An Open-Label, Randomized, Phase 3 Study to Evaluate Patritumab Deruxtecan Monotherapy versus Treatment of Physician's Choice in Hormone Receptor-Positive, HER2-negative Unresectable Locally Advanced or Metastatic Breast Cancer.

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