DS-8201a Versus Investigator's Choice for HER2-low Breast Cancer That Has Spread or Cannot be Surgically Removed [DESTINY-Breast04]

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 (2:1) 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:

- 60 hormone receptor (HR)-negative

- 240 HR-positive who have had prior therapy with a cyclin-dependent kinase (CDK) 4/6
inhibitor

- 240 HR-positive who are naive to treatment with CDK 4/6

There will be approximately 161 sites, including but not limited to, North America, Western
Europe, and Asia.

There are planned follow-up visits after permanent discontinuation of study treatment to
obtain information about subsequent treatment(s) and survival status.

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

- Has documented radiologic progression (during or after most recent treatment)

- Has adequate 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 Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1

- Has at least 1 protocol-defined measurable lesion

- Has protocol-defined adequate cardiac, bone marrow, renal, hepatic and blood clotting
functions

- If 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, current, or suspicion of interstitial lung disease/pneumonitis

- Has any medical history or condition that per protocol or in the opinion of the
investigator is inappropriate for the study