Background: Carboplatin-paclitaxel chemotherapy (with trastuzumab for HER2+ uterine serous carcinoma) is the standard of care first-line systemic treatment for recurrent or metastatic endometrial carcinoma (EC), which has a 5-year relative survival rate of only 17%. Worse survival outcomes have been shown for the mismatch repair deficient (dMMR) subtype of EC. Pembrolizumab (pembro), an anti-PD-1 antibody, showed compelling antitumor activity in previously treated, advanced MSI-H/dMMR EC in the phase 2 KEYNOTE-158 study (ORR, 48%; median duration of response [DOR], not reached; O’Malley JCO 2022). KEYNOTE-C93/GOG-3064/ENGOT-en15 (NCT05173987) is a phase 3, randomized, open-label study evaluating first-line pembro versus carboplatin-paclitaxel chemotherapy in patients with dMMR advanced or recurrent EC. Methods: Patients aged ≥18 years with histologically confirmed stage III/IV recurrent EC including carcinosarcoma (mixed Mullerian tumor), radiographically evaluable disease (measurable or nonmeasurable per RECIST v1.1), no prior systemic therapy (prior radiation with or without radiosensitizing chemotherapy > 2 weeks before first dose or prior hormonal therapy ≥1 week before randomization is permitted), and an ECOG PS ≤1 are eligible. Patients must have central confirmation of dMMR status. Approximately 350 patients will be randomized 1:1 to receive pembro 400 mg IV Q6W for 18 cycles (̃2 years) or carboplatin AUC 5 or 6 mg/mL/min IV Q3W and paclitaxel 175 mg/m² IV Q3W for 6 cycles (with option for > 6 cycles). Trastuzumab is permitted for patients in the chemotherapy arm with HER2+ serous EC. Randomization is stratified by disease status (newly diagnosed advanced EC vs recurrent EC) and histology (endometrioid vs nonendometrioid). Treatment will continue for the specified number of cycles or until PD or unacceptable toxicity. Patients in the chemotherapy arm have the option to receive pembro following confirmed PD by blinded independent central review (BICR). Tumor imaging will be performed Q9W from randomization to week 54 and Q12W thereafter. AEs will be assessed from randomization to 30 days (90 days for serious AEs) after treatment discontinuation and graded per NCI CTCAE version 5.0. Dual primary endpoints are PFS per RECIST v1.1 by BICR and OS. Secondary endpoints are ORR, disease control rate, and DOR per RECIST v1.1 by BICR; PFS per RECIST v1.1 by investigator review; PFS2 (ie, time from randomization to PD per investigator assessment or death from any cause after start of subsequent anticancer therapy); safety; and patient-reported outcomes. PFS and OS will be estimated by the Kaplan-Meier method, with treatment differences assessed by the stratified log-rank test and HRs with 95% CIs determined using a Cox proportional hazard model. Enrollment is ongoing. Clinical trial information: NCT05173987.