In patients with high-risk non–muscle-invasive bladder cancer, the addition of 1 year of the PD-L1 inhibitor durvalumab to standard induction and maintenance bacillus Calmette-Guérin (BCG) infusions led to a statistically significant and clinically meaningful improvement in disease-free survival compared with BCG induction and maintenance therapy alone, according to the final analysis of the phase III POTOMAC trial. These results were reported at the European Society for Medical Oncology (ESMO) Congress 20251 and simultaneously published in The Lancet.2 With a median follow-up exceeding 5 years, POTOMAC is one of the longest-running non–muscle-invasive bladder cancer studies, the investigators noted.
After a median follow-up of 60.7 months, the durvalumab/BCG combination reduced the risk of disease recurrence or death by 32% (hazard ratio [HR] = 0.68; P = .0154) in patients with high-risk tumors that were ≥ T1, high-grade; carcinoma in situ; or multiple, recurrent, and large (≥ 3 cm), according to Maria De Santis, MD, Head of the Interdisciplinary Uro-Oncology Section at Charité–Universitätsmedizin, Berlin, Germany. “There was an early and sustained separation of the Kaplan-Meier [curves] starting at less than 4 months…. POTOMAC supports 1 year of durvalumab with BCG induction and maintenance therapy as a potential new treatment in BCG-naive, high-risk non–muscle-invasive bladder cancer,” Dr. De Santis said during her Proffered Paper presentation.
Maria De Santis, MD
As Dr. De Santis noted, the standard treatment of BCG-naive, high-risk non–muscle-invasive bladder cancer is transurethral resection of the bladder tumor followed by BCG induction and maintenance, but early recurrence and disease progression occur in about 40% of patients within 2 years. For most patients who experience high-risk recurrence, the recommended treatment is radical cystectomy. The hope is that such aggressive treatment might be avoided by combining immunotherapy with BCG.
Durvalumab is the first perioperative immunotherapy approved for patients with muscle-invasive bladder cancer based on results from the NIAGARA phase III trial: perioperative durvalumab in combination with neoadjuvant chemotherapy significantly improved event-free survival and extended overall survival vs neoadjuvant chemotherapy and radical cystectomy alone.3
POTOMAC Design
POTOMAC is a global phase III open-label trial evaluating durvalumab in combination with BCG therapy in 1,018 patients with BCG-naive, high-risk non–muscle-invasive bladder cancer from more than 120 sites in 12 countries. Investigators randomly assigned 1,018 patients who had undergone transurethral resection of the bladder tumor (complete resection, including patients with residual carcinoma in situ) to one of three arms: (1) durvalumab plus BCG induction and maintenance therapy; (2) durvalumab plus BCG induction alone; or (3) BCG induction and maintenance therapy alone. Durvalumab was administered intravenously (1,500 mg every 4 weeks for 13 cycles), and intravesical BCG was given weekly × 6 weeks (induction) and as three doses at weekly intervals at 3, 6, 12, 18, and 24 months (maintenance therapy).
The primary endpoint was disease-free survival for durvalumab plus BCG induction and maintenance vs BCG alone. Disease-free survival was defined as recurrence of high-risk non–muscle-invasive bladder cancer (T1, high-grade Ta, or carcinoma in situ); presentation with muscle-invasive bladder cancer and/or metastatic disease; persistent carcinoma in situ at 6 months; or death by any cause in the absence of recurrence.
Additional Key Findings
A generally consistent treatment effect was seen with durvalumab across subgroups. Median disease-free survival was not yet reached in either treatment arm. The 24-month disease-free survival rates were 86.5% (95% CI = 82.2%–89.8%) for durvalumab plus BCG induction and maintenance and 81.6% (95% CI = 76.9%–85.3%) for BCG induction and maintenance alone.
Overall survival was not formally powered for analysis, but a descriptive assessment after 65.6 months showed a hazard ratio of 0.80 (95% CI = 0.53–1.20), reported Dr. De Santis. The secondary endpoint of disease-free survival with durvalumab plus BCG induction (without BCG maintenance) vs BCG (induction plus maintenance) was not statistically significant (HR = 1.14, 95% CI = 0.86–1.50).
“Durvalumab plus BCG induction and maintenance had a tolerable and manageable safety profile that was consistent with the known safety profiles of the individual agents, with no deaths due to treatment-related adverse events,” Dr. De Santis reported.
Grade 3 or 4 treatment-related adverse events occurred in 21% of patients with durvalumab and BCG (induction and maintenance), in 15% with durvalumab and BCG (induction alone), and in 4% with BCG (induction and maintenance). “Overall, these events were consistent with what we expected for durvalumab and BCG therapy, with dysuria, hematuria, and pollakiuria being the three most commonly reported in both arms,” she said.
