Study of Trastuzumab Deruxtecan Versus Standard of Care Chemotherapy for HER2-Expressing (IHC 3+/2+) Endometrial Cancer

Inclusion criteria

• Adults ≥18 years at the time the ICF is signed (Please follow local regulatory requirements if the legal age of consent for trial participation is \>18 years old)
• Has histologically confirmed diagnosis of epithelial endometrial carcinoma. All histology's are allowed except for sarcomas (carcinosarcomas are allowed).
• Is newly diagnosed FIGO 2023 Stage IIC (including Stage IICmp53abn) or Stage III Note: FIGO 2023 Stage IIC includes disease with aggressive histological types (aggressive histological types are composed of high-grade EECs (grade 3), serous, clear cell, undifferentiated, mixed, mesonephric-like, gastrointestinal mucinous type carcinomas, and carcinosarcomas) with any myometrial involvement. FIGO 2023 Stage III includes disease with local and/or regional spread of the tumor of any histological subtype.
• Has HER2-expression (IHC 3+/2+) per 2016 ASCO-CAP gastric cancer IHC scoring guidelines as confirmed by central laboratory testing.
• Has adequate archived tumor tissue sample (sample from surgery is strongly recommended) available for assessment of HER2 status by central laboratory. Key

Exclusion criteria

• Has uterine mesenchymal tumor such as an endometrial stromal sarcoma, leiomyosarcoma, or other types of pure sarcomas. Adenosarcomas are also not allowed.
• Has recurrent or FIGO 2023 Stage IV
• Has measurable residual tumor after surgery as determined by BICR assessment.
• Is known to have a POLE mutation from an approved and/or validated local test, according to local regulations, if available
• Has a medical history of MI within 6 months before randomization/enrollment, symptomatic CHF (NYHA Class II to IV). Participants with troponin levels above ULN at SCR (as defined by the manufacturer), and without any MI related symptoms should have a cardiologic consultation during SCR Period to rule out MI.
• Has a QTcF prolongation to \> 480 msec based on average of the SCR triplicate12-lead ECG. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli within 3 months of the trial enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.) and any autoimmune, connective tissue, or inflammatory disorder with potential pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.
• Has a history of (noninfectious) ILD/pneumonitis that required corticosteroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at SCR.