BACKGROUND: Patients with recurrent or metastatic endometrial cancer who have progressed on or after platinum-based chemotherapy and PD-(L)1 inhibitor therapy have limited treatment options and a poor prognosis. Sacituzumab govitecan is a trophoblast cell-surface antigen 2-directed antibody-drug conjugate approved for certain types of breast cancer. In the phase II TROPiCS-03 trial, sacituzumab govitecan demonstrated encouraging efficacy and manageable safety in heavily pretreated patients with advanced or metastatic endometrial cancer. PRIMARY OBJECTIVE(S): The ASCENT-GYN-01 trial aims to assess the efficacy and safety of sacituzumab govitecan versus treatment of the physician's choice in patients with endometrial cancer who have received platinum-based chemotherapy and PD-(L)1 inhibitor therapy. The primary objective is to compare the effect of sacituzumab govitecan versus treatment of the physician's choice on progression-free survival, assessed by blinded independent central review, and on overall survival. STUDY HYPOTHESIS: Patients with pretreated recurrent or persistent endometrial cancer will have improved progression-free survival and overall survival with sacituzumab govitecan compared with treatment of the physician's choice. TRIAL DESIGN: ASCENT-GYN-01 (ClinicalTrials.gov identifier NCT06486441) is a randomized, open-label, global phase III study. Patients will be randomized in a 1:1 ratio to receive sacituzumab govitecan or treatment of the physician's choice (doxorubicin or paclitaxel). MAJOR INCLUSION/EXCLUSION CRITERIA: Patients aged 18 years and older with documented evidence of recurrent or persistent endometrial cancer (endometrial carcinoma or carcinosarcoma) will be enrolled. Up to 3 prior lines of systemic therapy for endometrial cancer are allowed, including platinum-based chemotherapy and PD-(L)1 inhibitor therapy, either in combination or separately. Key exclusion criteria include uterine leiomyosarcoma or endometrial stromal sarcomas and prior treatment with a trophoblast cell-surface antigen 2-directed antibody-drug conjugate or topoisomerase I inhibitor. PRIMARY ENDPOINT(S): Dual primary endpoints are progression-free survival assessed by blinded independent central review and overall survival. SAMPLE SIZE: Approximately 640 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: June 2029. TRIAL REGISTRATION: NCT06486441; GOG-3104; ENGOT-en26; APGOT-EN2.