The reason for this trial is to compare DS-8201a to other treatments being used for breast cancer.

DS-8201a is a new medicine for breast cancer that has not been approved yet by the Food and Drug Administration. It is made of a drug and an antibody.

Each participant has a 2 out of 3 chance of receiving the new medicine.

This is a randomized, 2-arm, Phase 3, open-label, multicenter study to compare the safety and efficacy of DS8201a versus the physician's choice in HER2-low, unresectable and/or metastatic breast cancer subjects.

The study is expected to enroll ~360 DS-8201a subjects and ~180 physician's choice subjects. After ~60 hormone receptor (HR)-negative subjects have been enrolled, further enrollment will be limited to only subjects who have HR-positive disease. After ~240 HR-positive subjects who have not had prior therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor have been enrolled, further enrollment will be limited to only subjects who have had prior therapy with a CDK4/6 inhibitor.

The ~540 subjects will be randomized 2:1 to DS8201a versus the physician's choice of 1 of the following drugs:

• Capecitabine
• Eribulin
• Gemcitabine
• Paclitaxel
• Nab-paclitaxel

There will be approximately 164 sites, including but not limited to, North America, Western Europe, and Asia.

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

PFS based on BICR is defined as the time from the date of randomization to the earliest date of the first objective documentation of radiographic disease progression, assessed via BICR according to the modified response evaluation criteria in solid tumors (mRECIST) version 1.1, or death due to any cause.

First dose at Cycle 1 Day 1 should occur within 7 days after the date the subject is randomized.

Inclusion Criteria:

• Is the age of majority in their country
• Has pathologically documented breast cancer that:
  1. Is unresectable or metastatic.
  2. Has a history of low HER2 expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested).
  3. Is assessed by a central laboratory as low HER2 expression, defined as IHC 2+/ISH- or IHC 1+
  4. Is HR-positive or HR-negative. After ~60 HR-negative subjects are enrolled, further enrollment will be limited to only subjects who are HR-positive (either estrogen receptor positive or progesterone receptor positive per ASCO-CAP guidelines).
  5. Is documented refractory to endocrine therapy, defined as having progressed on at least 1 endocrine therapy and determined by the Investigator that subject would no longer benefit from further treatment from endocrine therapy.
  6. If HR-positive, has or has not been treated with a CDK4/6 inhibitor. After ~240 HR-positive subjects have been enrolled who have not had prior therapy with a CDK4/6 inhibitor, further enrollment of HR-positive subjects will be limited to subjects who have had prior therapy with a CDK4/6 inhibitor.
  7. Has been treated with at least 1 and at most 2 prior lines of chemotherapy in the metastatic setting. If recurrence occurred within 6 months of adjuvant chemotherapy, adjuvant therapy would count as 1 line of chemotherapy.
  8. Was never previously HER2-positive (IHC 3+ or ISH+) on prior pathology testing (per ASCO-CAP guidelines.)
  9. Was never previously treated with anti HER2 therapy.
• Has documented radiologic progression (during or after most recent treatment)
• Has an adequate archival tumor sample available for assessment of HER2 status by central laboratory (based on most recent available tumor tissue sample). If archival tissue is not available, a fresh biopsy is required.
• Has a recent tumor sample after the most recent treatment regimen or agree to undergo a tissue biopsy prior to randomization
• Has at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI), per modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1
• Has left ventricular ejection fraction (LVEF) ≥50%
• Has adequate renal function, defined as creatinine clearance ≥30 mL/min, as calculated using the CockcroftGault equation
• Has adequate hepatic function, defined as:
  1. Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤5 × upper limit of normal (ULN)
  2. Total bilirubin ≤1.5 × ULN) if no liver metastases or <3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
• If of reproductive/childbearing potential, agrees to follow instructions for method(s) of contraception

Exclusion Criteria:

• Is ineligible for all 5 of the options in the physician's choice arm, either because of previously receiving treatment in the metastatic setting with the comparator, or having a contraindication to treatment
• Has medical history of myocardial infarction within 6 months before randomization
• Has history of symptomatic congestive heart failure (New York Heart Association Class II to IV)
• Has corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (male) based on average of Screening triplicate 12-lead electrocardiograms (ECGs)
• Has a history of (noninfectious) 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, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms

NOTE: Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.