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Introduction: Our understanding of the biologic heterogeneity of endometrial cancer has improved, but which patients benefit from single-agent versus combination immune checkpoint blockade remains unclear., Methods: We conducted a single-center, randomized, open-label, phase 2 study of durvalumab 1500 mg (Arm 1) versus durvalumab 1500 mg plus tremelimumab 75 mg every 4 weeks (Arm 2) in patients with endometrial carcinoma. The primary endpoints were overall response rate (ORR) and progression-free survival (PFS) at 24 weeks. Patients were stratified by mismatch repair (MMR) status and carcinosarcoma histology. Using a Simon two-stage minimax design, we determined 40 patients per arm would provide 90% power and Type 1 error of 10%., Results: Eighty-two patients were enrolled; 77 were evaluable for toxicity (Arm 1: 38, Arm 2: 39) and 75 evaluable for efficacy (Arm 1: 37, Arm 2: 38). Patient were stratified by MMR status (Arm 1: 5, Arm 2: 4 were MMR-deficient). The ORR in Arm 1 was 10.8% (one-sided 90% CI: 4.8-100%); the ORR in Arm 2 was 5.3% (one-sided 90% CI: 1.4-100%). Since the primary endpoint of ORR was not met, 24-week PFS was not compared to historical controls per protocol specification. No new safety signals were identified., Conclusions: In these patients with predominantly MMR-proficient endometrial cancer, there was limited response with single-agent and combined immune checkpoint blockade. The pre-specified efficacy thresholds were not met for further evaluation. A deeper understanding of potential mechanisms of resistance to immunotherapy in MMR-proficient endometrial cancer is needed for the development of novel therapeutic approaches., Competing Interests: Declaration of Competing Interest Dr. Rubinstein reports grant support paid to the institution from Merck, Zentalis, and AstraZeneca. Dr. Iasonos reports consulting fees from Mylan. Dr. Friedman reports grant support paid to the institution from Genentech/Roche, Bristol Myers Squibb (BMS), Merck, AstraZeneca, and Daiichi; consulting fees from Seagen and BMS; and waived compensation for advisory board participation from Merck and Genentech. Dr. O'Cearbhaill reports meeting/travel support from the Gynecologic Oncology Foundation, Curio, and Hitech Health; participation in the advisory boards of Tesaro/GlaxoSmithKline (GSK), Regeneron, Seattle Genetics, Fresenius Kabi, Bayer, and CarinaBiotech (non-compensated); non-compensated steering committee participation for Tesaro/GSK and AstraZeneca; and grant support paid to the institution from Bayer/Celgene/Juno, Tesaro/GSK, Merck, the Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Marker Therapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, KitePharma, and the Gynecologic Oncology Foundation. Dr. Cadoo reports grant support paid to the institution from The Irish Cancer Society, MSD, and Immunogen; consulting fees from Nextcure, MJH Life Sciences, and GSK; honoraria from SGK, AstraZeneca, and MSD; meeting/travel support from Roche, Pfizer, and MSD; and board/committee participation for MSD, AstraZeneca, GSK, Eisai, The National Cancer Control Programme Ireland (voluntary), and the ARC Cancer Support Centers (voluntary). Dr. Kyi reports grant support paid to the institution from Merus, Gritstone, and BMS; consulting fees from Scenic Immunology BV and OncLive; and meeting/travel support from the Conquer Cancer Foundation and Gritstone. Dr. Zamarin reports grant support paid to the institution from AstraZeneca, Roche, Plexxikon, and Synthekine; patents from Merck and Newcastle Disease Virus for Cancer Therapy; consulting fees from Memgen, Celldex, Agenus, Astellas, AstraZeneca, Crown Biosciences, Roche, GSK, Hookipa, ImmunOS, Kalivir, Synologic Therapeutics, Synthekine, Takeda, Targovax, Tessa Therapeutics, and Xencor; and stock options from Accurius Therapeutics, ImmunOS Therapeutics, and Calidi Biotherapeutics. Dr. Aghajanian reports grant support paid to the institution from Abbvie, Clovis, Genentech, and AstraZeneca; consulting fees from Eisai/Merck, Mersana Therapeutics, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation for Blueprint Medicine; and unpaid participation on the Board of Directors of the GOG Foundation and NRG Oncology. Dr. Billinson reports stock ownership in Abbvie and Johnson and Johnson. Dr. Makker reports unpaid board participation for Eisai, Merck, Clovis, Faeth, Duality, Morphyes, Karyopharm, Novartis, Lilly and Immunocore. The authors have no potential conflicts of interest to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)