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Clinical Trial
. 2025 Aug;31(8):2806-2814.
doi: 10.1038/s41591-025-03738-z. Epub 2025 May 31.

Sasanlimab plus BCG in BCG-naive, high-risk non-muscle invasive bladder cancer: the randomized phase 3 CREST trial

Neal D Shore  1 , Thomas B Powles  2 , Jens Bedke  3 , Matthew D Galsky  4 , Joan Palou Redorta  5 , Ja Hyeon Ku  6 , Michal Kretkowski  7 , Evanguelos Xylinas  8 , Boris Alekseev  9 , Dingwei Ye  10 , Félix Guerrero-Ramos  11 , Alberto Briganti  12 , Girish S Kulkarni  13 , Julia Brinkmann  14 , Anna-Maria Calella  15 , Rossano Cesari  16 , Anthony Eccleston  17 , Elisabete Michelon  18 , Jennifer Vermette  19 , Caimiao Wei  20 , Gary D Steinberg  21
Affiliations
Clinical Trial

Sasanlimab plus BCG in BCG-naive, high-risk non-muscle invasive bladder cancer: the randomized phase 3 CREST trial

Neal D Shore et al. Nat Med. 2025 Aug.

Erratum in

Abstract

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 .

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Conflict of interest statement

Competing interests: N.D.S. reports research/consulting: Allessa, Amgen, Artera, Astellas, AstraZeneca, Aura Biosciences, Bayer, Bristol Myers Squibb, Caris, CG Oncology, Daiichi Sankyo, Dendreon, Glytheryx, Invitae, Janssen, MDxhealth, Merck, Minomic, Novartis, Nusano, PhotoCure, Pfizer, Sumitomo, Telix, Tolmar, Tutelix and Urogen. T.B.P. reports honoraria: Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Elexis, Gilead, Incyte, Ipsen, Johnson & Johnson, Mashup, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche and Seagen; consulting or advisory role: Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Elexis, Gilead, Incyte, Ipsen, Johnson & Johnson, Mashup, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche and Seagen; research funding: Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Elexis, Incyte, Ipsen, Johnson & Johnson, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche and Seagen; and travel, accommodations or expenses: Astellas, AstraZeneca, Gilead, Ipsen, Merck Sharp & Dohme, Pfizer and Roche. J. Bedke reports financial interests from Astellas, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Ipsen, Janssen, Merck Sorono, Merck Sharp & Dohme, Pfizer, Roche, Nektar, Novartis and Seagen and membership in the European Association of Urology and the Renal Cell Carcinoma Guidelines Panel (Vice-Chairman). M.D.G. reports stock and other ownership interests: Pfizer, Merck and Gilead Sciences; research funding: Merck, Bristol Myers Squibb, Mirati Therapeutics, Seagen, Alliance Foundation Trials, Alliance for Clinical Trials in Oncology, Clovis Oncology, Arvinas, ALX Oncology, Hoosier Cancer Research Network, Novartis, Acrivon Therapeutics, Astellas, Genentech, Accuray, PCCTC, G1 Therapeutics, OncoC4, Flare Therapeutics, Loxo/Lilly, Roche and Pfizer; other relationships: Elsevier, Medscape and Research to Practice; uncompensated relationships: G1 Therapeutics and Loxo/Lilly. J.P.R. reports advisory/consultancy roles for Arquer Diagnostics, Biotech, BTA Pharmaceuticals, Combat, Genomic Expression and Olympus; steering committee membership for AstraZeneca, Bristol Myers Squibb, Janssen and Pfizer; grant or research support from Arquer Diagnostics, Biotech, BTA Pharmaceuticals, Cepheid, TARIS Biomedical and Nucleix; and research funding from Pfizer. J.H.K. reports research funding from Pfizer. M.K. reports research funding from