DISCLOSURE: Dr. De Santis has served as a consultant or advisor to Amgen, Astellas Pharma, AstraZeneca, Basilea, Bayer, Bioclin, Bristol Myers Squibb, Eisai, Ferring Pharmaceuticals, Gilead Sciences, Immunomedics, Ipsen, Janssen, Merck Sharp & Dohme, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, SeaGen, and Thermosome.
REFERENCES
1. De Santis M, Palou J, Nishiyama H et al: Durvalumab in combination with Bacillus Calmette-Guerin (BCG) for BCG-naive, high-risk non-muscle-invasive bladder cancer: Final analysis of the phase III, open-label, randomised POTOMAC trial. ESMO Congress 2025. Abstract LBA108. Presented October 17, 2025.
2. De Santis M, Redorta JP, 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. October 17, 2025 (early release online).
3. Powles T, Catto JWF, Galsky MD, et al: Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med 391:1773-1786, 2024.
EXPERT POINT OF VIEW
The invited discussant of the phase III POTOMAC trial was Bradley McGregor, MD, FASCO, Director of Clinical Research for the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. Dr. McGregor noted that POTOMAC was the second study to show a benefit to combining an immune checkpoint inhibitor, durvalumab, with bacillus Calmette-Guérin (BCG) in non–muscle-invasive bladder cancer. It joins the previous CREST trial,1 which showed improved event-free survival with the addition of the investigational PD-1 inhibitor sasanlimab to BCG. A third study, ALBAN,2 showed no advantage to adding atezolizumab to BCG.
Bradley McGregor, MD, FASCO
Dr. McGregor pointed out that PD-L1 is increased in patients with BCG-resistant disease, offering a rationale for adding immune checkpoint blockade to BCG earlier in treatment to potentially enhance outcomes. In doing so, he noted, significant improvement in event-free survival was observed in POTOMAC (hazard ratio [HR] = 0.68) and CREST (HR = 0.68)—but was lacking in ALBAN (HR = 0.98). Offering a few thoughts on this disparity, he said that ALBAN had a shorter maintenance period—12 months vs 24 in the other two trials—and less BCG exposure—14 cycles vs 20 in POTOMAC and 21 in CREST.
Furthermore, its population may have been a lower-risk group, he added. “What stood out to me is that ALBAN had the highest percentage of patients with carcinoma in situ overall but the lowest proportion of pure carcinoma in situ and less Ta and T1 patients,” he said. “POTOMAC also allowed patients with multiple, recurrent, and large (≥ 3 cm) tumors, so it’s a different patient population.”
The two positive studies also reflected some differences in safety. For instance, in the CREST trial, Dr. McGregor noted, the rate of grade ≥ 3 treatment-related adverse events was 30% with sasanlimab plus BCG vs 21% with durvalumab plus BCG, and those of any grade were observed in 43% vs 27%, respectively. Additionally, with sasanlimab, 20% of patients required steroids, and there were two treatment-related events in the induction arm.
“The median follow-up for POTOMAC is over 60 months, and prolonged follow-up is important, as we think about our long-term therapies…. The benefits of immune checkpoint blockade in combination with 2 years of BCG therapy must be weighed against the risk of short- and long-term toxicities,” he added.
Dr. McGregor also emphasized that although checkpoint inhibitors add value to BCG, they are not a replacement for adequate BCG therapy. “During this continuing BCG shortage, we cannot substitute that with systemic immune checkpoint blockade,” he said. “Both POTOMAC and CREST have shown numerically inferior outcomes when we remove the maintenance BCG. Maintenance BCG remains an important aspect of the management of high-grade non–muscle-invasive disease.”
Dr. McGregor shared these thoughts moving forward. “The 3-year event-free survival of any of our trials is 75% to 80% with modern, adequate BCG therapy. That said, there was a clear benefit in POTOMAC and CREST with the addition of immune checkpoint blockade, about 5% to 7%. Adequate BCG therapy remains a very high bar, and that bar got just even higher,” he concluded.
DISCLOSURE: Dr. McGregor reported personal financial relationships with Arcus Biosciences, AstraZeneca, Aveo, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Exelixis, Genmab, Gilead Sciences, Hexagon, Lilly, and Pfizer.
REFERENCES
1. 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 31:2806-2814, 2025.
2. Roupret M, Bertaut A, Pignot G, et al: ALBAN: A phase III, randomized, open-label, international study of intravenous atezolizumab and intravesical Bacillus Calmette-Guérin (BCG) vs BCG alone in BCG-naive high-risk, non-muscle-invasive bladder cancer. ESMO Congress 2025. Abstract LBA107. Presented October 17, 2025.
