Bacillus Calmette–Guérin (BCG) induction and maintenance (I+M) after transurethral resection of bladder tumor is standard of care (SOC) in high-risk non-muscle invasive bladder cancer (NMIBC). However, disease recurrence/progression occurs in approximately 40% of patients at 2 years, with unfavorable prognosis. Limited bladder-sparing therapeutic options exist, and no improvements to response durability have been observed in decades. CREST is a global, phase 3, randomized trial evaluating subcutaneous sasanlimab in combination with BCG-I+M (Arm A), sasanlimab in combination with BCG-I (Arm B) or BCG-I+M (Arm C) in BCG-naive high-risk NMIBC. The primary endpoint was investigator-assessed event-free survival (EFS) for Arm A versus Arm C; key secondary endpoints were EFS (Arm B versus Arm C) and overall survival. Patients were randomized 1:1:1 to Arm A (N = 352), Arm B (N = 352) and Arm C (N = 351). The trial met its primary endpoint with a statistically significant and clinically meaningful prolongation of EFS (Arm A versus Arm C); hazard ratio, 0.68 (95% confidence interval: 0.49–0.94); one-sided P = 0.0095. The 36-month estimated EFS rates were 82.1% (Arm A) and 74.8% (Arm C). EFS benefit for Arm A versus Arm C was observed across prespecified subgroups, including carcinoma in situ (CIS) and T1. The safety profile of the combination was consistent with the known profiles. To our knowledge, sasanlimab is the first anti-PD-1 antibody to show a clinically meaningful prolongation of EFS when combined with BCG-I+M versus SOC in patients with BCG-naive high-risk NMIBC. Sasanlimab combined with BCG-I+M has the potential to redefine the treatment paradigm and clinical decision-making for patients with BCG-naive high-risk NMIBC. ClinicalTrials.gov identifier: NCT04165317.
From intravesical to systemic immunotherapy: management of high-risk non-muscle invasive bladder cancer in the phase 3 CREST trial
Commentary by Dr. Elisabeth Grobet-Jeandin
Immunotherapy in bladder cancer is far from new: intravesical bacillus Calmette–Guérin (BCG), introduced nearly half a century ago, remains the cornerstone of treatment for high-risk non-muscle-invasive bladder cancer (HR NMIBC). Yet, beyond BCG, the therapeutic armamentarium for HR NMIBC is limited for patients pursuing bladder-sparing strategies. Modern immunotherapies, which show promise in addressing this unmet need, have therefore generated substantial enthusiasm within the uro-oncology community.
As with other randomised clinical trials investigating systemic checkpoint inhibitors in BCG-naïve HR NMIBC, such as KEYNOTE-676 (NCT03711032), POTOMAC (NCT03528694), ALBAN (NCT03799835) and SunRIse-3 (NCT05714202), the phase III randomised CREST trial evaluated the addition of subcutaneous sasanlimab (a monoclonal antibody that blocks the interaction between PD-1 and PD-L1/PD-L2) to standard BCG therapy in patients with BCG-naïve HR-NMIBC [1]. The investigators demonstrated an improved event-free survival (EFS) with sasanlimab + BCG compared with BCG alone, with a hazard ratio of 0.68 (95%CI: 0.49-0.94; p=0.0095) and a 36-month EFS of 82.1% versus 74.8%. The benefit was consistent across prespecified subgroups, particularly in patients with carcinoma in situ (CIS) or T1 disease, reinforcing the potential of PD-1 blockade to overcome BCG resistance mechanisms.
Safety, however, warrants careful scrutiny. The addition of sasanlimab was associated with substantially higher rates of grade ≥3 adverse events (29.1% in the combination arm versus 6.3% with BCG alone), driven largely by immune-related toxicities. Although the safety profile was generally in line with known checkpoint inhibitor toxicities, its impact on patient adherence and clinical feasibility must not be underestimated, particularly in an elderly population with comorbidities. Furthermore, health-related quality of life, assessed using the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30), showed a greater decline in the sasanlimab arm compared with BCG alone (-5.7 versus -1.0), although the difference was not considered clinically significant.
Another key finding is that BCG induction without maintenance, even when combined with sasanlimab, did not provide an EFS benefit over standard BCG, reaffirming the importance of BCG maintenance in optimising outcomes. Moreover, unlike historical data suggesting BCG failure rates of near 40% at two years [2], the BCG-only group in the CREST trial achieved a 3-year EFS of nearly 75%, underscoring the durability of response with properly delivered induction and two-year maintenance therapy.
To conclude, BCG remains the cornerstone of high-risk NMIBC, with its efficacy potentially boosted by adjunctive systemic immunotherapy. While the CREST trial does not immediately redefine standard care, it establishes BCG plus systemic immunotherapy as a credible option in BCG-naïve patients. As combination therapies reshape NMIBC treatment, seamless teamwork between urologists and oncologists becomes essential.
[1] Shore ND, Powles TB, Bedke J, Galsky MD, Palou Redorta J, Ku JH, et al. Sasanlimab plus BCG in BCG-naive, high-risk non-muscle invasive bladder cancer: the randomized phase 3 CREST trial. Nat Med 2025;31:2806–14.
[2] Sylvester RJ, van der Meijden APM, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006;49:466–465; discussion 475-477.