DESTINY-Endometrial01: A Phase III Study of Trastuzumab Deruxtecan Plus Rilvegostomig or Pembrolizumab as First-Line Treatment of HER2-Expressing (IHC 3+/2+), Mismatch Repair Proficient (pMMR) Endometrial Cancer

Inclusion Criteria

• •* Participants must be ≥ 18 years of age at the time of screening. Other age restrictions may apply as per local regulations.
• •* Histologically confirmed diagnosis of epithelial endometrial carcinoma. All histologies are allowed except for sarcomas (carcinosarcomas are allowed).
• •* Following surgery or diagnostic biopsy, participant must have primary advanced disease (Stage III/IV) or first recurrent endometrial cancer and meet at least one of the following criteria:
• •* Primary Stage III (per FIGO 2023) disease with measurable disease at baseline per RECIST 1.1 based on the investigator's assessment.
• •* Primary Stage IV disease (per FIGO 2023) regardless of presence of measurable disease at baseline.
• •* First recurrent disease regardless of presence of measurable disease at baseline.
• •* Endometrial cancer with HER2 IHC expression of 3+ or 2+ as assessed by prospective central testing.
• •* Endometrial cancer that is determined pMMR by prospective central IHC testing.
• •* Provision of adequate FFPE tumor tissue sample of a tumor lesion that was not previously irradiated for central HER2, MMR, and PD-L1 IHC testing and valid central test results for randomization/ stratification.
• •* Prior therapy:
• •* Naïve to first-line systemic anticancer therapy. Participants may have received one prior line of adjuvant/neoadjuvant chemotherapy with curative intent (chemotherapy or chemoradiation) if disease recurrence or progression occurred ≥ 6 months after last dose of chemotherapy. Prior trastuzumab in the adjuvant/neoadjuvant setting is allowed.
• •* No prior exposure to ADCs or immune checkpoint inhibitors including (but not limited to) anti-PD-1/PD-L1/PD-L2 and anti-CTLA-4 antibodies and therapeutic anticancer vaccines.
• •* Participants may have received prior radiation therapy for the treatment of endometrial cancer. Prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para-aortic radiation therapy, and/or intravaginal brachytherapy. Adequate treatment washout period is required.
• •* Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1.
• •* Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days before randomization.
• •* Adequate organ and bone marrow function within 14 days before randomization.