AUA 2026: Expanded POTOMAC analyses support durvalumab plus BCG

Expanded efficacy and safety analyses from the phase 3 POTOMAC trial (NCT03528694), presented at the 2026 American Urological Association (AUA) Annual Meeting by Neal D. Shore, MD, FACS, demonstrated that durvalumab (Imfinzi) combined with BCG induction and maintenance therapy reduced the risk of high-risk disease recurrence or death by 32% compared with BCG induction and maintenance alone in patients with BCG-naive, high-risk non–muscle invasive bladder cancer (NMIBC), with expanded data providing new information on early recurrence, time to cystectomy, papillary tumor subgroups, and immune-mediated adverse events.^1,2

Trial background and primary end point

POTOMAC enrolled 1018 patients with BCG-naive, high-risk NMIBC and randomly assigned them 1:1:1 to durvalumab 1500 mg intravenously every 4 weeks for 13 cycles plus BCG induction and maintenance (D+BCG I+M; n=339), durvalumab plus BCG induction only (D+BCG I only; n=339), or BCG induction and maintenance alone (BCG I+M; n=340). The first patient was enrolled in June 2018, and the last dose of BCG was administered in January 2023, with a data cutoff of April 3, 2025. The primary analysis, published in The Lancet in 2025,² demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) for D+BCG (I+M) vs BCG (I+M) alone: HR was 0.68 (95% CI, 0.50–0.93); stratified log-rank was P = .0154. Median follow-up was 60.7 months, representing 24% DFS maturity. DFS rates at 12, 24, 36, and 48 months were 92%, 87%, 82%, and 80%, respectively, in the D+BCG (I+M) arm vs 87%, 82%, 77%, and 75% in the BCG (I+M) arm. Median DFS was not reached (NR) in the D+BCG (I+M) arm (95% CI, NR–NR) and was NR (95% CI, 74.0–NR) in the BCG (I+M) arm. No detrimental effect on overall survival (OS) was observed: HR 0.80 (95% CI, 0.53–1.20), with a median follow-up of more than 5 years (66 months).

"The POTOMAC trial was presented at ESMO [European Society for Medical Oncology] in 2025, published in The Lancet, and essentially showed that there was a statistically significant and clinically meaningful improvement in disease-free survival by combining one year of Q1 month durvalumab with induction maintenance BCG maintenance for 2 years. There was no [detrimental effect on] overall survival," said Shore, director of research at START Carolinas/Carolina Urologic Research Center in Myrtle Beach, South Carolina.^2.

Early high-risk recurrence and BCG-unresponsive disease

In NMIBC, early high-risk disease recurrence is associated with worse outcomes, and BCG-unresponsive disease is an indication for radical cystectomy per current guidelines.^3,4 A high-risk disease event was defined as high-risk NMIBC recurrence (high-grade Ta, T1, or carcinoma in situ [CIS]), persistent CIS at 6 months, MIBC, and/or metastatic disease. In a post hoc exploratory analysis of events within the first year, 53 of 339 patients (16%) in the D+BCG (I+M) arm experienced a high-risk disease event compared with 69 of 340 (20%) in the BCG (I+M) arm. Median time from randomization to a high-risk disease event was 14.1 months in the D+BCG arm vs 8.3 months in the BCG arm. At 12 months or less, 24 of 53 patients (45%) in the D+BCG arm had an event vs 42 of 69 (61%) in the BCG arm; at 6 months or less, 14 of 53 (26%) vs 29 of 69 (42%), respectively; and at 3 months or less, 7 of 53 (13%) vs 14 of 69 (20%).

