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. 2025 Oct 17:S0140-6736(25)01897-5.
doi: 10.1016/S0140-6736(25)01897-5. Online ahead of print.

Durvalumab in combination with BCG for BCG-naive, high-risk, non-muscle-invasive bladder cancer (POTOMAC): final analysis of a randomised, open-label, phase 3 trial

Maria De Santis  1 , Joan Palou Redorta  2 , Hiroyuki Nishiyama  3 , Michał Krawczyński  4 , Artur Seyitkuliev  5 , Andrey Novikov  6 , Félix Guerrero-Ramos  7 , Ruslan Zukov  8 , Minoru Kato  9 , Takashi Kawahara  10 , Lieven Goeman  11 , Javier Puente  12 , Eva Hellmis  13 , Thomas Powles  14 , Piotr Radziszewski  15 , Kilian M Gust  16 , Paul Vasey  17 , Pierre Bigot  18 , Yves Fradet  19 , Jarmo Hunting  20 , Jon Armstrong  21 , Suliman Boulos  22 , Stephan Hois  23 , Neal D Shore  24 ; POTOMAC Investigators
Collaborators, Affiliations

Durvalumab in combination with BCG for BCG-naive, high-risk, non-muscle-invasive bladder cancer (POTOMAC): final analysis of a randomised, open-label, phase 3 trial

Maria De Santis et al. Lancet. .

Abstract

Background: Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) often have recurrence or progression after transurethral resection of bladder tumour (TURBT) and subsequent BCG therapy. We aimed to evaluate whether 1 year of durvalumab with BCG could improve outcomes versus BCG alone for these patients.

Methods: This randomised, open-label, phase 3 trial enrolled patients aged 18 years or older with BCG-naive, high-risk NMIBC who underwent TURBT. Patients were randomly allocated (1:1:1) to receive intravenous durvalumab (every 4 weeks for 13 cycles) plus intravesical BCG induction (weekly for 6 weeks) and maintenance (three doses at weekly intervals at 3, 6, 12, 18, and 24 months), durvalumab plus BCG induction, or BCG induction and maintenance (comparison group). The primary endpoint was investigator-assessed disease-free survival in the durvalumab plus BCG induction and maintenance group versus the comparison group in the intention-to-treat population. This study is registered at ClinicalTrials.gov (NCT03528694) and EudraCT (2017-002979-26) and is ongoing but is no longer enrolling patients.

Findings: Between June 18, 2018, and Oct 2, 2020, 1350 patients were assessed for eligibility, among whom 1018 patients were randomly allocated: 339 to the durvalumab plus BCG induction and maintenance group (of whom 336 [99%] initiated and 180 [53%] completed treatment), 339 to the durvalumab plus BCG induction group (337 [99%] initiated and 239 [71%] completed treatment), and 340 to the comparison group (339 [>99%] initiated and 182 [54%] completed treatment). At a median follow-up of 60·7 months (IQR 51·5-66·5), there were 67 (20%) disease-free survival events in the durvalumab plus BCG induction and maintenance group and 98 (29%) events in the comparison group, resulting in a 32% reduction in the risk of recurrence of high-risk disease or death by any cause with durvalumab plus BCG induction and maintenance versus the comparison group (hazard ratio 0·68 [95% CI 0·50-0·93]; log-rank p=0·015). Among patients who received at least one dose of study treatment, grade 3 or 4 treatment-related adverse events occurred in 71 (21%) of 336 patients in the durvalumab plus BCG induction and maintenance group, 52 (15%) in the durvalumab plus BCG induction only group, and 13 (4%) of 339 patients in the comparison group. No treatment-related adverse events led to death.

Interpretation: Among patients with BCG-naive, high-risk NMIBC, 1 year of durvalumab combined with BCG induction and maintenance therapy showed a statistically significant and clinically meaningful improvement in disease-free survival versus BCG induction and maintenance alone. The combination had a manageable safety profile, consistent with that of the individual therapies. These results support 1 year of durvalumab in combination with BCG induction and maintenance therapy as a potential new treatment for this patient population.

Funding: AstraZeneca.

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Conflict of interest statement

