Targeting BCG resistance in high-risk NMIBC

In this video, Daniel Antonio González Padilla, MD, a urologist with the Clínica Universidad de Navarra in Madrid, Spain,discusses the clinical rationale behind the CREST and POTOMAC trials in high- and very high-risk non–muscle invasive bladder cancer (NMIBC), as well as key differences in their design that may help explain divergent efficacy signals.¹

González Padilla emphasizes that high-risk NMIBC remains an area of major unmet need. Despite complete endoscopic resection and appropriate intravesical BCG therapy, recurrence rates can reach 30% to 50% within 5 years, and progression rates range from 10% to 40%. Progression often leads to muscle-invasive disease, which may require radical cystectomy, underscoring the limitations of existing therapies. Although BCG has been the standard of care for decades and remains the most effective available treatment, outcomes remain suboptimal for many patients.

Both the CREST and POTOMAC trials were designed to address this gap by building on a biologically plausible hypothesis: PD-1 pathway activation may contribute to mechanisms of BCG resistance. As a result, each trial explored whether adding an immune checkpoint inhibitor—durvalumab (Imfinzi) in CREST or sasanlimab in POTOMAC—to standard BCG could improve patient outcomes compared with BCG alone.

When comparing trial designs, González Padilla notes that CREST and POTOMAC were largely similar, with only a few meaningful distinctions. POTOMAC used the European Association of Urology (EAU) risk classification system, which includes certain patients—such as those with multiple large, recurrent low-grade tumors—not typically categorized as high risk under American guidelines. Additionally, POTOMAC allowed enrollment of patients who had previously received BCG, provided more than three years had elapsed since their last dose.

Although detailed data on the number and characteristics of these patients are unavailable, González Padilla suggests that these differences may have diluted treatment effects in POTOMAC, potentially contributing to the slightly lower absolute benefit observed compared with CREST.

REFERENCE

1. González-Padilla DA, Subiela JD, Villacampa-Aubá F. Immune checkpoint inhibitors for high-risk non-muscle invasive bladder cancer: Lessons learnt from the CREST and POTOMAC trials. J Urol. 2025 Nov 25:101097JU0000000000004864. doi:10.1097/JU.0000000000004864