Adjuvant Immune Checkpoint Inhibitors After Radical Surgery for High-Risk Urothelial Carcinoma: A Meta-Analysis

Abstract Background: Patients with high-risk muscle-invasive urothelial carcinoma (MIUC) remain at substantial risk of recurrence following radical surgery. Adjuvant immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have emerged as a potential strategy to reduce recurrence and improve survival outcomes. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating adjuvant ICIs versus observation or placebo in high-risk MIUC. Data were extracted for disease-free survival (DFS), overall survival (OS), distant metastasis-free survival (DMFS), recurrence-free survival beyond the urothelial tract (RFS-extraUT), and health-related quality of life (HRQoL). Standardized mean differences (SMDs) were used to express effect sizes with 95% confidence intervals (CIs), and pooled using inverse-variance weighting under common- and random-effects models. Heterogeneity and subgroup analyses were performed according to drug class, PD-L1 status, and clinical covariates. Results: Nine study-level comparisons from four phase III RCTs (CheckMate 274, IMvigor010, AMBASSADOR, and related updates; n > 2,200) were included. Adjuvant ICIs significantly prolonged DFS compared with control (SMD — 0.32; 95% CI —0.44 to — 0.21; p < 0.001), with consistent benefits across subgroups and low heterogeneity (I 2 = 25%). OS benefit was emerging, with nivolumab demonstrating significant advantage at extended follow-up (HR 0.76; 95% CI 0.61—0.96), while pembrolizumab and atezolizumab yielded neutral OS results. Conclusions: Adjuvant PD-1/PD-L1 inhibitors improve DFS and show emerging OS benefits without compromising HRQoL in high-risk MIUC. Nivolumab has demonstrated the most robust long-term survival evidence to date, supporting its role as standard of care. Further biomarker-driven trials are warranted to refine patient selection. Keywords: Adjuvant therapy; Immune checkpoint inhibitors; Nivolumab; Urothelial carcinoma; Disease-free survival; Overall survival; PD-L1.