Regarding BCG-unresponsive disease, the data showed that the addition of durvalumab did not impair patients’ ability to receive adequate BCG therapy: 291 of 336 patients (87%) in the D+BCG (I+M) arm and 315 of 339 patients (93%) in the BCG (I+M) arm received adequate BCG. Among patients with high-risk NMIBC recurrence or persistent CIS, 37 of 339 (11%) in the D+BCG arm and 54 of 340 (16%) in the BCG arm met BCG-unresponsive criteria;⁵ of those, 24 of 37 (65%) in the D+BCG arm vs 44 of 54 (81%) in the BCG arm were BCG-unresponsive.²

"What is important to recognize is that the addition of durvalumab, a checkpoint blocker, did not impact the patients’ ability to receive adequate BCG—the classic 5 plus 2, which has a consensus recommendation," Shore stated.

Time to cystectomy and cystectomy-free survival

Time-to-cystectomy data, a secondary end point presented for the first time at AUA 2026, showed a numerical trend favoring D+BCG (I+M). Cystectomy events occurred in 13 of 339 patients (4%) in the D+BCG (I+M) arm vs 21 of 340 (6%) in the BCG (I+M) arm (HR 0.63; 95% CI, 0.31–1.24). Median time to cystectomy among patients who underwent the procedure was 19.0 months in the D+BCG arm vs 14.1 months in the BCG arm. Among patients with BCG-unresponsive disease, 2 of 24 (8%) in the D+BCG (I+M) arm underwent cystectomy compared with 11 of 44 (25%) in the BCG (I+M) arm.¹

In a post hoc exploratory analysis, cystectomy-free survival—defined as time from randomization to cystectomy or death—also showed a favorable trend for D+BCG (I+M): 49 events (14%) vs 70 events (21%) in the BCG (I+M) arm; HR 0.69 (95% CI, 0.48–0.99). Median cystectomy-free survival was NR in the D+BCG arm (95% CI, NR–NR) vs NR (95% CI, 78.3–NR) in the BCG arm. Shore noted that POTOMAC has the longest follow-up, out to 5 years, among phase 3 trials evaluating an immunotherapy agent combined with BCG induction and maintenance.¹

"This is the first time we’ve been able to show this time to cystectomy, which was a prespecified end point, showed a trend in the durva-BCG vs the BCG-alone arm with fewer patients undergoing cystectomy," Shore said. "The numbers are small, but there’s clearly a trend."

DFS benefit across papillary tumor subgroups

Approximately 91% of the intent-to-treat (ITT) population had some form of papillary disease. In the papillary-only subgroup (D+BCG n=217; BCG n=220), which represented 64% to 65% of the ITT population, 37 of 217 patients (17%) in the D+BCG arm had DFS events vs 65 of 220 (30%) in the BCG arm: HR 0.56 (95% CI, 0.37–0.84); P=.0046. A forest plot of DFS across papillary subgroups showed HRs that were consistently more favorable than the ITT HR of 0.68 (95% CI, 0.50–0.93): any papillary tumors (with or without CIS), HR 0.61 (95% CI, 0.43–0.84); any T1, HR 0.55 (95% CI, 0.36–0.82); T1 only, HR 0.48 (95% CI, 0.28–0.79); and T1 high grade/G3 only, HR 0.55 (95% CI, 0.31–0.95). Taken together, these data represent a 39% to 52% reduction in the risk of high-risk disease recurrence or death across papillary tumor subgroups with D+BCG (I+M) vs BCG (I+M).¹

"What you’re really seeing is a 39% to 50% reduction in the rate of high-risk disease recurrence or death across the papillary tumor subgroups," Shore said. "These [HRs] in comparison to the [ITT] of 0.68 are all better."¹

Overall survival in papillary subgroups

No detrimental effect on OS was observed with the addition of durvalumab across any papillary subgroup. At a median follow-up of 65.6 months in the D+BCG arm (65.9 months overall; 14% OS maturity), deaths occurred in 41 of 339 patients (12%) in the D+BCG (I+M) arm vs 52 of 340 (15%) in the BCG (I+M) arm in the ITT population (HR 0.80; 95% CI, 0.53–1.20). OS HRs across papillary subgroups were: any papillary tumors, HR 0.77 (95% CI, 0.49–1.18); papillary only, HR 0.68 (95% CI, 0.42–1.09); any T1, HR 0.67 (95% CI, 0.39–1.14); T1 only, HR 0.52 (95% CI, 0.27–0.93); and T1 HG/G3 only, HR 0.58 (95% CI, 0.29–1.13). No grade 5 adverse events were attributed to durvalumab in any arm.¹

