Inclusion criteria

Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of locally-advanced, unresectable, or metastatic breast carcinoma.
• Human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) status appropriate for enrollment in cohort.
• HER2 status determined by most recent local assessment based on American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) guidelines for assessment of HER2 in BC for interpretation of HER2 expression and amplification
• HER2+: immunohistochemistry (IHC) 3+ or IHC 2+/in situ hybridization (ISH)+
• HER2-low: IHC 1+/ISH-negative or untested or IHC 2+/ISH-negative
• HER2-ultralow: IHC 0 with membrane staining (any staining of the membrane in \>0 and ≤10% of cancer cells) o HR+ disease is determined as either estrogen receptor (ER) and/or progesterone receptor (PgR) positive \[ER or PgR ≥1%\]) and HR negative disease is determined as both ER and PR negative \[ER and PgR \<1%\]) per ASCO/CAP guidelines in the advanced disease setting. If a patient has had multiple ER/PgR results for advanced disease, the most recent test result will be used to confirm eligibility. Prior therapy requirements for Cohort 1 (HER2+, HR+ or HR- participants):
• Received prior trastuzumab, pertuzumab and a taxane if available as local first line standard of care therapy for advanced disease.
• Prior tucatinib based therapy is allowed.
• Must have progression on or after, or be intolerant to, T-DXd in any line advanced disease setting.
• No more than 3 prior systemic cytotoxic therapy regimens (including antibody drug conjugates \[ADCs\]) for Locally Advanced (LA)/metastatic breast cancer (mBC). Participants previously treated with (neo)adjuvant cytotoxic therapy and have disease relapsed within 6 months of cytotoxic treatment is considered to have received 1 line of cytotoxic therapy for LA/mBC. Prior therapy requirements for Cohort 2 (HR+/HER2-low participants):
• No more than 3 prior systemic cytotoxic therapy regimens (including ADCs) for LA/mBC. Participants previously treated with (neo)adjuvant cytotoxic therapy and have disease relapsed within 6 months of cytotoxic treatment is considered to have received 1 line of cytotoxic therapy for LA/mBC.
• Participants with known germline breast cancer gene (BRCA) mutation must have received a poly-ADP ribose polymerase (PARP) inhibitor, where available and not medically contraindicated.
• Must have progression on or after, or be intolerant to, trastuzumab deruxtecan (T-DXd) in any line advanced disease setting.
• Must have intolerance to endocrine therapy (ET) or ET refractory disease:
• Progressed on ≥2 lines of ET for LA/mBC AND had received a cyclin-dependent kinase (CDK)4/6 inhibitor in the adjuvant or metastatic setting if available as local standard of care and not contraindicated. OR • Progressed on 1 line of ET for LA/mBC AND had a relapse while on adjuvant ET after definitive surgery for primary tumor AND had received a cyclin-dependent kinase (CDK) 4/6 inhibitor in the adjuvant or advanced setting if available as local standard of care and not contraindicated. Prior therapy requirements for Cohort 3 (HR+/HER2-ultralow or HR-/HER2-low \[HER2 low TNBC\] participants):
• No more than 4 prior systemic cytotoxic chemotherapy regimens (including ADCs) for advanced or mBC. Participants previously treated with (neo)adjuvant cytotoxic therapy and have disease relapsed within 6 months of cytotoxic treatment is considered to have received 1 line of cytotoxic therapy for LA/mBC.
• Known germline BRCA mutation must have received a PARP-inhibitor if available as local standard of care therapy and not medically contraindicated.
• Prior sacituzumab govitecan is allowed.
• Prior T-DXd is allowed.
• Participants with HR negative (TNBC), HER2-low and programmed cell death receptor ligand 1 (PD-L1)-positive (combined positive score \[CPS\] ≥10) tumors must have received pembrolizumab (or other PD-L1 inhibitor) with chemotherapy if available as local standard of care therapy and not medically contraindicated.
• Participants with HR+/HER2-ultra low tumors must have received at least 1 antihormonal therapy in any setting or be ineligible for ET.

• Participants with HR+/HER2-ultra low tumors must have had prior therapy with a CDK4/6 inhibitor in the adjuvant or advanced setting. Exclusion Criteria