# First-line treatments for BCG-naïve non-muscle invasive bladder cancer: a systematic review and meta-analysis

## TL;DR

This study finds that combining systemic immune treatments with bladder cancer therapy improves outcomes but increases severe side effects.

## Contribution

The study evaluates first-line combination therapies for BCG-naïve non-muscle invasive bladder cancer using a systematic review and meta-analysis.

## Key findings

- Systemic ICIs added to BCG reduced recurrence-related events but increased severe adverse events.
- Modifications to intravesical BCG alone did not significantly improve outcomes.
- High-grade recurrence-free survival did not reach statistical significance in sensitivity analysis.

## Abstract

To evaluate novel intravesical and systemic combination therapies for improving outcomes in BCG-naïve patients with non-muscle invasive bladder cancer (NMIBC), this systematic review and meta-analysis assessed first-line treatment strategies, including combinations with systemic immune-checkpoint inhibitors (ICIs).

In this prospectively registered review (CRD420251163026), MEDLINE, Embase, Web of Science, and the ESMO 2025 abstract book were searched for randomized controlled trials (RCTs) evaluating first-line therapies in BCG-naïve NMIBC. Meta-analyses estimated HRs for recurrence-related time-to-event outcomes (disease-free and event-free survival). Grade ≥ 3 treatment-related adverse events were pooled as relative risks (RRs). Risk of bias was assessed using the Cochrane RoB 2 tool.

Out of 5202 records screened, six RCTs including 3485 patients were eligible. Modifications to intravesical BCG alone (three trials, n = 895) did not significantly improve recurrence-related outcomes. Systemic ICIs given additional to intravesical BCG significantly reduced recurrence-related events compared to BCG alone (HR 0.77, 95%CI 0.6–0.97, n = 1899; number needed to treat at two years: 25), but increased grade ≥ 3 treatment-related adverse events by a statistically and clinically significant margin (RR 3.97, 95% CI 2.53–6.22, n = 1879; number needed to treat to harm one patient: 5). Sensitivity analysis using the ALBAN alternative endpoint of high-grade recurrence-free survival yielded HR 0.78 (95% CI 0.59–1.02), not reaching statistical significance. Limitations included heterogeneity in trial design and endpoint definitions.

In BCG-naïve NMIBC, systemic ICIs combined with intravesical BCG improve recurrence-related outcomes but are offset by a substantially increased risk of severe treatment-related adverse events. These findings highlight the need for careful, risk-based, biomarker-guided patient selection to balance over- and undertreatment within a shared decision-making process.

The online version contains supplementary material available at 10.1007/s00345-025-06180-5.