Adding the PD-L1 inhibitor durvalumab to bacillus Calmette-Guérin (BCG) induction and maintenance therapy delayed high-risk events and improved cystectomy-free survival in patients with BCG-naive, high-risk non–muscle-invasive bladder cancer (NMIBC), according to expanded analyses from the phase III POTOMAC trial.1 The findings were presented by Neal D. Shore, MD, FACS, Medical Director of START Carolinas/Carolina Urologic Research Center, during the plenary session at the 2026 American Urological Association (AUA) Annual Meeting in Washington, DC.
Neal D. Shore, MD, FACS
The analyses built on previously reported findings showing a statistically significant and clinically meaningful improvement in disease-free survival with durvalumab plus BCG induction and maintenance compared with BCG induction and maintenance alone, previously presented by Maria De Santis, MD at a plenary session at ESMO 2025.2 In the expanded analyses, the addition of durvalumab was associated with fewer high-risk events, fewer early high-risk events, fewer BCG-unresponsive recurrences, and longer cystectomy-free survival.
Dr. Shore noted that the key clinical question was whether the potential for fewer recurrences, delayed progression, and longer cystectomy-free survival outweighed the added burden of intravenous durvalumab and its immune-mediated adverse events.
Dr. Shore told attendees at the AUA Annual Meeting that he viewed that tradeoff as worthwhile for appropriately selected patients, but emphasized that the choice should be made through shared decision-making. “I think it’s important for patients to appreciate that there are increases in side effects, but there’s a benefit to be gained,” he said. “So, one has to understand a person’s risk tolerance vs their risk aversion to get the clinical benefit.”
“And what is the clinical benefit for the high-risk, non–muscle-invasive bladder cancer patient?” Dr. Shore continued. “We’re trying to prevent [patients] from getting not only recurrences, which require more resections and biopsies and anesthesia … but also, more importantly, progression to the point of disease getting more invasive within the bladder wall, and ultimately leading to the consideration for bladder removal.”
Treatment Context
Patients with high-risk NMIBC are typically treated with transurethral resection followed by intravesical BCG. However, recurrence is common, and patients who experience early high-risk recurrence or develop BCG-unresponsive disease often have worse outcomes. After BCG failure, radical cystectomy is the preferred treatment option for many patients, but it can substantially affect quality of life.
In POTOMAC, eligible patients had undergone transurethral resection of their bladder tumor (TURBT), with complete resection of all Ta or T1 papillary disease; however, patients with residual carcinoma in situ after TURBT were eligible. Patients were randomly assigned 1:1:1 to (1) durvalumab plus BCG induction and maintenance, (2) durvalumab plus BCG induction, or (3) BCG induction and maintenance alone.
The expanded analyses discussed here focused on (1) durvalumab plus BCG induction and maintenance vs (3) BCG induction and maintenance alone.
A high-risk event was defined as recurrence of high-risk NMIBC (high-grade Ta/T1 disease or carcinoma in situ), persistent carcinoma in situ at 6 months, or progression to muscle-invasive bladder cancer or metastatic disease.
Expanded Efficacy Findings
Among 1,018 patients in POTOMAC, 339 patients were assigned to the durvalumab plus BCG induction group discussed in the original study; among the two groups discussed in this analysis, 339 were randomly assigned to durvalumab plus BCG induction and maintenance and 340 were assigned to BCG induction and maintenance alone. Treatment was received by 336 and 339 patients, respectively. Median follow-up was 60.7 months.
High-risk events were reported in 53 patients in the durvalumab-plus-BCG arm and 69 patients in the BCG-alone arm. Median time to a high-risk event was 14.1 months vs 8.3 months, respectively.
Early high-risk events, defined as occurring within 1 year of randomization, were less common with durvalumab plus BCG. Among patients with high-risk events, 45% in the durvalumab-plus-BCG group had an early high-risk event compared with 61% in the BCG-alone group.
At the time of recurrence, 65% of patients in the durvalumab-plus-BCG group and 81% in the BCG-alone group met criteria for BCG-unresponsive disease.
Time to cystectomy showed a trend favoring durvalumab plus BCG induction and maintenance vs BCG induction and maintenance alone, although the maturity of the analysis was low. The hazard ratio was 0.63, and median time to cystectomy was 19 months with durvalumab plus BCG vs 14 months with BCG alone. Cystectomy-free survival also favored durvalumab plus BCG, corresponding to a 31% reduction in the risk of cystectomy or death.
