A Clinical Study of Patritumab Deruxtecan to Treat Breast Cancer (MK-1022-016)

Researchers are looking for other ways to treat breast cancer (BC) that is hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) and either unresectable locally advanced or metastatic. * HR positive (HR+) means the cancer cells have proteins that attach to estrogen or progesterone (hormones) which help the cancer to grow and spread * HER2 negative (HER2-) means the cancer cells have a low amount of a protein called HER2 * Unresectable locally advanced means the cancer cannot be completely removed by surgery and has spread into nearby tissue or muscles * Metastatic means the cancer has spread to other parts of the body Treatment for this type of breast cancer usually includes endocrine therapy (ET) and sometimes a second treatment. The main goal of this study is to learn if people who receive patritumab deruxtecan (also known as HER3-DXd and MK-1022) live longer overall or without the cancer growing/spreading, compared to people who receive chemotherapy or a different drug called trastuzumab deruxtecan.

Inclusion Criteria: The main inclusion criteria include but are not limited to the following: * Has a diagnosis of hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2)- invasive breast carcinoma that is either locally advanced disease not amenable to resection with curative intent (herein called unresectable) or metastatic disease not treatable with curative intent * Has centrally-confirmed HR+ and HER2- results and human epidermal growth factor receptor 3 (HER3) evaluable results from a biopsy obtained from a distant metastatic site or a locally advanced lesion on or after the most recent line of therapy (with certain exceptions) * Must have had progression or recurrence on prior cyclin-dependent kinase (CDK)4/6 inhibitor + endocrine therapy (ET) with one of the following: * Radiographic disease progression, as assessed by the investigator, on CDK4/6 inhibitor + ET as 1L for treatment of unresectable locally advanced or metastatic HR+/HER2- breast cancer. CDK4/6 inhibitor + ET must be the only line of therapy received in the advanced setting, or * Disease recurrence, either radiographic and/or confirmed histologically via biopsy as assessed by the investigator, while on adjuvant ET in combination with a CDK4/6 inhibitor OR within 24 months from the date of last dose of adjuvant CDK4/6 inhibitor * Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology * Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy * Has an Eastern Cooperative Oncology Group performance status of 0 or 1 assessed within 7 days before randomization Exclusion Criteria: The main exclusion criteria include but are not limited to the following: * Has breast cancer amenable to treatment with curative intent * Is eligible to receive additional endocrine-based treatment in the advanced setting as determined by the investigator * Has a known germline breast cancer gene (BRCA) mutation (deleterious or suspected deleterious) where poly (ADP-ribose) polymerase (PARP) inhibitor(s) is a potential treatment option * Has current visceral crisis or is at risk for impending visceral crisis that has or may cause imminent organ compromise and/or other life-threatening complications * Has any of the following: a pulse oximeter reading \<92% at rest, or requires intermittent supplemental oxygen, or requires chronic supplemental oxygen * Has uncontrolled, significant cardiovascular disease or cerebrovascular disease * Has ≥Grade 2 peripheral neuropathy. * Has clinically significant corneal disease * Has received prior chemotherapy for unresectable locally advanced or metastatic breast cancer * Has received prior treatment with an anti-HER3 antibody and/or antibody-drug conjugate that consists of a topoisomerase I inhibitor (eg, T-DXd) or any other topoisomerase I inhibitor therapy * Has received prior systemic anticancer therapy within 4 weeks (or 5 half-lives, whichever is shorter) before randomization; participants previously treated with ET plus a CDK4/6 inhibitor may participate as long as at least 2 weeks have elapsed since the last dose of therapy was administered * Has received prior radiotherapy for non-central nervous system disease, or required corticosteroids for radiation-related toxicities, within 14 days of the first dose of study intervention * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy * Has known additional malignancy that is progressing or has required active treatment within the past 3 years * Has history of (noninfectious) pneumonitis/interstitial lung disease (ILD) that required steroids, has current pneumonitis/interstitial lung disease, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at Screening * Has severe hypersensitivity (≥Grade 3) to HER3-DXd and/or any of its excipients * Has severe hypersensitivity (≥Grade 3) to all the available TPC and/or any of their excipients