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.
Future directions for BCG-naïve high-risk non-muscle invasive bladder cancer management: Outcomes from the POTOMAC Trial, a real paradigmatic shift?
Non-muscle-invasive bladder cancer (NMIBC) continues to represent a significant global healthcare burden. Within its disease heterogeneity, in recent years the high-risk (HR) subgroup achieved particular attention. Despite the well-established standard of care (SOC), represented by transurethral resection of the bladder tumour (TURBT) followed by a one/three-year maintenance regimen of adjuvant Bacillus Calmette–Guérin (BCG), treatment failure still remains a major concern, as approximately up to 40% of patients experience recurrence within one year and up to 20% eventually progress to muscle-invasive bladder cancer (MIBC) [1].
According to the European Association of Urology (EAU) Guidelines, BCG-unresponsive disease encompasses all BCG-refractory tumours, defined by persistence or progression of high-grade lesions within six months of initiating or during maintenance BCG therapy, and early BCG-relapsing tumours, characterised by high-grade recurrence within six months following completion of maintenance therapy [2].
Although BCG has been employed in the management of bladder cancer for several decades, its precise mechanism of action remains incompletely elucidated [3]: the biological mechanisms underlying this unresponsiveness are poorly understood and likely multifactorial, involving complex tumour-bladder microenvironment interactions and host immune factors [4].
In this scenario, given the substantial risk of tumour recurrence and progression, upfront radical cystectomy (RC) with urinary diversion is proposed as the SOC for BCG-unresponsive NMIBC patients, yielding cancer-specific survival (CSS) rates exceeding 80%. However, a considerable proportion of patients decline RC due to concerns regarding perioperative morbidity and the consequent impact on quality of life (QoL) [5].
As a result, additional bladder-sparing therapies (BSTs) are developing, highlighting the urgent need to develop and validate novel therapeutic strategies for this challenging population [6].
Such emerging therapeutic approaches include immune checkpoint inhibitors (ICIs), oncolytic viral therapies, advanced intravesical drug delivery systems, and targeted molecular agents [7].
In September 2025, the United States (US) Food and Drug Administration (FDA) approved TAR-200, a sustained-release intravesical gemcitabine delivery system for BCG-unresponsive patients with a Carcinoma in situ (CIS) component [8]. Furthermore, the SunRISe-3 Phase III trial is evaluating the efficacy and safety of TAR-200 combined with systemic Cetrelimab, TAR-200 monotherapy, versus standard BCG therapy in patients with BCG-naıve HR NMIBC [7].
In the BCG-naive HR NMIBC setting, several ongoing Phase III trials are investigating the combination of BCG with ICIs, including ALBAN (Atezolizumab; NCT03799835), KEYNOTE-676 (Pembrolizumab; NCT03711032), CREST (Sasanlimab; NCT04165317) and POTOMAC (Durvalumab; NCT03528694).
To date, Sasanlimab was the first anti-PD-1 antibody to demonstrate a significant improvement of event-free survival (EFS) in BCG-naive HR NMIBC patients when administered systemically in combination with BCG induction and maintenance rather than current SOC alone (HR: 0.68, 95%CI:0.49–0.94, p=0.0095) [9].
In October 2025, De Santis Maria et al. reported in The Lancet the final analysis of the POTOMAC Trial [10], aligning with the most recent scientific evidence of the CREST study in its potential to transform the management and treatment of BCG-naive HR NMIBC patients. The POTOMAC trial is a phase III, randomised, global, multicentre study that enrolled 1018 patients between June 2018 and October 2020. Eligible participants were ≥18 years old, had a histologically confirmed diagnosis of HR NMIBC following TURBT, including 375 patients [37%] with CIS and 659 [65%] with papillary disease only. All patients were BCG-naive and they were randomly assigned in a 1:1:1 ratio to one of three treatment arms: n=339 systemic intravenous Durvalumab administered every 4 weeks for 13 cycles plus intravesical BCG induction (weekly for six weeks) and maintenance (three weekly instillations at 3, 6, 12, 18, and 24 months); n=339 Durvalumab plus BCG induction only; n=340 current SOC BCG induction and maintenance as the comparator arm. Overall, the duration of ICI exposure was one year, and the median follow-up was around 60 months. The study met its primary endpoint, demonstrating improvement in disease-free survival (DFS) in the Durvalumab plus BCG induction and maintenance group thus resulting in a 32% reduction in the risk of HR disease recurrence or death from any cause compared with the control group (HR 0.68, 95% CI 0.50–0.93; p=0.015), thereby supporting the hypothesis that PD-1/PD-L1 pathway inhibition in combination with intravesical BCG can improve outcomes in early BC settings. Additionally, at 24 months the proportion of patients alive and free from HR disease recurrence was 86.5% (95% CI: 82.2–89.8) in the durvalumab plus BCG induction and maintenance group versus 81.6% (95% CI: 76.9–85.3) in the comparison group. By the data cutoff of April 3, 2025, all patients had discontinued study treatment. Treatment completion rates were 53% in the durvalumab plus BCG induction and maintenance group, 71% in the durvalumab plus BCG induction-only group, and 54% in the comparison group. The most frequent reason for treatment discontinuation was the occurrence of an adverse event (AEs), reported in the 27%, 16%, and 17% of patients, respectively. AEs of any cause were more frequent in the Durvalumab plus BCG induction and maintenance group (97%) versus the comparator arm (91%), and treatment-related AEs (such as immune-mediated) were reported in 89% and 72% of patients, respectively. Notably, grade 3-4 treatment-related AEs occurred in 21% of patients in the durvalumab plus BCG induction and maintenance group versus 4% in the control group, while serious treatment-related AEs occurred in 13% and 4%, respectively.
