Novel BCG Combination or Modified BCG Regimens in BCG-Naïve High-risk Non-muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis
In brief
Systemic immunotherapy plus BCG reduces high-grade recurrence by one-third, raises severe toxicity threefold
In five phase III trials of BCG-naïve high-risk non-muscle-invasive bladder cancer, adding a checkpoint inhibitor to standard BCG lowered the risk of high-grade tumor recurrence by about 37% but increased grade 3 or higher adverse events from 6% to 25%. The benefit was modest, heterogeneous, and not linked to survival improvement, so routine use is not justified without biomarker selection.
- Journal
- European urology focus (Q1)
- Published
- 15 July 2026
- Study design
- Systematic review / meta-analysis of RCTs
- Evidence level
- Level 1, High (CEBM 1a)
- Authors
- Maxime Pattou, Morgan Rouprêt, Ashish Kamat, Stephen A Boorjian, Paolo Gontero, Shahrokh F Shariat, et al.
- PMID
- 42457481
- DOI
- 10.1016/j.euf.2026.06.019
Why clinicians should know about it
Abstract
BACKGROUND AND OBJECTIVE: Despite Bacillus Calmette-Guerin (BCG) remaining the standard of care for high-risk non-muscle-invasive bladder cancer (HR-NMIBC), novel combination strategies are being actively investigated. Comparative evidence on the efficacy and tolerability of these regimens in BCG-naïve patients remains limited. The objective of this study was to synthesize and compare the efficacy and safety of treatments for BCG-naïve HR-NMIBC evaluated in randomized controlled trials (RCTs). METHODS: A systematic search of PubMed, Embase, and Web of Science was performed through October 20, 2025, following a registered protocol (PROSPERO CRD420251079219). Eligible studies were phase III RCTs enrolling adults with BCG-naïve HR-NMIBC that reported recurrence-free survival (RFS), event-free survival (EFS), disease-free survival (DFS), and common terminology criteria for adverse events (CTCAE)-graded AEs. Two independent reviewers extracted data following PRISMA guidelines. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Random-effects meta-analyses and a frequentist network meta-analysis (NMA) were performed. Primary outcomes were tumor recurrences, with secondary outcomes including EFS and DFS, AEs, and subgroup analyses. KEY FINDINGS: Five phase III RCTs (n = 3486) met inclusion criteria. Pooled analyses showed 1-yr and 2-yr EFS/DFS for combination therapy of 87% (95% CI 85-89) and 82% (95% CI 79-85) versus 84% (95% CI 82-87) and 78% (95% CI 75-81) with BCG (induction + maintenance [I + M]). In trials with centrally-adjudicated high-grade recurrence, ICI + BCG (I + M) reduced HG-recurrence (RR 0.63; 95% CI 0.41-0.98). Including ALBAN attenuated the effect (RR 0.75; 95% CI 0.50-1.12). Subgroup analyses favored ICI + BCG (I + M) in CIS and T1 disease (HR 0.68; 95% CI 0.50-0.92). Grade ≥3 treatment-related AEs occurred in 25% of combination-treated patients versus 6% with BCG alone. LIMITATIONS: Interpretation is limited by heterogeneity in treatment regimens, diagnostic definitions, and incomplete reporting of key prognostic factors, including variant histology, lymphovascular invasion, programmed cell death ligand 1 status, and transurethral resection of bladder tumor quality, contributing to between-study variability. CONCLUSION AND CLINICAL IMPLICATIONS: The modest, heterogeneity-sensitive recurrence benefit of adding systemic ICI to BCG (I + M), set against a marked increase in toxicity and no demonstrated survival gain, does not justify routine systemic intensification in unselected BCG-naïve HR-NMIBC. Its use should instead be individualized to higher-risk subgroups pending biomarker-driven selection and mature survival data.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.