This study is designed to compare the anti-tumor activity as well as the safety and efficacy of DS-8201a versus T-DM1 in HER2-positive, unresectable and/or metastatic breast cancer subjects previously treated with trastuzumab and taxane.

Inclusion Criteria:

1. Must be competent and able to comprehend, sign, and date an Institutional Review Board (IRB) or Ethics Committee (EC) approved ICF before performance of any study-specific procedures or tests.

2. Adults ≥18 y old. (Please follow local regulatory requirements if the legal age of consent for study participation is >18 y old.)

3. Pathologically documented breast cancer that:

   1. is unresectable or metastatic.
   2. has confirmed HER2-positive expression as determined according to American Society of Clinical Oncology - College of American Pathologists guidelines evaluated at a central laboratory.23
   3. was previously treated with trastuzumab and taxane in the advanced/ metastatic setting or progressed within 6 mo after neoadjuvant or adjuvant treatment involving a regimen including trastuzumab and taxane.

4. Documented radiologic progression (during or after most recent treatment or within 6 mo after completing adjuvant therapy).

5. Subjects must be HER2-positive as confirmed by central laboratory assessment of most recent tumor tissue sample available. If archived tissue is not available, a fresh biopsy is required.

6. Presence of at least 1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1

Exclusion Criteria:

1. Prior treatment with an anti-HER2 ADC (such as T-DM1) in the metastatic setting. Prior treatment in the adjuvant/neoadjuvant setting would be allowed if progression of disease did not occur within 12 mo of end of adjuvant therapy.

2. Uncontrolled or significant cardiovascular disease, including any of the following:

   1. History of myocardial infarction within 6 mo before randomization;
   2. History of symptomatic congestive heart failure (New York Heart Association Class II to IV);
   3. Troponin levels consistent with myocardial infarction as defined according to the manufacturer within 28 d prior to randomization;
   4. Corrected QT interval (QTc) prolongation to > 470 ms (females) or >450 ms (male) based on average of Screening triplicate 12-lead ECG;
   5. LVEF < 50% within 28 d prior to randomization

3. Has a history of (noninfectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.

4. Spinal cord compression or clinically active central nervous system (CNS) metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.

   • Subjects with clinically inactive brain metastases may be included in the study.
   • 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 wk must have elapsed between the end of whole brain radiotherapy and study enrollment.

5. Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.

6. History of severe hypersensitivity reactions to other mAbs.

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.

Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.