Safety profile and immune-mediated adverse events

The safety profile of D+BCG (I+M) in patients with papillary-only tumors was consistent with the overall safety population. In the papillary-only subgroup (D+BCG n=215; BCG n=219), any-cause adverse events (AEs) were reported in 208 patients (97%) in the D+BCG arm vs 193 (88%) in the BCG arm; maximum grade 3 or 4 AEs occurred in 73 (34%) vs 35 (16%), respectively; serious AEs in 64 (30%) vs 38 (17%); and AEs leading to death in 5 (2%) vs 4 (2%), with no treatment-related fatal events in either arm. Any-grade immune-mediated AEs (imAEs) occurred in 58 patients (27%) in the papillary-only D+BCG group, consistent with 91 of 336 patients (27%) in the overall D+BCG (I+M) safety population.¹

The most common imAEs in the overall D+BCG (I+M) safety population were hypothyroid events (36 patients; 11%), hepatic events (17 patients; 5%), dermatitis/rash (11 patients; 3%), and hyperthyroid events (8 patients; 2%). Grade 3 or 4 imAEs occurred in 27 of 336 patients (8%), and imAEs leading to discontinuation of any treatment occurred in 32 patients (10%). Of the 91 patients in the overall safety population who experienced any imAE, 43 (47%) had resolved events, 15 (16%) had resolving events, 3 (3%) had resolved with sequelae, and 30 (33%) had events that were not resolved at the time of data cutoff; thus, 67% had imAEs that were resolved or resolving.¹

"The safety profile of combining durva and BCG induction maintenance with papillary-only tumors was consistent with the overall safety population," Shore noted, adding that immune-mediated AEs are "important for our colleagues to become comfortable with."

Conclusions and clinical implications

Shore concluded that the full body of POTOMAC data supports 1 year of durvalumab in combination with BCG induction and maintenance as a potential new treatment paradigm for patients with BCG-naive, high-risk NMIBC.

"I think these data clearly support one year of durvalumab in combination with induction maintenance BCG as a potential new treatment for patients with BCG high-risk NMIBC with the appropriate shared decision-making conversation," Shore said.

DISCLOSURE: Shore served as co-principal investigator on the POTOMAC trial and has reported advisory/consulting relationships and research funding from AstraZeneca, which sponsored the POTOMAC trial.

References

1. Shore ND, De Santis M, Redorta JP, et al. Durvalumab in combination with bacillus Calmette-Guérin induction and maintenance in BCG-naïve, non-muscle-invasive bladder cancer: expanded efficacy and safety analyses from POTOMAC. Presented at: 2026 American Urological Association Annual Meeting; May 15–18, 2026; Washington, DC. https://tinyurl.com/4hj9287w

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 3 trial. Lancet. 2025;406(10516):2221-2234. doi:10.1016/S0140-6736(25)01897-5

3. Gontero P, Birtle A, Capoun O, et al. European Association of Urology guidelines on non–muscle-invasive bladder cancer (TaT1 and carcinoma in situ)—a summary of the 2024 guidelines update. Eur Urol. 2024;86(6):531-549. doi:10.1016/j.eururo.2024.07.027

4. Holzbeierlein JM, Bixler BR, Buckley DI, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline: 2024 amendment. J Urol. 2024;211(4):533-538. doi:10.1097/JU.0000000000003846

5. BCG-unresponsive non-muscle invasive bladder cancer: developing drug and biological products for treatment: guidance for industry. FDA. August 2024. https://www.fda.gov/media/101468/download