Inclusion Criteria:

• Patients must be ≥ 18 years of age.
• Pathologically documented breast cancer that:
  • is advanced or metastatic;
  • has a history of HER2-low or negative expression defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) or HER2 IHC 0 (ISH- or untested);
  • has HER2-low or HER2 IHC >0 <1+ expression;
  • was never previously HER2-positive. is documented HR+ disease in the metastatic setting;
  • No prior chemotherapy for advanced or metastatic breast cancer;
  • Has adequate tumor samples for assessment of HER2 status.
• Must have had either:
  • Disease progression on endocrine therapy + CDK4/6 inhibitor within 6 months of starting first line treatment for metastatic disease and considered appropriate for chemotherapy as the next treatment by the investigator; OR
  • Disease progression on at least 2 previous lines of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors) administered for the treatmentof metastatic disease.
• Has protocol-defined adequate organ and bone marrow function.

Exclusion Criteria:

• Ineligible for all options in the investigator's choice chemotherapy arm.
• Lung-specific intercurrent clinically significant illnesses.
• Uncontrolled or significant cardiovascular disease or infection.
• Active or prior documented interstitial lung disease (ILD)/pneumonitis or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
• Patients with spinal cord compression or clinically active central nervous system metastases.
• Prior randomization or treatment in a previous trastuzumab deruxtecan study regardless of treatment arm assignment.

Eligibility last updated 11/24/21. Questions regarding updates should be directed to the study team contact.