Study of Belzutifan (MK-6482) Plus Fulvestrant for ER+/HER2- Metastatic Breast Cancer (MK-6482-029/LITESPARK-029)

Inclusion Criteria:

• Has a diagnosis of estrogen receptor positive (ER+)/human epidermal growth factorreceptor negative (HER2-) invasive breast carcinoma that is either locally advanceddisease not amenable to resection or metastatic disease not treatable with curativeintent

• Has documented radiographic confirmation of disease progression during or after thelast administered endocrine therapy (ET)

• Provides additional tissue from the same sample used to determine ER and HER2 statuslocally

• Has received ET in the noncurative setting and has 1) Radiographic diseaseprogression on 12 months or more of ET in combination with CDK4/6 inhibitor in thenoncurative setting or 2) Received at least 2 lines of ET in the noncurative settingincluding CDK4/6 inhibitor where the CDK 4/6 inhibitor was discontinued due tointolerance

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

• Participants who have AEs due to previous anticancer therapies must have recoveredto ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequatelytreated with hormone replacement or participants who have ≤Grade 2 neuropathy areeligible

• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible ifthey have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeksprior to the first dose of study intervention and have undetectable HBV viral loadprior to randomization

Exclusion Criteria:

• Has Breast cancer amenable to treatment with curative intent

• Is unable to receive any of the endocrine therapies (ETs) (ie, fulvestrant orexemestane)

• Has known difficulty in tolerating oral medications, unable to swallow orallyadministered medication, or conditions which would impair absorption of oralmedications such as uncontrolled nausea or vomiting (ie, CTCAE =Grade 3 despiteantiemetic therapy), ongoing gastrointestinal obstruction, motility disorder,malabsorption syndrome, or prior gastric bypass

• Has advanced/metastatic, symptomatic visceral spread at risk of rapidly evolvinginto life-threatening complications

• Has active, bleeding diathesis, or on oral anti-vitamin K medication

• Has history of noninfectious pneumonitis/interstitial lung disease includingradiation pneumonitis that required steroids or has current pneumonitis/interstitiallung disease

• Has a known germline BRCA mutation (deleterious or suspected deleterious) and hasreceived previous treatment with poly-ADP ribose polymerase (PARP) inhibition eitherin the adjuvant or metastatic setting

• Has received prior fulvestrant in the adjuvant, unresectable locally advanced, ormetastatic setting

• Has received any line of cytotoxic chemotherapy or PARP inhibitor in theunresectable or noncurative advanced/metastatic setting

• Has received prior radiotherapy for non-central nervous system (CNS) disease orrequired corticosteroids for radiation-related toxicities including radiationpneumonitis, within 14 days of the first dose of study intervention

• Is currently receiving either a strong inhibitor or inducer of CYP3A4 that cannot bediscontinued for the duration of the study

• Has received prior systemic anticancer therapy including investigational agentswithin 4 weeks before randomization

• Has received a live or live-attenuated vaccine within 30 days before the first doseof study intervention

• Has concurrent active Hepatitis B and Hepatitis C virus infection

• Has clinically significant cardiac disease, including unstable angina, acutemyocardial infarction within 6 months from Day 1 of study medication administration,or New York Heart Association Class III or Class IV congestive heart failure

• Has not adequately recovered from major surgery or have ongoing surgicalcomplications