Study of Opevesostat (MK-5684) Versus Alternative NHA in mCRPC (MK-5684-003)

Inclusion Criteria:

• Has histologically- or cytologically-confirmed adenocarcinoma of the prostatewithout small cell histology.

• Has prostate cancer progression while on androgen deprivation therapy (or postbilateral orchiectomy) within 6 months before Screening

• Has current evidence of distant metastatic disease (M1 disease) documented by eitherbone lesions on bone scan and/or soft tissue disease by computed tomography/magneticresonance 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 metastaticcastration-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 tissuenot previously irradiated

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1assessed within 7 days of randomization

• Has had prior treatment with PARPi or were deemed ineligible to receive treatment bythe 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 areineligible for cabazitaxel treatment as determined by the investigator or haverefused treatment

• If participant received first generation anti-androgen therapy before screening, theparticipant has evidence of disease progression >4 weeks since the last flutamidetreatment 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 thedate of randomization

• Participants with human immunodeficiency virus (HIV) infection must have wellcontrolled HIV on antiretroviral therapy (ART)

• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible ifthey have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeksand have undetectable HBV viral load before randomization

• Participants with history of hepatitis C virus (HCV) infection are eligible if HCVviral load is undetectable at Screening.

• Participants who can produce sperm must agree to the following during the studytreatment period and for at least 7 days after the last dose of opevesostat, for atleast 30 days after the last dose of abiraterone acetate, and for at least 3 monthsafter the last dose of enzalutamide: EITHER be abstinent OR must agree to use malecondom

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, includingthromboembolic events

• Has a history of seizure within 6 months of providing documented informed consent orany condition that may predispose to seizures within 12 months before the date ofrandomization

• Has a history of clinically significant ventricular arrhythmias

• Has received an anticancer monoclonal antibody (mAb) within 4 weeks before the dateof randomization, or has not recovered from adverse events (AEs) due to mAbsadministered more than 4 weeks before the date of randomization

• Has undergone major surgery, including local prostate intervention (except prostatebiopsy), within 28 days before the date of randomization, and has not recovered fromthe toxicities and/or complications

• Participants who have not adequately recovered from major surgery or have ongoingsurgical complications

• Has used herbal or medicinal products that may have hormonal anti-prostate canceractivity and/or are known to decrease prostate-specific Antigen (PSA) (eg, sawpalmetto, megesterol acetate, citrus pectin polysaccharide) within 4 weeks beforethe date of randomization

• Has received radium-223 or lutetium-177 within 4 weeks before the date ofrandomization, or has not recovered to Grade ≤1 or baseline from AEs due toradium-223 or lutetium-177 administered more than 4 weeks before the date ofrandomization

• Has received treatment with 5-αreductase inhibitors (eg, finasteride ordutasteride), estrogens, or cyproterone within 4 weeks before the date ofrandomization

• Has received colony-stimulating factors within 28 days before the date ofrandomization

• Has received a whole blood transfusion in the last 120 days before the date ofrandomization. Packed red blood cells and platelet transfusions are acceptable ifnot given within 28 days of the date of randomization

• Has received prior targeted small molecule therapy or NHA treatment within 4 weeksbefore the first dose of study intervention as follows: enzalutamide or apalutamidewithin 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 therapyor any other form of immunosuppressive therapy within 7 days prior the first dose ofstudy medication

• Has a known additional malignancy that is progressing or has required activetreatment within the past 3 years

• Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis

• Has an active autoimmune disease that has required systemic treatment in past 2years

• 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) oruncontrolled hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥90 mm Hg, in 2out of 3 recordings with optimized antihypertensive therapy)

• Is unable to swallow capsules/tablets

• Is currently being treated with cytochrome 450-inducing antiepileptic drugs forseizures

• Participants on an unstable dose of thyroid hormone therapy within 6 months beforethe start of the study intervention

• Received prior systemic anticancer therapy including investigational agents within 4weeks before the first dose of study intervention

• Received prior radiotherapy within 2 weeks of start of study intervention, orradiation-related toxicities, requiring corticosteroids

• Received a live or live-attenuated vaccine within 30 days before the first dose ofstudy intervention

• Systemic use of the following medications within 2 weeks before the first dose ofstudy intervention: strong CYP3A4 inducers (eg, avasimibe, carbamazepine,lumacaftor, phenobarbital, rifampicin, rifapentine, or St John's Wort); P-gpinhibitors (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