Background: The standard treatment for advanced EC is still platinum-based combination CT, regardless of the histology, molecular status and the patient’s profile. However, EC patients are a particularly frail group of patients, often with co-morbidities. Tolerance of CT can be difficult and induce long-term toxicities. In advanced EC disease, MMRd/MSI-H tumors represent 15 to 20 % of cases. Preclinical data suggest that these tumors are more resistant to platinum. On the other hand, anti-PD1 immunotherapy has shown impressive results among MMRd/MSI-H EC patients after platinum-based CT. The aim of this study is to de-escalade the first line advanced/metastatic treatment of patients with MMRd/MSI-H endometrial cancer with the objective to avoid carboplatin-paclitaxel related toxicities by substituting CT with the PD1 inhibitor dostarlimab. Methods: DOMENICA is an ongoing international randomized, open-label, phase III trial. 142 patients with MMRd/MSI-H EC Stage III or Stage IV or first recurrent disease without curative treatment (surgery, radiation therapy, +/- adjuvant CT) will be randomized (1:1) to receive either 4 cycles of dostarlimab 500mg every 3 weeks followed by dostarlimab 1000mg every 6 weeks as maintenance up to 2 years or 6 cycles of carboplatin-paclitaxel. A cross over is allowed from the CT arm to the dostarlimab arm at first progression. The maximum treatment duration with dostarlimab will be 24 months. Stratification factors are prior adjuvant CT, prior pelvic radiotherapy. The primary endpoint is the progression-free survival (PFS). Secondary endpoints include overall survival (OS), PFS2, quality of life, best objective response rate, disease control rate, duration of response rate, safety, tolerability, time to first and second subsequent therapy, efficacy of second systemic therapies, pharmacokinetics description and immunogenicity determination. The study is designed to expect a 17.8-months PFS in dostarlimab arm and a 10-months PFS in the CT arm, translating to a hazard ratio of 0.58. A protocol amendment is submitted to increase patient population (with extended eligibility criteria, PFS hypothesis). Status: The DOMENICA/GINECO-EN105b/ENGOT-en13 trial is currently recruiting, the first patient was randomized in April 2022. Clinical trial information: NCT05201547.