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

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 therecurrent or 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 biopsiesprior to randomization for:

1. assessment of HER2 status

2. assessment of post-treatment status

• Has at least 1 measurable lesion per Response Evaluation Criteria In Solid Tumors 1.1

• Has protocol-defined adequate cardiac, bone marrow, renal, hepatic and bloodclotting functions

• Male and female participants of reproductive/childbearing potential, agrees tofollow instructions for method(s) of contraception and agrees to avoid preservingova or sperm for at least 4.5 months after treatment (or longer, per locallyapproved 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 drugconjugate

• 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 thatrequired steroids, has current ILD/pneumonitis, or suspected ILD/pneumonitis thatcannot be ruled out by imaging at screening

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