Adding Immune Checkpoint Inhibitors to BCG: Risks & Rewards in NMIBC

Does Combining Immunotherapy with BCG Improve Bladder Cancer Outcomes?

The advancement of cancer treatment has introduced a variety of innovative methods, with immunotherapy becoming a focal point in recent years. For patients facing non-muscle invasive bladder cancer (NMIBC), the combination of Bacillus Calmette-Guérin (BCG) therapy with immune checkpoint inhibitors offers a potential new approach. However, recent studies raise questions about the effectiveness and safety of this combination.

Understanding the Trials: POTOMAC, ALBAN, and CREST

At the 2025 European Society for Medical Oncology (ESMO) annual meeting, details from three pivotal phase 3 trials involving immune checkpoint inhibitors alongside standard BCG therapy were presented. The trials are known as POTOMAC, ALBAN, and CREST. They specifically target high-risk patients who have undergone standard treatment regimens, such as transurethral resection of bladder tumors followed by BCG induction.

POTOMAC studied the addition of durvalumab (Imfinzi) to BCG, reporting an improvement in two-year disease-free survival from 81.6% to 86.5%. Conversely, ALBAN tested atezolizumab (Tecentriq) and revealed no significant event-free survival benefits. CREST focused on the investigational PD-1 blocker sasanlimab, showing a 7.3% absolute increase in event-free survival compared to BCG alone. Yet, these marginal advantages came with notable safety concerns, as evidenced by increased serious side effects, particularly immune-related events.

The Dichotomy of Efficacy and Toxicity

While the combination treatment offers some promise, the potential for severe side effects cannot be overstated. According to findings from the trials, grade 3 or higher treatment-related adverse events occurred in nearly 30% of patients receiving sasanlimab compared to just 6.3% in those receiving standard BCG therapy. Similarly, in POTOMAC, adverse events were reported in 21% of patients receiving durvalumab. This highlights a troubling reality: for every small benefit in reducing recurrences, a much larger number of patients may experience life-threatening side effects.

Challenges in Cystectomy-Free Survival

A critical statistic missing from the trials raises further concern: none of the studies reported data on cystectomy-free survival. This absence means that while some patients might avoid additional TURBT procedures, they could still face bladder removal, which is often the primary concern for those with NMIBC. As Dr. Bradley McGregor, a lead discussant on the trials, noted, the question of whether patients can retain their bladders remains unresolved.

What Lies Ahead: The Need for Tailored Treatments

The future of using immune checkpoint inhibitors alongside BCG therapy lies in refining patient selection. Currently, it’s challenging to identify which patients would genuinely benefit from the add-ons, as emphasized by McGregor. Emerging research on biomarkers could illuminate which patients might see worthwhile outcomes from this combination therapy, facilitating a more personalized approach to NMIBC treatment.

Overall, while these trials underscore potential advancements in NMIBC treatment, they also reflect a sobering reality about the risks involved. As more data becomes available, it is pivotal for the medical community to gain deeper insights into the complexities of immunotherapy in bladder cancer.