A Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (T-DM1) in High-risk HER2-positive Participants With Residual Invasive Breast Cancer Following Neoadjuvant Therapy (DESTINY-Breast05)

Key Inclusion Criteria:

• Adults ≥18 years old (local regulatory requirements will apply if the legal age ofconsent for study participation is >18 years old).

• Pathologically documented HER2-positive breast cancer (BC):

• HER2-positive expression defined as an immunohistochemistry (IHC) score of 3+and/or positive by in situ hybridization (ISH) confirmed prior to studyrandomization.

• Histologically confirmed invasive breast carcinoma.

• Clinical stage at disease presentation: T1-4, N0-3, M0; patients presenting withT1N0 tumors are not eligible.

• Pathologic evidence of residual invasive carcinoma in the breast and/or axillarylymph nodes following completion of neoadjuvant therapy meeting one of the followinghigh-risk criteria:

• Inoperable breast cancer at presentation (prior to neoadjuvant therapy),defined as clinical stages T4, N0-3, M0 or T1-3, N2-3, M0.

• Operable at presentation, defined as clinical stages T1-3,N0-1,M0, withaxillary node positive disease (ypN1-3) following neoadjuvant therapy.

• Completion of neoadjuvant systemic therapy, including taxane-based chemotherapy andHER2-directed treatment prior to surgery.

• Systemic therapy must consist of at least 6 cycles of neoadjuvant therapy witha total duration of at least 16 weeks, including at least 9 weeks oftrastuzumab (± pertuzumab) and at least 9 weeks of taxane-based chemotherapy tobe completed prior to surgery. Patients may have received an anthracycline aspart of neoadjuvant therapy in addition to taxane chemotherapy.

• Adequate excision as confirmed per medical records: surgical removal of allclinically evident disease in the breast and axillary lymph nodes.

• An interval of no more than 12 weeks between the date of last surgery and the dateof randomization.

• Known hormone receptor (HR) status, per local laboratory assessment, as defined byASCO-CAP guidelines (≥1%): HR positive status defined by either positive estrogenreceptor (ER) and/or positive progesterone receptor (PR).

status. HR-negative status defined by both known negative ER and known negative PR.

• Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior torandomization.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening.

• Has adequate organ function within 14 days before randomization.

Key Exclusion Criteria:

• Stage IV (metastatic) BC.

• History of any prior (ipsi- or contralateral) breast cancer except lobular carcinomain situ (LCIS).

• Evidence of clinically evident gross residual or recurrent disease followingneoadjuvant therapy and surgery.

• Prior treatment with T-DXd, T-DM1 or other anti-HER2 antibody-drug conjugate (ADC)or prior enrollment in a clinical study of T-DXd (regardless of treatment arm)

• History of exposure to the following cumulative doses of anthracyclines:

• Doxorubicin > 240 mg/m^2

• Epirubicin or Liposomal Doxorubicin-Hydrochloride > 480 mg/m^2

• For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m^2

• History of other malignancy within the last 5 years except for appropriately treatedCIS of the cervix, nonmelanoma skin carcinoma, Stage I melanoma skin carcinoma,Stage I uterine cancer, or other appropriately treated non-breast malignancies withan outcome similar to those mentioned above.

• History of (noninfectious) interstitial lung disease (ILD)/pneumonitis that requiredsteroids and/or has ILD/pneumonitis noted on computed tomography (CT) scan of thechest at Screening (asymptomatic interstitial changes confined to recent radiationtherapy fields are not excluded).

• Known pulmonary compromise resulting from intercurrent pulmonary illnessesincluding, but not limited to, any underlying pulmonary disorder (eg, pulmonaryemboli within three months prior to randomization, severe asthma, severe chronicobstructive pulmonary disease [COPD], restrictive lung disease).

• Any autoimmune, connective tissue or inflammatory disorders (eg, Rheumatoidarthritis, Sjogren's, sarcoidosis, etc) where there is documented or a suspicion ofpulmonary involvement or pneumonectomy at the time of screening.

• Medical history of myocardial infarction (MI) within 6 months before randomization,symptomatic congestive heart failure (CHF) (New York Heart Association Class II toIV), troponin levels consistent with MI as defined according to the manufacturer 28days prior to randomization.