Therefore, together with the findings of the CREST study, the POTOMAC trial supports the hypothesis that adding an ICI to BCG induction and maintenance may address a critical unmet therapeutic need in patients at risk for BCG resistance, potentially mitigating treatment failure and improving clinical outcomes compared with BCG alone.
Considering the well-established international guidelines for the management of HR NMIBC, the findings of the POTOMAC trial raise important questions regarding its potential to refine and possibly redefine routine clinical practice in this setting.
Firstly, previous results have shown a critical profile of tolerability of ICIs in this clinical context. Although the incidence of severe treatment-related AEs associated with Durvalumab in POTOMAC was consistent with established safety profiles for ICIs in general, toxicity must be carefully weighed when selecting therapy for HR NMIBC patients, as the burden of immune-related adverse effects may influence treatment adherence and complicate subsequent clinical management. Therefore, specialists must be aware and adequately prepared to recognise and manage AEs and further refinement of AEs classification and handling strategies would be essential.
Another consideration refers to the capacity of healthcare systems to implement this multidisciplinary treatment approach for all BCG-naive patients with HR NMIBC. As systemic ICIs and intravesical BCG are typically administered in separate clinical environments, the administration of both therapies will require sustained coordination between urologists and medical oncologists. Establishing streamlined treatment pathways will be essential, as logistical challenges may otherwise compromise treatment adherence and potentially affect clinical outcomes.
Lastly, concerns regarding the cost-effectiveness of ICIs integration into current SOC are necessary. Although POTOMAC achieved its primary endpoint, the absolute improvement in 2 years of DFS events is approximately 5% [10]. This achievement represents such a modest clinical result, consequently careful evaluation is warranted to determine whether the broad implementation of this resource-intensive and high-cost therapeutic strategy would be justified for all patients with HR NMIBC.
In conclusion, in current clinical practice many patients with BCG-unresponsive NMIBC ultimately receive either additional courses of intravesical BCG monotherapy or no further treatment, as intravesical chemotherapy is still challenging to access, clinical trials are limited in availability and patients are reluctant to undergo upfront surgery [5]. Comparative evidence assessing oncological outcomes between BST and upfront RC remains limited, as it is largely derived from single-institution studies. Nevertheless, current data suggest that oncological outcomes among BCG-resistant HR NMIBC patients managed with BST may not necessarily be inferior [11,12].
Future investigations should address several key aspects. First, the considerable heterogeneity in treatment-response rates observed even within narrowly defined NMIBC risk categories underscores the existing need to elucidate such biological mechanisms driving this variability [5]. Second, comprehensive long-term studies integrating tumour-specific characteristics, emerging therapeutic strategies, and multidisciplinary perspectives are essential to potentially optimise clinical decision-making [13]. Eventually, greater attention should be given to treatment intensity, toxicity profiles, and patients’ QoL, as these factors remain insufficiently characterised in current NMIBC research and should be considered as core components of further evaluations [14].
REFERENCES
[1] Brouzes H, Ourfali S, Fassi-Fehri H, et al. Predicting recurrence and progression in NMIBC: A multi-event and temporal analysis approach. Fr J Urol. 2025 Oct;35(9):102921. doi: 10.1016/j.fjurol.2025.102921. Epub 2025 Jun 21. PMID: 40550272.
