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

Key Inclusion Criteria:

* ≥ 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).
* Participant must have primary advanced disease (Stage III/IV) or recurrent endometrial cancer and meet at least one of the following criteria:

  1. Primary Stage III (per FIGO 2023) disease with measurable disease at baseline per RECIST 1.1 based on the investigator's assessment.
  2. Primary Stage IV (per FIGO 2023) disease regardless of presence of measurable disease at baseline.
  3. Recurrent disease regardless of presence of measurable disease at baseline.
* Endometrial cancer with HER2 IHC expression of 3+ or 2+ by prospective central testing.
* Endometrial cancer that is determined pMMR by prospective central testing.
* Provision of an adequate FFPE tumor tissue sample for central HER2, MMR, and PD-L1 IHC testing.
* Prior therapy:

  1. No prior chemotherapy for the treatment of EC, except for one prior line of adjuvant/ neoadjuvant chemotherapy with curative intent (chemotherapy or chemoradiation) if completed ≥ 6 months prior to signature of the main ICF. Prior trastuzumab in the adjuvant/neoadjuvant setting is allowed.
  2. No prior exposure to antibody-drug conjugates or immune checkpoint inhibitors
  3. Participants may have received prior radiation therapy for the treatment of endometrial cancer. Adequate treatment washout period is required
  4. Participants may have received prior hormonal therapy for the treatment of endometrial cancer. Adequate treatment washout period is required
* ECOG 0-1.
* Left ventricular ejection fraction ≥ 50% within 28 days before randomization.
* Adequate organ and bone marrow function within 14 days before randomization.
* The participant is not considered a candidate for curative therapy in the judgment of the investigator.

Key Exclusion Criteria:

* Any severe or uncontrolled systemic diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or would jeopardize compliance with the protocol.
* Active or ongoing serious chronic gastrointestinal conditions associated with diarrhea, primary immunodeficiency, or non-infectious skin disease requiring systemic treatment.
* Active or prior documented autoimmune or inflammatory disorders requiring chronic systemic treatment with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs.
* History of (non-infectious) ILD/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
* Lung criteria:

  1. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease, etc.).
  2. Any autoimmune, connective tissue or inflammatory disorders where there is documented, or a suspicion of pulmonary involvement at the time of screening.
  3. Prior pneumonectomy (complete).
* History of myocardial infarction or unstable angina within 6 months before randomization, or symptomatic congestive heart failure (NYHA Class II to IV), clinically significant arrhythmia, uncontrolled hypertension, cardiomyopathy of any etiology or history of myocarditis.
* History of organ transplant or allogeneic stem cell transplant.
* Spinal cord compression or clinically active central nervous system metastases. Participants with clinically inactive brain metastases may be included in the study.
* Evidence of any of the following infections:

  1. Active tuberculosis
  2. HIV infection that is not well controlled.
  3. Active hepatitis B or C infection.