Traditional and next-generation bacillus Calmette-Guérin based treatment strategies for bacillus Calmette-Guérin unresponsive non-muscle-invasive bladder cancer in the era of emerging therapies.

PURPOSE OF REVIEW: Bacillus Calmette-Guérin (BCG) remains the standard of care for high-risk non-muscle-invasive bladder cancer (NMIBC), yet up to 40-50% of patients experience treatment failure, leaving limited alternatives to avoid radical cystectomy. This narrative review critically examines both traditional and emerging BCG-based strategies - including repeat induction and modern combination regimens - for patients with BCG-unresponsive NMIBC.

RECENT FINDINGS: BCG monotherapy after BCG failure has shown limited effectiveness, with recent studies reporting 12-month disease-free survival (DFS) rates of 60-70%. Nonetheless, BCG continues to serve as an immunotherapeutic backbone in combination strategies. Chemo-immunotherapy regimens, particularly those using gemcitabine or mitomycin C, have achieved 1-year DFS rates of up to 80%. Combinations with cytokines and immunocytokines - such as interferon-α or nogapendekin alfa inbakicept-pmln (NAI) - have demonstrated DFS rates of 45-61%, and NAI has recently received FDA approval. Immune checkpoint inhibitors (e.g., pembrolizumab, durvalumab, atezolizumab) in combination with BCG have shown DFS rates ranging from 42 to 73% at 12 months. However, many studies are limited by small sample sizes and heterogeneous designs.

SUMMARY: Despite its limited efficacy as monotherapy in unresponsive cases, BCG retains therapeutic relevance as part of combination strategies that enhance its immunologic activity. Emerging data suggest that these BCG-based regimens offer a promising, bladder-sparing alternative for patients who are ineligible for or decline radical cystectomy. Ongoing and future trials will be essential to define optimal combinations and identify which patients are most likely to benefit, thereby enabling appropriate patient selection.