The Evolving Landscape of Systemic Immunotherapy for Bacillus Calmette-Guérin-naïve High-risk Non-muscle-invasive Bladder Cancer: At the Edge of a Tsunami?

Background And Objective: Treatment options for high-risk (HR) non-muscle-invasive bladder cancer (NMIBC) are still limited. The addition of systemic immunotherapy to intravesical bacillus Calmette-Guérin (BCG) instillations is currently being explored as an initial strategy for BCG-naïve HR NMIBC patients to enhance treatment effectiveness and decrease the risk of BCG failure.

Methods: A collaborative narrative review of the literature by the Cancer Committee of the French Association of Urology (CC-AFU) was carried out to describe ongoing studies assessing systemic immunotherapy in BCG-naïve HR NMIBC patients, focus on the different study designs, and evaluate the clinical pertinence of the endpoints. In total, 37 references published between 2003 and 2025 were included in our review.

Key Findings And Limitations: The ongoing phase 3 trials in BCG-naïve HR NMIBC patients include CREST (sasanlimab; NCT04165317), ALBAN (atezolizumab; NCT03799835), POTOMAC (durvalumab; NCT03528694), KEYNOTE-676 (pembrolizumab; NCT03711032), and SunRISe-3 (cetrelimab; NCT05714202). These five randomized, multicenter, multinational, open-label studies are evaluating the efficacy and safety of systemic intravenous or subcutaneous immunotherapy in combination with intravesical BCG, or in combination with TAR-200 in SunRISe-3, compared with BCG alone in BCG-naïve HR NMIBC patients. Recently, the CREST and POTOMAC studies demonstrated statistically significant and clinically meaningful improvements in event-free and disease-free survival, respectively, heralding a new therapeutic era in this field. Other results from these studies are expected between 2025 and 2030.

Conclusions And Clinical Implications: The combination of systemic immunotherapy with intravesical BCG instillations is being investigated and may become a new therapeutic strategy for BCG-naïve HR NMIBC.