This study will compare DS-8201a to physician choice standard treatment.

Participants must have HER2-low breast cancer that has been treated before.

Participants' cancer:

• Cannot be removed by an operation
• Has spread to other parts of the body

This is a randomized, 2-arm, Phase 3, open-label, multicenter study to compare the safety and efficacy of trastuzumab deruxtecan versus the physician's choice (2:1) in HER2-low, unresectable and/or metastatic breast cancer participants.

The Sponsor proposes to define a new HER2-low population in this trial including tumors with IHC 1+ and IHC 2+/ISH- HER2 expression.

Inclusion Criteria:

• Is the age of majority in their country
• Has pathologically documented breast cancer that:
  1. Is unresectable or metastatic
  2. Has low-HER2 expression defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested)
  3. Is HR-positive or HR-negative
  4. Has progressed on, and would no longer benefit from, endocrine therapy
  5. Has been treated with 1 to 2 prior lines of chemotherapy/adjuvant in the metastatic setting
  6. Was never previously HER2-positive (ICH 3+ or ISH+) on prior pathology testing (per American Society of Clinical Oncology-College of American Pathologists [ASCO-CAP] guidelines)
• Has documented radiologic progression (during or after most recent treatment)
• Has adequate archival tumor samples available or is wiling to provide fresh biopsies prior to randomization for:
  1. assessment of HER2 status
  2. assessment of post-treatment status
• Has at least 1 protocol-defined measurable lesion
• Has protocol-defined adequate cardiac, bone marrow, renal, hepatic and blood clotting functions
• Male and female participants of reproductive/childbearing potential, agrees to follow instructions for method(s) of contraception and agrees to avoid preserving ova or sperm for at least 4.5 months after treatment (or longer, per locally approved labels)

Exclusion Criteria:

• Is ineligible for all options in the physician's choice arm
• Has breast cancer ever assessed with high-HER2 expression
• Has previously been treated with any anti-HER2 therapy, including an antibody drug conjugate
• Has uncontrolled or significant cardiovascular disease
• Has spinal cord compression or clinically active central nervous system metastases
• Has history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
• Has any medical history or condition that per protocol or in the opinion of the investigator is inappropriate for the study