Efficacy and Safety of Checkpoint Inhibitors Combined with Bacillus Calmette-Guérin (BCG) in BCG-naïve High-risk Non-muscle-invasive Bladder Cancer: Synthesis of Evidence from the ALBAN, CREST, and POTOMAC Trials.

Intravesical bacillus Calmette-Guérin (BCG) therapy remains the cornerstone for high-risk non-muscle-invasive bladder cancer (NMIBC), but up to 40% of patients experience disease recurrence or progression within 2 yr. We conducted a systematic review and meta-analysis of three phase 3 randomized trials POTOMAC, CREST, and ALBAN; n = 2590) in BCG-naïve high-risk NMIBC disease treated with a combination of BCG and an immune checkpoint inhibitor (ICI). Overall risk of bias was low for all studies. Combination therapy with BCG maintenance was associated with better event-free survival (EFS) in comparison to BCG alone (pooled hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.60-0.99; Q = 3.29, p = 0.2). Using the HR for high-grade recurrence from ALBAN, the pooled estimate was directionally consistent, but not statistically significant (HR 0.78, 95% CI 0.58-1.04; Q = 3.94, p = 0.1). Overall survival was comparable between groups (HR 0.92, 95% CI 0.67-1.26). Grade ≥3 treatment-related adverse events were more frequent with combination therapy (risk ratio [RR] 3.66, 95% CI 2.56-5.24 for BCG induction only; RR 3.97, 95% CI 2.54-6.21 for BCG induction + maintenance). There was a moderate decline in patient-reported quality of life in the ICI + BCG maintenance arms. These findings are supported by moderate-certainty evidence for EFS. BCG monotherapy remains the benchmark for BCG-naïve high-risk NMIBC. ICI addition improves EFS but increases high-grade toxicity, which should prompt cautious and individualized adoption pending mature survival data.