Non–muscle-invasive bladder cancer (NMIBC), representing 75% of initial bladder cancer diagnoses, presents a clinical challenge due to its high recurrence and progression rates, particularly in intermediate high-risk cases. While intravesical Bacillus Calmette-Guérin (BCG) therapy post-TURBT is standard and effective, more than half of these patients still face recurrence. Because BCG is the only market leader in NMIBC, it has long been challenging to penetrate into the BCG-naïve space. Any therapy that outperforms BCG in this patient group could gain several advantages (untapped market, lack of competition, first-mover advantage, etc.). The continuous shortage for BCG-naïve high-risk disease suggests the need for more BCG strains and alternate therapies that do not rely on use of BCG.

At ASCO 2025, Pfizer shared results from the phase III CREST study (NCT04165317), evaluating the efficacy of subcutaneous sasanlimab combined with BCG in non–muscle-invasive bladder cancer. Patients were randomized into three arms: Arm A received sasanlimab with BCG (induction and maintenance), Arm B received sasanlimab with induction BCG only, and Arm C received BCG alone (induction and maintenance). 

Post hoc investigator-assessed event-free survival (EFS) analyses compared Arm A versus Arm C, focusing on baseline carcinoma in situ (CIS) and T1 tumors. EFS was defined as the time to high-grade recurrence, disease progression, persistent CIS, or death from any cause.

• Patients with CIS (n = 88) who received the combination achieved a 36-month EFS rate of 83.0% vs 71.8% in the BCG alone arm (n = 88). The stratified HR for EFS was 0.53 (95% CI, 0.285-0.982). 

• Patients with T1 tumors in the combination arm (n = 204) experienced a 36-month EFS rate of 81.3% vs 72.2% in the BCG alone arm (n = 194). The stratified HR for EFS was 0.63 (95% CI, 0.406-0.963).

According to recent data, the safety profile for adverse events (AEs) was in line with established safety profiles. Five (1.4%) patients in arm C and 62 (17.7%) individuals in arm A experienced serious treatment-related adverse events. Neither arm A nor arm C's patients died as a result of treatment-related adverse events.

KOL insights

“New bladder cancer treatment options that help reduce rates of disease recurrence or progression are long overdue. Up to 50% of patients with high-risk non-muscle invasive bladder cancer may experience failure of BCG intravesical immunotherapy, yet it has been the standard of care after tumor resection for decades.” – Expert Opinion

“Patients with BCG-naive, high-risk NMIBC have high rates of recurrence and progression.”  – Expert Opinion

Conclusion 

The NMIBC market is gaining traction, with several therapies expected to enter the major markets by 2034. Given the extensive range of treatments currently in development, the market for therapies targeting BCG-unresponsive high-risk NMIBC is extremely competitive. While the goal of NMIBC key players is to start with the BCG-unresponsive high-risk NMIBC segment, there is opportunity to expand growth into other market segments, such as intermediate NMIBC and BCG-naïve.

It is important to highlight that the BCG-naïve NMIBC segment has long been challenging to penetrate, given the dominance of BCG as the sole market holder in NMIBC. However, any drug that surpasses BCG’s CRR could gain a significant advantage in this patient segment. For BCG naïve high-risk disease, ongoing shortage indicates the need for non-BCG-based alternative therapies and additional BCG strains. The current scarcity of BCG has given NMIBC key players a chance to enter this BCG-dominated market. Major companies, including Merck (KEYTRUDA + BCG), ImmunityBio (ANKTIVA + BCG), Roche (TECENTRIQ + BCG), Pfizer (Sasanlimab + BCG), and AstraZeneca (IMFINZI + BCG), are focusing on combination therapies with BCG to enhance the efficacy of drug rather than replacing BCG.

In BCG-naïve NMIBC, the CREST phase III study offers encouraging new data. The combination of sasanlimab with BCG (both induction and maintenance) significantly improved EFS in the overall population and high-risk BCG-naive subgroups with CIS or T1 tumors at baseline. With 3-year EFS rates exceeding 80%, this regimen demonstrates clinically meaningful and durable responses, suggesting a potential practice-changing, bladder-preserving alternative for patients who are not candidates for cystectomy. If confirmed in future studies and approved, sasanlimab + BCG could fill a major treatment gap and redefine the standard of care for high-risk, BCG-naive NMIBC.