DOMENICA: dostarlimab versus chemotherapy alone in first-line MMR-deficient advanced endometrial cancer patients

Immunotherapy (IO) in endometrial cancer (EC) is the standard of care in the second line setting in combination with an anti-angiogenic agent. Randomized clinical trials have reported results supporting the addition of IO to chemotherapy (paclitaxel plus carboplatin) in the first-line setting in advanced EC patients in the global population, with high efficacy in mismatch repair deficient (MMRd) patients. These trials were not designed to answer this de-escalation question in the MMRd population, who benefit greatly from IO. The international, randomized phase III, DOMENICA trial compares first-line dostarlimab versus chemotherapy alone (with planned cross-over) for advanced MMRd EC. Our primary endpoint will be progression-free survival. The key secondary endpoints will be overall survival, safety and quality of life [NCT05201547]. Endometrial cancer (EC) is divided into four biological sub-groups. One of them is defined by mismatch repair deficiency (MMRd). MMRd in cancer is associated with microsatellite instability and a high mutation rate, leading to the creation of numerous neo-antigens and a strong immune environment. Immunotherapy (IO) is associated with numerous successes for MMRd patients, such as in colorectal cancer. IO for EC is now the standard of care in the second-line setting in association with a tyrosine-kinase inhibitor after the result of the KEYNOTE-775 study. Four randomized studies have been conducted among advanced EC patients testing IO and chemotherapy in the first line (regardless of MMR status): RUBY with dostarlimab, NRG-GY-018 with pembrolizumab, AtTEnd with atezolizumab and DUO-E with durvalumab reporting positive result particularly in MMRd population. However, for MMRd patients, the benefit of adding chemotherapy to immunotherapy and the associated toxicity is not clear. Even more so when we take into account the characteristics of EC patients, often elderly with comorbidities (e.g.obesity, diabetes, etc) The ongoing phase 3 multicentric randomized DOMENICA trial will address the question of de-escalation by comparing carboplatin-paclitaxel to dostarlimab alone in the first-line setting in advanced MMRd EC. A cross-over to dostarlimab is planned in the chemotherapy group. Our primary endpoint will be progression-free survival. The key secondary endpoint will be overall survival. Other secondary endpoints will be safety and quality of life. Translational studies will be performed to explore immune biomarkers and the geriatric population. Registration number on ClinicalTrial.gov is [NCT05201547]. Immunotherapy is particularly efficient in deficient MMR cancer patients with advanced/metastatic endometrial cancer. Recent trials showed a benefit of the association of immunotherapy with chemotherapy in a first-line setting. However, chemotherapy remains toxic (especially as “real-world” patients are often frail), and could be avoided for MMRd patients. The international phase III randomized DOMENICA trial has been designed to evaluate Dostarlimab vs chemotherapy alone for first-line advanced MMRd EC.