Pfizer. E.X. reports consulting or advisory role: Pfizer, Ferring and Boston Scientific and research funding: Ferring and Pfizer. B.A. reports honoraria: AstraZeneca, Astellas, Eisai, Janssen, Bayer, Merck Sharp & Dohme, Merck, Pfizer, Roche and Bristol Myers Squibb; consulting or advisory role: AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Janssen, Merck, Pfizer, Merck Sharp & Dohme, Roche and Eisai; speakers’ bureau: Janssen, Astellas, Pfizer, AstraZeneca, Bayer, Merck, Bristol Myers Squibb, Merck Sharp & Dohme, Eisai and Roche; research funding: AstraZeneca, Merck, Bayer, Astellas, Janssen, Bristol Myers Squibb, Pfizer, ICON Clinical Research, Eisai, Merck Sharp & Dohme and Roche; and travel, accommodations and expenses: AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Janssen, Merck Sharp & Dohme, Pfizer and Sanofi. D.Y. reports research funding from Pfizer. F.G.-R. reports research support/principal investigator: Johnson & Johnson, Pfizer, Taris, Bristol Myers Squibb, Roche, Seagen, AstraZeneca, Combat Medical, Cepheid, Fidia, Astellas, UroGen and Merck Sharp & Dohme; employment: SERMAS (Servicio Madrileño de Salud); consultancy: Johnson & Johnson, Pfizer, Merck, Roche, Taris, Combat Medical, AstraZeneca, Merck Sharp & Dohme and Bristol Myers Squibb; stockholder: CG Oncology; speakers’ bureau: Janssen, Nucleix, Merck Sharp & Dohme, Pfizer, Merck, Bristol Myers Squibb, AstraZeneca, Palex, Combat Medical, Johnson & Johnson and Recordati; travel: Pfizer, Recordati, Ipsen, Combat Medical, Alter, Salvat, Nucleix, AstraZeneca, Fidia and Johnson & Johnson; advisory board: AstraZeneca, Bristol Myers Squibb, Combat Medical, Johnson & Johnson, Nucleix, Pfizer, Taris, Roche and Merck Sharp & Dohme; and manuscript support: Pfizer, Janssen, Combat Medical, AstraZeneca, Johnson & Johnson and Bristol Myers Squibb. A.B. reports consulting or advisory role: Astellas, Janssen-Cilag, OPKO Health, MDxHealth, Ferring, Bayer, AstraZeneca, Hauora and Pfizer; speakers’ bureau: Astellas; and research funding: Sandoz-Novartis, Merck Sharp & Dohme and Pfizer. G.S.K. reports honoraria: AbbVie, Tersera, Bayer, Knight Pharmaceuticals, AstraZeneca Canada and PhotoCure; consulting or advisory role: Merck, Theralase, Janssen Oncology, Ferring, Verity Pharmaceuticals, Bristol Myers Squibb, EMD Serono, Pfizer, Novartis and enGene; research funding: Johnson & Johnson/Janssen and Pfizer. J. Brinkmann reports employment: Pfizer Pharma GmbH. A.-M.C. reports employment: Pfizer SRL. R.C. reports employment: Pfizer SRL. A.E. reports employment: Pfizer Ltd. E.M. reports employment: Pfizer Inc. J.V. reports employment: Pfizer Inc. C.W. reports employment: Pfizer Inc. G.D.S. reports advisory/consultancy roles: Heat Biologics, CG Oncology, PhotoCure, Merck, Roche/Genentech, Ciclomed, Taris Biomedical (now Janssen), MDxHealth, Fidia Farmaceutici, UroGen, Ferring, Aduro, Boston Scientific, Bristol Myers Squibb, AstraZeneca, Pfizer, Janssen, Epivax Therapeutics, Natera, FKD, EnGene Bio, Sesen Bio, BioCanCell (now Archiano), Nucleix, Ipsen, Combat Medical, Astellas, FerGene, Dendreon, AbbVie, Seagen, Verity Pharmaceuticals, Regeneron, STIMIT, Vyriad, Protara, xCures, Nonagen, Nanology and Imvax; clinical trial protocol committee membership for Bristol Myers Squibb, CG Oncology, Fidia, Janssen, Merck, Pfizer, PhotoCure, Protara and Seagen; stock/shares in CG Oncology, EnGene Bio, EpiVax Therapeutics and UroGen; and research funding from Pfizer.

