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

Primary Outcome Measures

1. Progression-free survival (PFS), as assessed by BICR
   Defined as time from randomization until progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR), or death due to any cause.

Secondary Outcome Measures

1. Overall Survival (OS)
   Defined as the time from randomization until the date of death due to any cause.
2. Progression Free Survival (PFS) as assessed by the investigator
   PFS by investigator has the same attributes as estimand of PFS by BICR except tumor assessment is by the investigator.
3. Time from randomization to second progression or death (PFS2)
   PFS2 will be defined as the time from randomization to the earliest of the progression event (following the initial investigator-assessed progression), after first subsequent therapy, or death.
4. Objective response rate (ORR), as assessed by BICR and investigator
   ORR as assessed and confirmed by BICR is defined as the proportion of participants who have a complete response (CR) or partial response (PR), as determined and confirmed by BICR. ORR as assessed and confirmed by the investigator has the same attributes as estimand of ORR by BICR except tumor assessment per the investigator.
5. Duration of response (DoR), as assessed by BICR and investigator
   DoR as assessed by BICR will be defined as the time from the date of first documented response of confirmed responders until date of documented progression per RECIST 1.1, or death due to any cause. DoR as assessed by the investigator has the same attributes as estimand of DoR by BICR except tumor assessment per the investigator.
6. Safety and tolerability
   Safety and tolerability will be evaluated in terms of AEs/serious AEs (SAEs), AESI, vital signs, clinical safety laboratory assessments, ECG and ECHO/MUGA scan results.
7. Pharmacokinetics of T-DXd, total anti-HER2 antibody, DXd and rilvegostomig
   Serum concentration of T-DXd, total anti-HER2 antibody, DXd and rilvegostomig.
8. Immunogenicity of T- DXd and rilvegostomig
   Presence of ADAs for T-DXd or rilvegostomig.
9. Patient-reported tolerability
   Patient-reported tolerability will be described among participants, as treated, using the following outcomes: * Symptomatic AEs: Descriptive summary of the proportion of participants reporting symptomatic AEs while on treatment, as assessed by items from the EORTC Item Library and the FACT/GOG-NTX-4 * Overall side-effect bother: Descriptive summary of the proportion of participants reporting overall side-effect bother on the PGI-TT while on treatment
10. Progression-free survival (PFS) according to MMR status to determine the clinical utility of a MMR diagnostic test
    PFS is defined as time from randomization until progression per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) as assessed by BICR, or death due to any cause.
11. Overall survival (OS) according to MMR status to determine the clinical utility of a MMR diagnostic test
    OS defined as the time from randomization until the date of death due to any cause.
12. Progression-free survival (PFS) according to HER2 expression to determine the clinical utility of a HER2 diagnostic test
    PFS is defined as time from randomization until progression per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) as assessed by BICR, or death due to any cause.
13. Overall survival (OS) according to HER2 expression to determine the clinical utility of a HER2 diagnostic test
    OS is defined as the time from randomization until the date of death due to any cause.