United States, 78731

Contacts

Study Coordinator

512-427-9400

Texas Oncology - Gulf Coast ( Site 8002)

Recruiting

Houston, Texas, United States, 77024

Contacts

Study Coordinator

713-467-1722

University of Virginia Health System ( Site 0054)

Recruiting

Charlottesville, Virginia, United States, 22908

Contacts

Study Coordinator

434-327-3029

Blue Ridge Cancer Care ( Site 0004)

Recruiting

Roanoke, Virginia, United States, 24014

Contacts

Study Coordinator

540-982-0237

Fred Hutchinson Cancer Center ( Site 0013)

Recruiting

Seattle, Washington, United States, 98109

Contacts

Study Coordinator

617-413-9079

Medical College of Wisconsin ( Site 0020)

Recruiting

Milwaukee, Wisconsin, United States, 53226

Contacts

Study Coordinator

414-805-4600

Cross Cancer Institute ( Site 0332)

Recruiting

Edmonton, Alberta, Canada, T6G 1Z2

Contacts

Study Coordinator

7804328762

The Ottawa Hospital - General Campus-The Ottawa Hospital Cancer Centre ( Site 0336)

Recruiting

Ottawa, Ontario, Canada, K1H 8L6

Contacts

Study Coordinator

613-737-7700

Sunnybrook Research Institute ( Site 0331)

Recruiting

Toronto, Ontario, Canada, M4N 3M5

Contacts

Study Coordinator

647-533-1023

Princess Margaret Cancer Centre ( Site 0330)

Recruiting

Toronto, Ontario, Canada, M5G 2M9

Contacts

Study Coordinator

(416) 946-4501

Centre Intégré de Santé et de Services Sociaux de la Montérégie-Centre ( Site 0328)

Recruiting

Greenfield Park, Quebec, Canada, J4V 2H1

Contacts

Study Coordinator

4504665000 ext 3226

Centre intégré de cancérologie du CHU de Québec Université Laval, Hôpital de l'Enfant-Jésus ( Site 0327)

Recruiting

Québec, Quebec, Canada, G1J 1Z4

Contacts

Study Coordinator

418 525-4444

More Information

Sponsor

Merck Sharp & Dohme LLC

Last update posted

Oct 6, 2026

Last verified

Oct, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-10-09. This information was provided to ClinicalTrials.gov by Merck Sharp & Dohme LLC on 2026-10-06. Recruitment status is synced daily from ClinicalTrials.gov and may not reflect the sponsor's current status. Confirm during your call.