Safety and Implementation
Immune-mediated adverse events occurred in 27% of patients treated with durvalumab plus BCG induction and maintenance. At the data cutoff, 9% of patients had unresolved immune-mediated adverse events.
The most common immune-mediated adverse events were hypothyroid events, reported in 11% of patients; hepatic events, reported in 5%; and dermatitis or rash, reported in 3%. Among those events, 50% of hypothyroid events, 100% of hepatic events, and 82% of dermatitis or rash events had resolved or were resolving.
“One of the questions I oftentimes receive is: is it feasible for urologists to administer and manage durvalumab themselves? I think it absolutely is,” Dr. Shore said. “However, with anything new that has a different mechanism of action and safety profile, one needs to become knowledgeable and familiar, not only with the mechanism of action, but also the safety, tolerability, adverse event management, education for patients and their families before beginning therapy, and what to expect afterwards.”
For practices that do not manage immunotherapy directly, coordination with a nearby medical oncologist is an important and workable approach, he added.
“Do the improved cancer-specific outcomes make the trade-off of adding an infusion of a checkpoint inhibitor, such as durvalumab, to the BCG regimen worthwhile?” he said. “I would unequivocably answer yes, 100%, while assuming a patient and caregiver comprehensive shared decision-making discussion.”
He emphasized again that, “Patients should have the opportunity to have choice.”
Expert Point of View
Commenting on findings from the expanded analyses of the phase III POTOMAC trial,1,2 Elizabeth Koehne, MD, a urologic oncologist at the University of Wisconsin-Madison, said the expanded POTOMAC analysis continued to show a benefit with the PD-L1 inhibitor durvalumab plus BCG, but she characterized the magnitude of benefit as modest.
“The expanded POTOMAC analysis continued to demonstrate a modest benefit in reducing high-risk non–muscle-invasive tumor recurrences and delaying time to recurrence,” Dr. Koehne said. “This safety analysis showed a reasonable toxicity profile with 8% of patients experiencing significant side effects and 10% of patients stopping treatment due to side effects.”
She said the reduction in high-risk events was clinically meaningful, but she cautioned against overinterpreting some of the secondary analyses.
“This is a very difficult disease stage for patients and for clinicians to manage because, while it’s relatively rare for patients diagnosed with NMIBC to die of their disease, recurrences are very common,” Dr. Koehne said. “Some reduction in the recurrence risk is great, but patients would like the risk to be zero at any point.”
The cystectomy-related findings also require caution. “From these data, there was a trend in fewer patients undergoing cystectomy, but the number of patients in both arms who had a cystectomy was too low for this to be statistically significant,” she noted.
That said, bladder preservation remains highly important for patients. “Most patients hope to avoid cystectomy, as it is a major life-changing surgery,” she said. “However, cystectomy can also finally be a cure for patients who have been battling this disease for years and suffering urinary or other side effects of the various treatments.”
Dr. Koehne emphasized that the trade-off will not be the same for every patient. “For many patients, the added immune-mediated adverse events and effort required for the IV infusion of durvalumab are not worth the potential added efficacy,” she said. “However, there are some highly motivated patients who would be willing to risk the extra side effects and take the time to possibly delay or prevent recurrences.”
A biomarker that could help identify which patients are most likely to respond to BCG alone, BCG plus durvalumab, or other options would be helpful, she added. Many practices would also need to address logistics around durvalumab infusions, particularly because most urologists do not oversee intravenous treatment and would need to coordinate with medical oncology.
DISCLOSURE: Dr. Shore reported 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. Dr. Koehne reported no conflicts of interest.
REFERENCES
1. Shore ND, De Santis M, Palou Redorta J, et al: Durvalumab with bacillus Calmette-Guérin therapy for high-risk non–muscle-invasive bladder cancer: Expanded efficacy and safety analyses from POTOMAC. Abstract 26-9547. 2026 American Urological Association Annual Meeting. Presented May 15, 2026.
2. De Santis M, Palou Redorta J, Nishiyama H, et al: Durvalumab plus bacillus Calmette-Guérin induction and maintenance in patients with high-risk, BCG-naïve, non-muscle-invasive bladder cancer (POTOMAC): A multicentre, open-label, randomised, phase III trial. Lancet 406:2221-2234, 2025.
