Treatment options for BCG-unresponsive non–muscle-invasive bladder cancer: An updated review of the post-BCG therapeutic landscape

Abstract

Non–muscle-invasive bladder cancer (NMIBC) constitutes the majority of urothelial carcinoma diagnoses; however, treatment failure following standard intravesical Bacillus Calmette–Guérin (BCG) immunotherapy remains a critical challenge in urologic oncology. Approximately 30–40% of patients experience recurrence, prompting the adoption of strict regulatory definitions for BCG-unresponsive disease to identify those who derive minimal benefit from further BCG instillations. Although radical cystectomy remains the oncologic gold standard for this high-risk population, its associated morbidity and impact on quality of life underscore the urgent need for effective bladder-sparing alternatives. This review provides a comprehensive update on the rapidly evolving therapeutic landscape, examining key mechanisms of BCG resistance, including impaired tumor internalization and immune escape mediated by programmed death-ligand 1 upregulation. We evaluate systemic immune checkpoint inhibition, highlighting the approved role of pembrolizumab and emerging evidence supporting sasanlimab in BCG-naïve disease. Novel intravesical approaches are discussed, including gene therapies such as nadofaragene firadenovec, oncolytic immunotherapy with cretostimogene grenadenorepvec, and cytokine-based strategies using the interleukin-15 superagonist nogapendekin alfa-inbakicept. Advances in drug delivery systems, notably the TAR-200 sustained-release platform, and targeted therapies such as erdafitinib for fibroblast growth factor receptor-altered tumors are also critically assessed. Overall, NMIBC management is transitioning from a binary choice between BCG and surgery toward a personalized, bladder-preserving paradigm.