Figures

Fig. 1
Fig. 1. CONSORT diagram.
aThe first patient was randomized on 20 January 2020, and the last patient was randomized on 16 November 2021. bOne patient was a screen failure but was randomized in error. cTwo patients withdrew from study treatment in the sasanlimab + BCG-I arm due to recurrence of low-grade disease. dLack of efficacy refers to patients who experience an EFS event of recurrence of high-grade disease, persistence of CIS or progression of disease. CRF, case report form.
Fig. 2
Fig. 2. Analysis of EFS in the intent-to-treat population for sasanlimab + BCG-I+M versus BCG-I+M and sasanlimab + BCG-I versus BCG-I+M.
For EFS, an event was defined as the first of recurrence of high-grade disease, progression of disease, persistence of CIS (for patients with CIS at randomization) or death due to any cause. a, Kaplan–Meier estimates of EFS for sasanlimab + BCG-I+M versus BCG-I+M according to treatment arm in the intent-to-treat population. The dashed lines indicate EFS at 24 months and 36 months. b, Kaplan–Meier estimates of EFS for sasanlimab + BCG-I versus BCG-I+M according to treatment arm in the intent-to-treat population. The dashed lines indicate EFS at 24 months and 36 months.
Fig. 3
Fig. 3. Forest plot of the analyses of EFS in prespecified subgroups for sasanlimab + BCG-I+M versus BCG-I+M.
The HR for EFS in all patients was calculated on the basis of an analysis stratified by the presence of CIS at randomization (yes or no) and geography (United States, Western Europe and Canada or rest of world). In each subgroup, the HR for EFS was estimated with the use of unstratified Cox proportional hazards models. Data are presented as HR (center) with 95% CIs (error bars).
Fig. 4
Fig. 4. Analysis of OS in the intent-to-treat population.
a, Kaplan–Meier estimates of OS for sasanlimab + BCG-I+M versus BCG-I+M. b, Kaplan–Meier estimates of OS for sasanlimab + BCG-I versus BCG-I+M.
Extended Data Fig. 1
Extended Data Fig. 1. Analysis of event-free survival in the patients with carcinoma in situ at randomization (with or without papillary tumors) for sasanlimab + BCG-I+M vs BCG-I+M.
For EFS, an event was defined as the first of recurrence of high-grade disease, progression of disease, persistence of CIS (for patients with CIS at randomization), or death due to any cause. Kaplan-Meier estimates of EFS according to treatment arm. The dashed line indicates EFS at 36 months. BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; CIS, carcinoma in situ; EFS, event-free survival.
Extended Data Fig. 2
Extended Data Fig. 2. Analysis of event-free survival in the patients with T1 tumor (with or without carcinoma in situ) for sasanlimab + BCG-I+M vs BCG-I+M.
For EFS, an event was defined as the first of recurrence of high-grade disease, progression of disease, persistence of CIS (for patients with CIS at randomization), or death due to any cause. Kaplan-Meier estimates of EFS according to treatment arm. The dashed line indicates EFS at 36 months. BCG-I, Bacillus Calmette-Guérin induction regimen of intravesical Bacillus Calmette-Guérin; BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; CIS, carcinoma in situ; EFS, event-free survival.
Extended Data Fig. 3
Extended Data Fig. 3. Forest plot of the analysis of event-free survival in prespecified subgroups for sasanlimab + BCG-I vs BCG-I+M.
The hazard ratio for EFS in all patients was calculated on the basis of an analysis stratified by the presence of carcinoma in situ at randomization (yes or no) and geography (US, Western Europe and Canada, or rest of world). In each subgroup, the hazard ratio for EFS was estimated with the use of unstratified Cox proportional-hazards models. Data are presented as hazard ratio (center) with 95% confidence intervals (error bars). BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; CIS, carcinoma in situ; CRF, case report form; EFS, event-free survival.
Extended Data Fig. 4
Extended Data Fig. 4. Probability of remaining in Complete Response for patients with CIS at randomization who achieved Complete Response for sasanlimab + BCG-I+M vs BCG-I+M.
Kaplan-Meier estimates for duration of complete response for sasanlimab + BCG-I+M vs BCG-I+M in for patients with CIS at randomization who achieved CR. The dashed lines indicate the probability of remaining in complete response at 12, 24 and 36 months. BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; CIS, carcinoma in situ.
Extended Data Fig. 5
Extended Data Fig. 5. Plot of mean change from baseline over time for EORTC QLQ-C30 global health status by visit.
BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; C, cycle; D, day.
See this image and copyright information in PMC

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