Declaration of interests MDS reports consulting roles for AAA, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, Bristol Myers Squibb, Eisai, Ferring, Gilead Sciences, Immunomedics, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, SeaGen, and Thermosome; honoraria from AAA, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, Bristol Myers Squibb, Eisai, Ferring, Gilead Sciences, Immunomedics, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, and SeaGen; support for attending meetings and/or travel from AAA, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, Bristol Myers Squibb, Eisai, Ferring, Gilead Sciences, Immunomedics, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, and SeaGen; unpaid participation on data safety monitoring boards or advisory boards for Thermosome Hyperthermia trial, GUSTO DMEC (academic trial Sheffield), and AURORA (academic trial Southampton); and unpaid leadership or fiduciary role in ESMO bladder cancer CPG and German S3 bladder cancer guidelines. JPR reports consulting roles for AstraZeneca, Fidia, Jemedis, Olympus, and Pfizer; and participation on advisory boards for AstraZeneca, Fidia, and Pfizer. HN reports grants or contracts from Chugai Pharma and Astellas; consulting roles for Ono Pharmaceutical, AstraZeneca, Janssen, and Merck Sharp & Dohme; and honoraria for speakers bureaus from Astellas, Merck Sharp & Dohme, Nippon Kayaku, Merck Biopharma, AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, and Pfizer. AN reports honoraria from Eisai; and travel, accommodations, and expenses from Biocad. FG-R reports consulting roles for Johnson & Johnson, Pfizer, Merck, Roche, Taris, Combat Medical, AstraZeneca, MSD, Bristol Myers Squibb, enGene, and Nanobots Therapeutics; honoraria from or participation in speakers bureaus for Janssen, Nucleix, MSD, Pfizer, Merck, Bristol Myers Squibb, AstraZeneca, Palex, Combat Medical, Johnson & Johnson, and Recordati; expert testimony for Nucleix and Menarini Diagnostics; travel, accommodations, and expenses from Pfizer, Recordati, Ipsen, Combat Medical, Alter, Salvat, Nucleix, AstraZeneca, Fidia, and Johnson & Johnson; patents planned, issued or pending from Danae UroGenomics; participation on a data safety monitoring board or advisory board for MDS and enGene; and holding stocks in CG Oncology, Johnson & Johnson, and Pfizer. RZ reports honoraria from Astellas Pharma, AstraZeneca, Johnson & Johnson, Merck, Novartis, Pfizer, Aegean, Roche, and Biocad; research funding from AstraZeneca, Bristol Myers Squibb, Johnson & Johnson, MSD, Novartis, and Roche. MKa reports honoraria from or participation in speakers bureaus for Pfizer, Merck, Astellas, MSD, Janssen, Ono Pharmaceutical, Bristol Myers Squibb, MC Medical, Nippon Kayaku, and AstraZeneca; and participation on a data safety monitoring board or advisory board for Astellas, MSD, AstraZeneca, Merck, and Janssen. JP reports consulting roles from Pfizer and Roche; honoraria for lectures from AstraZeneca, Eisai, Janssen, MSD, Pfizer, Bristol Myers Squibb, and Merck; travel for attending meetings from Janssen, Pfizer, and Merck; and participation in advisory boards for AstraZeneca, Janssen, MSD, Pfizer, Bristol Myers Squibb, and Merck. TP reports grants or contracts from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck/MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai; consulting roles for AstraZeneca, Exelixis, Ipsen, Novartis, Bristol Myers Squibb, Incyte, Merck/MSD, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, Mashup, and Gilead Sciences; honoraria from AstraZeneca, Exelixis, Ipsen, Novartis, Bristol Myers Squibb, Incyte, Merck/MSD, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, Mashup, and Gilead Sciences; payment for expert testimony from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck/MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai; support for attending meetings and/or travel from Roche, Pfizer, MSD, AstraZeneca, Ipsen, Gilead Sciences, and Astellas. PR reports grants or contracts from AstraZeneca. KMG reports grants or contracts from Bristol Myers Squibb (paid to institution); consulting roles for Astellas, AstraZeneca, Bristol Myers Squibb, Cepheid, Ferring, Ipsen, Johnson & Johnson, Merck, MSD, Pfizer, and Roche; honoraria or participation in speakers bureaus for Astellas, AstraZeneca, Bristol Myers Squibb, Cepheid, Ferring, Ipsen, Johnson & Johnson, Merck, MSD, Pfizer, and Roche; travel, accommodations, and expenses from Allergan, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Johnson & Johnson, Merck, MSD, Novartis, Pfizer, Pierre Fabre, and Roche; participation on a data safety monitoring board or advisory board for Astellas, AstraZeneca, Bristol Myers Squibb, Cepheid, Ferring, Ipsen, Johnson & Johnson, Merck, MSD, Pfizer, and Roche; and leadership or fiduciary role in the Austrian Uro-Oncology Working Group (unpaid). YF reports grants or contracts from Merck and TerSera. JH reports consulting roles for Novartis. JA, SB, and SH report holding stocks in and being an employee of AstraZeneca. NDS reports consulting roles for Alessa, Amgen, Asieris Pharmaceuticals, Astellas, AstraZeneca, Aura Biosciences, Bayer, BioProtect, Bristol Myers Squibb, CG Oncology, Clarity, Dendreon, Exact Imaging, Ferring, Fize Medical, Glytherix, Immunity Bio, Invitae, Janssen, Lantheus, Lilly, MDxhealth, Merck, Minomic, Myriad, Novartis, Nusano, Pfizer, Photocure, Promaxo, Protara, Sumitomo, Telix, Tolmar, Tutelix, and UroGen. All other authors declare no competing interests.

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