Trastuzumab Deruxtecan (T-DXd) in Patients Who Have Hormone Receptor-negative and Hormone Receptor-positive HER2-low or HER2 IHC 0 Metastatic Breast Cancer

Inclusion Criteria:

* Sign and date the main informed consent form
* Must agree to provide a newly obtained or archival baseline biopsy from primary and/or metastatic lesion.
* Pathologically documented Breast Cancer (BC) tumor

  * Is unresectable and/or metastatic.
  * Is hormone receptor-negative or hormone receptor-positive.

    * Must include percentage of positively stained cells to characterize if hormone receptor-positive or -negative.
  * Has confirmed HER2 IHC 1+ or IHC 2+/ISH- (HER2-low) status or HER2 IHC 0 status as determined according to ASCO CAP 2018 guidelines1 based on sample collected during Tissue Screening as described above.
  * Was never previously HER2-positive (IHC 3+ or IHC 2+/ISH+) on prior pathology testing (per ASCO CAP guidelines).
  * Was never previously treated with anti-HER2 therapy in the metastatic setting.
* Has had at least one and up to two prior lines of therapy in the metastatic setting.

  * In participants with hormone receptor-positive HER2-low metastatic BC (Cohort 3):

    * Has recurrent disease \<2 years from the initiation of adjuvant ET OR
    * Has disease progression on CDK4/6 inhibitor-based regimen within 12 months of completion of adjuvant therapy with a CDK4/6 inhibitor OR
    * Has disease progression within the first 12 months of CDK4/6 in the first line metastatic setting
* Presence of at least one measurable lesion based on computed tomography or magnetic resonance imaging.
* Participants with brain metastases are allowed in the study. The brain lesion(s) should be small (\<2 cm), untreated, asymptomatic, not requiring urgent medical intervention, and are asymptomatic and clinically stable.
* Has an Eastern Cooperative Oncology Group performance status of 0 or 1.
* Has a minimum life expectancy of 12 weeks at Screening.
* Has a left ventricular ejection fraction ≥50% within 28 days before enrollment.
* Has adequate organ and bone marrow function within 28 days before enrollment.
* Has adequate treatment washout period before enrollment.
* Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception.

Exclusion Criteria:

* Prior treatment with an antibody drug conjugate (ADC).
* Uncontrolled or significant cardiovascular disease.
* Has a corrected QT interval prolongation.
* Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
* Has spinal cord compression or clinically active central nervous system metastases.
* Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, other solid tumors curatively treated, or contralateral BC.
* Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.
* Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
* Has an uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
* Active primary immunodeficiency, known uncontrolled active human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection.
* Has history of receiving a live, attenuated vaccine (messenger RNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study drug.
* Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline.
* Is pregnant or breastfeeding or planning to become pregnant.
* Lung-specific intercurrent clinically significant illnesses.
* Any autoimmune, connective tissue, or inflammatory disorders.
* Prior complete pneumonectomy.