Endometrial Cancer: Dostarlimab/Chemo Improves OS in Frontline RUBY Trial

Bradley J. Monk, MD, Florida Cancer Specialists & Research Institute, discusses the results and implications of the GOG-3031/ENGOT-EN6 trial, known as the RUBY trial, a randomized phase 3 study investigating the addition of immunotherapy to standard chemotherapy for first-line treatment of recurrent or metastatic endometrial cancer. The post hoc analysis of the study was presented as a poster at the 2025 ESMO Congress.

Monk begins by framing the core question of the RUBY trial: whether a superior treatment could be developed to replace the decades-old regimen of carboplatin and paclitaxel. He notes that 2 major trials attempted to address this need, one utilizing pembrolizumab (Keytruda) and the other using dostarlimab (Jemperli), as was used in RUBY. Both studies were presented at the Society of Gynecologic Oncology in 2023 and published simultaneously in The New England Journal of Medicine.

A key distinction was drawn between the 2 trials. The pembrolizumab study, conducted through the NCI mechanism, investigated patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) disease and those with mismatch repair proficient (pMMR) disease in separate cohorts. Because the pembrolizumab study was unblinded and did not track patient-reported outcomes, overall survival (OS) could not be reliably evaluated.

In contrast, the RUBY trial, a GOG Partners international study, was designed to inform OS. Monk reports that, at a subsequent ESMO meeting with simultaneous publication in Annals of Oncology, the RUBY trial definitively demonstrated a survival advantage for adding dostarlimab to chemotherapy. This benefit was observed not only in the overall population but also in the pMMR subgroup.

The data confirm that a checkpoint inhibitor—specifically dostarlimab—should be added. While the benefit was robust in the dMMR population (with an OS hazard ratio of 0.69), the improvement was less pronounced in the pMMR subset, although still clinically meaningful at a 7-month median improvement in OS.

Monk then addresses a crucial clinical question prompted by the less robust outcome in the pMMR/non-MSI group: whether immunotherapy should be reserved for recurrence in these patients, where they could receive the FDA-approved combination of pembrolizumab and lenvatinib (Lenvima), which also confers a survival advantage. However, the conclusion offered was unambiguous: patients require the best available treatment at the time of diagnosis of metastatic and recurrent endometrial cancer, as "you never catch up if you get behind."

The ultimate recommendation is to utilize immune checkpoint blockade in the front-line setting, even for pMMR patients. This approach leaves other opportunities, such as antibody-drug conjugates (ADCs), for the recurrence setting, citing the FDA-approved ADC trastuzumab deruxtecan (T-DXd; Enhertu) as an example.

The discussion concludes by noting a continuous effort to improve outcomes further in the frontline pMMR setting, even beyond the dostarlimab-chemotherapy combination. Monk discusses a current study, GOG-3119 (TroFuse-033), for which he serves as the global principal investigator, aiming to add sacituzumab tirumetecan—a differentiated TROP2 ADC—to pembrolizumab in the pMMR subset to enhance survival and patient quality of life.