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Background: Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer., Methods: The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m 2 ) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866., Findings: Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18·5 months (IQR 13·2-21·5) in the durvalumab group and 18·4 months (13·2-23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0·84; 95% CI 0·65-1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3-80·0) with durvalumab and 73·3% (68·4-77·5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy)., Interpretation: Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care., Funding: AstraZeneca., Competing Interests: Declaration of interests BJM reports institutional research funding from Novartis, Amgen, Genentech, Lilly, Janssen, Array BioPharma, Tesaro, Morphotek, Pfizer Advaxis, AstraZeneca, ImmunoGen, Regeneron, and Nucana. Honoraria from Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Clovis Oncology, Eisai, Genmab/Seattle Genetics, ImmunoGen, Iovance Biotherapeutics, Merck, Mersana, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, TESARO/GKS, Vascular Biogenics, GOG Foundation, Elevar Therapeutics, Novocure, Gradalis, Karyopharm Therapeutics, Bayer, EMD Merck, Macrogenics, Sorrento Therapeutics, US Oncology, and Myriad Pharmaceuticals; a leadership position for US Oncology; speakers’ bureau participation for Roche/Genentech, AstraZeneca, Clovis Oncology, Eisai, TESARO/GSK, and Merck; served in a consulting or advisory role for Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Clovis Oncology, Eisai, Genmab/Seattle Genetics, GOG Foundation, ImmunoGen, Iovance Biotherapeutics, Merck, Mersana, Myriad Pharmaceuticals, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, TESARO/GSK, Vascular Biogenics, Gradalis, Karyopharm Therapeutics, Sorrento Therapeutics, Novocure, Bayer, Elevar Therapeutics, EMD Merck, Gradalis, and US Oncology. TT reports personal fees from AstraZeneca, Chugai, JGOG, and Zeria, outside the submitted work. JCVL reports funding, provision of study material, medical writing, and processing charges for the present work and grants from AstraZeneca; consulting fees and honoraria from AstraZeneca and Bristol Myers Squibb outside the submitted work; travel support from AstraZeneca, Merck Sharp and Dohme, Novartis, and Pfizer; served as an advisor for AstraZeneca; grants for clinical research from AstraZeneca, Bristol Myers Squibb, Janssen, Merck Sharp and Dohme, Novartis, Roche, and Sanofi, outside the submitted work. RS-F received an institutional research grant from Merck Sharp and Dohme and served at an advisory board for Merck Sharp and Dohme; and received lecture honoraria from AstraZeneca, Bristol Myers Squibb, Medison, Merck Sharp and Dohme, Neopharm, Novartis, and Roche, outside the submitted work. UM reports institutional grants from Varian Medical Systems and was a RT Steering Committee member for CALLA study. MdPED reports institutional funding from AstraZeneca for the present work and served as an advisor for AstraZeneca, outside the submitted work. SL has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events and participated on a data safety monitoring board or advisory board for AstraZeneca, Bristol Myers Squibb Boehringer Ingelheim, Merck, Roche, and Novartis, and has a leadership or fiduciary role for Iylon Precision Oncology. FJRG reports support for the present work from AstraZeneca, grants from AstraZeneca, Janssen, Lilly Company, Merck Sharp and Dohme, Roche, and Sanofi; travel support from BioGentec, and an unpaid leadership role with the Comite de Etica e Investigacion del Hospital Civil de Guadalajara, outside the submitted work. NV reports personal research funding from AstraZeneca, Merck Sharp and Dohme, and Roche; Consulting fees or honoraria from Tecnofarma, MSD, and Roche; and is currently the Vice President of the Peruvian Mastology society, outside the submitted work. DA reports funding for this clinical trial was made to his institute from AstraZeneca; an institutional grant from Takeda Pharmaceutical; consulting fees from AbbVie; honoraria from AstraZeneca, AbbVie, MSD, Takeda Pharmaceutical, and Chugai; participated in an advisory board for Takeda Pharmaceutical, AstraZeneca, and MSD; and was the president of the Asian Society of Gynecologic Oncology, the Chairperson of the Japan Society of Gynecologic Oncology, and the Vice President of the Japan Gynecologic Oncology Group. ML reports grants for clinical research from AstraZeneca, Bristol Myers Squib, Merck Sharp and Dohme, and Roche; consulting fees, honoraria, and travel support from Roche, outside the submitted work. J-YL reports personal research funding from AstraZeneca and Merck Sharp and Dohme; institutional funding from Clovis Oncology, Immunogen, Janssen Oncology, Merck, Merck Sharp and Dohme, and Synthon; served an advisory role for AstraZeneca, Merck Sharp and Dohme, Roche, and Takeda. FR reports personal fees from AstraZeneca. YR reports subcontract funding from NIH SBIR grant R44CA254844, compensation from Medical Physics Journal Editorial as the Deputy Editor, and personal fees from AstraZeneca for case review. SW is an employee and shareholder at AstraZeneca and has patents at GlaxoSmithKline UK Ltd and AstraZeneca. AL and HD are employees and shareholders at AstraZeneca. ATN received medical writing support for this manuscript funded by AstraZeneca, is a shareholder and was an employee of AstraZeneca during this study; and is a current employee at Merck. JM reports honoraria and consulting fees from AstraZeneca, Varian Medical Systems, Merck, Primmune, Agenus Bio; grants from NRG Oncology; royalties from Springer Medical Books for published work; and support for attending meetings and travel from NRG Oncology. XW, RT, MM, QZ, COK, SV, RS, YK, W-FC, and GK have nothing to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)