Combination Strategies to Enhance Bacillus Calmette-Guérin Efficacy for Nonmuscle-Invasive Bladder Cancer

Bacillus Calmette-Guérin (BCG) is the standard of care therapy for high-risk nonmuscle-invasive bladder cancer (NMIBC). However, up to half of patients will experience treatment failure, and many face considerable adverse effects, which can lead to dose reduction and intolerance. Novel bladder-sparing approaches with favorable risk-to-benefit ratio are thus critical in NMIBC.

A narrative review of the literature was performed of English-language MEDLINE indexed articles and abstracts of resistance mechanisms to BCG and combination-based strategies to enhance the efficacy of BCG intravesical therapy in high-risk NMIBC.

Treatment options for high-risk NMIBC have expanded considerably over the last few years. Combination strategies represent an opportunity to enhance the effectiveness of BCG and promote durable response. Combination therapies that aim to reduce immunosuppressive cellular populations (regulatory T cells, myeloid-derived suppressor cells) and immune checkpoint blockade offer mechanisms to overcome resistance to BCG therapy. Chemoimmunotherapy and immunotherapy-based combinations represent a bladder preservation strategy that needs to be weighed against oncological efficacy, toxicity, and cost-effectiveness.

BCG-based combination therapies have emerged as a strategy to overcome BCG resistance and promote durable responses. Despite their promise, combination design is endless, and adoption remains challenging due to overlapping mechanisms of resistance, adverse events associated with systemic therapy and/or additional intravesical therapy, and financial burden. Long-term multiarm trials are needed for direct comparative analyses between combinations of agents to inform oncological efficacy, safety profile, and cost-effectiveness.