CONTEXT: Adjuvant immune checkpoint inhibitors (ICIs) have recently emerged as guideline-recommended treatments of high-risk muscle-invasive urothelial carcinoma (MIUC). However, there is limited evidence regarding the optimal candidates and the differential efficacy of adjuvant ICI regimens. OBJECTIVE: To synthesize and compare the efficacy and safety of adjuvant ICIs for high-risk MIUC using updated data from phase III randomized controlled trials. EVIDENCE ACQUISITION: In April 2024, three databases were searched for eligible randomized controlled trials that evaluated oncologic outcomes in patients with MIUC treated with adjuvant ICIs. Pairwise meta-analysis (MA) and network meta-analyses were performed to compare the hazard ratios of oncological outcomes, including disease-free survival (DFS), overall survival (OS), and adverse events. Subgroup analyses were conducted on the basis of predefined clinicopathological features. EVIDENCE SYNTHESIS: Three randomized controlled trials that assessed the efficacy of adjuvant nivolumab, pembrolizumab, and atezolizumab were included in the MAs and network meta-analyses groups. Pairwise MAs showed that treatment with adjuvant ICIs significantly improved DFS [hazards ratio: 0.77, 95% confidence interval (CI): 0.66-0.90] as well as OS (hazards ratio: 0.87, 95% CI 0.76-1.00) in patients with MIUC compared with in the placebo/observation group. The DFS benefit was prominent in patients who underwent neoadjuvant chemotherapy (P = 0.041) and in those with bladder cancer (P = 0.013) but did not differ across programmed death-ligand 1 and lymph node status. Adjuvant ICI therapy was associated with increased risk of any (OR: 2.98, 95% CI 2.06-4.33) and severe adverse events (OR: 1.78, 95% CI 1.49-2.13). The treatment rankings revealed that pembrolizumab for DFS (84%) and nivolumab for OS (93%) had the highest likelihood of improving survival. CONCLUSIONS: Our analyses demonstrated the DFS and OS benefits of adjuvant ICIs for high-risk MIUC. Furthermore, patients with bladder cancer who underwent neoadjuvant chemotherapy appeared to be the optimal candidates for adjuvant ICIs regarding prolonged DFS. Adjuvant ICIs are the standard of care for high-risk MIUC, and differential clinical behaviors and efficacy will enrich clinical decision-making.

2nd Department of Urology Centre of Postgraduate Medical Education Warsaw Poland

Department of Maternal Infant and Urologic Sciences Policlinico Umberto 1 Hospital 'Sapienza' University of Rome 00185 Rome Italy

Department of Minimally Invasive and Robotic Urology Wrocław Medical University Wrocław Poland

Department of Surgery S H Ho Urology Centre The Chinese University of Hong Kong Hong Kong China

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology and Neurourology Marien Hospital Herne Ruhr University Bochum 44625 Herne Germany

Department of Urology Claude Huriez Hospital CHU Lille 59000 Lille France

Department of Urology Comprehensive Cancer Center Innsbruck Medical University of Innsbruck Innsbruck Austria

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology Fundació Puigvert Autonomous University of Barcelona 08193 Barcelona Spain

Department of Urology Gregorio Marañón University Hospital 28007 Madrid Spain

Department of Urology Hospital Universitario Ramón y Cajal IRYCIS Universidad de Alcala 28034 Madrid Spain

Department of Urology King Fahad Specialist Hospital Dammam Saudi Arabia

Department of Urology La Croix Du Sud Hospital Quint Fonsegrives France

Department of Urology Luzerner Kantonsspital 6000 Luzern Switzerland

Department of Urology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan

Department of Urology San Raffaele Hospital and Scientific Institute Milan Italy

Department of Urology The Jikei University School of Medicine 3 19 18 Nishi shimbashi Minato ku Tokyo 105 8471 Japan

Department of Urology The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital 1066 CX Amsterdam The Netherlands

Department of Urology University of Texas Southwestern Medical Center Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Division of Urology Department of Special Surgery The University of Jordan Amman Jordan

Division of Urology Geneva University Hospitals Geneva Switzerland

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

The Specialist Centre for Kidney Cancer Royal Free Hospital London UK

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