[2] Kamat, A, Colombel, M, Sundi D, et al. BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG. Nat Rev Urol 14, 244–255 (2017). doi: 10.1038/nrurol.2017.16. Epub 2017 Feb 21. PMID: 28248951.
[3] Mukherjee N, Julián E, Torrelles JB, Svatek RS. Effects of Mycobacterium bovis Calmette et Guérin (BCG) in oncotherapy: Bladder cancer and beyond. Vaccine. 2021 Dec 8;39(50):7332-7340. doi: 10.1016/j.vaccine.2021.09.053. Epub 2021 Oct 7. PMID: 34627626; PMCID: PMC9056065.
[4] Claps F, Pavan N, Ongaro L, et al. BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets. Int J Mol Sci. 2023 Aug 9;24(16):12596. doi: 10.3390/ijms241612596. PMID: 37628785; PMCID: PMC10454200.
[5] Taylor JI, Kamat AM, O’Donnell MA, et al. Long-term outcomes of bladder-sparing therapy vs radical cystectomy in BCG-unresponsive non-muscle-invasive bladder cancer. BJU Int. 2025 Feb;135(2):260-268. doi: 10.1111/bju.16509. Epub 2024 Aug 25. PMID: 39183466; PMCID: PMC11745998.
[6] Subiela JD, Scilipoti P, Contieri R, et al. Management Dilemma for Very High-risk Non-muscle-invasive Bladder Cancer: Real-World Data Challenge the Guideline Recommendation for Upfront Radical Cystectomy. Eur Urol. 2025 Sep;88(3):228-230. doi: 10.1016/j.eururo.2025.05.005. Epub 2025 May 14. PMID: 40374480.
[7] Filon M, Schmidt B. New Treatment Options for Non-Muscle-Invasive Bladder Cancer. Am Soc Clin Oncol Educ Book. 2025 Jan;45(2): e471942. doi: 10.1200/EDBK-25-471942. Epub 2025 Feb 11. Erratum in: Am Soc Clin Oncol Educ Book. 2025 Jun;45(3): e471942CX1. doi: 10.1200/EDBK-25-471942CX1. PMID: 39933135.
[8] U.S. Food and Drug Administration. FDA approves gemcitabine intravesical system for non–muscle-invasive bladder cancer [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; [cited 2025 Nov 16]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-gemcitabine-intravesical-system-non-muscle-invasive-bladder-cancer
[9] Shore ND, Powles TB, Bedke J, et al. Sasanlimab plus BCG in BCG-naive, high-risk non-muscle invasive bladder cancer: the randomized phase 3 CREST trial. Nat Med. 2025 Aug;31(8):2806-2814. doi: 10.1038/s41591-025-03738-z. Epub 2025 May 31. Erratum in: Nat Med. 2025 Aug;31(8):2815. doi: 10.1038/s41591-025-03894-2. PMID: 40450141; PMCID: PMC12353837.
[10] De Santis M, Palou Redorta J, Nishiyama H, et al; 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. Lancet. 2025 Nov 8;406(10516):2221-2234. doi: 10.1016/S0140-6736(25)01897-5. Epub 2025 Oct 17. PMID: 41115436.
[11] Howard JM, Cook GS, Tverye A, et al. Outcomes of patients with bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer as defined by the U.S. Food and Drug Administration. Bladder Cancer. 2022 Sep 15;8(3):303-314. doi: 10.3233/BLC-211657. PMID: 38993682; PMCID: PMC11181681.
[12] Tan WS, Grajales V, Contieri R, et al. Bladder-sparing treatment in patients with bacillus Calmette-Guerin-unresponsive non-muscle-invasive bladder cancer: an analysis of long-term survival outcomes. Eur Urol Open Sci. 2023 May 13; 53:16-22. doi: 10.1016/j.euros.2023.04.013. PMID: 37441349; PMCID: PMC10334230.
[13] Parmar MK, Barthel FM, Sydes M, et al. Speeding up the evaluation of new agents in cancer. J Natl Cancer Inst. 2008 Sep 3;100(17):1204-14. doi: 10.1093/jnci/djn267. Epub 2008 Aug 26. PMID: 18728279; PMCID: PMC2528020.
[14] Bessa A, Rammant E, Enting D, et al. The need for supportive mental wellbeing interventions in bladder cancer patients: a systematic review of the literature. PLoS One. 2021 Jan 28;16(1): e0243136. doi: 10.1371/journal.pone.0243136. PMID: 33507907; PMCID: PMC7842965.