Durvalumab plus BCG may best serve patients with high-grade T1 NMIBC

Systemic therapy with a checkpoint inhibitor plus BCG is a legitimate first-line option for BCG-naive high-risk non-muscle-invasive bladder cancer (NMIBC), but urologists should optimize BCG delivery before intensifying treatment, according to Tom Jayram, MD.¹ Jayram, director of the Advanced Therapeutics Center at Urology Associates, P.C. in Nashville, Tennessee, shared his perspective in a presentation titled “Systemic Therapy in BCG-Naïve NMIBC: Is It Worth It?” at the 2026 LUGPA Annual Meeting.¹

Jayram noted a recent update to the National Comprehensive Cancer Network (NCCN) Guidelines added BCG plus durvalumab (Imfinzi) as a category 2A recommendation for BCG-naive high-risk NMIBC.¹ For many years, BCG induction followed by maintenance has stood as the preferred standard of care in this setting.¹

Jayram grounded his case for BCG optimization in NIMBUS, a randomized trial of 345 patients at 51 institutions in 5 countries.² The reduced-frequency arm received induction instillations at weeks 1, 2, and 6, plus maintenance at weeks 1 and 3 of months 3, 6, and 12. The standard-frequency arm received 6 weekly induction instillations and 3 weekly maintenance instillations at the same time points.²

Recurrence at 24 months occurred in 34% of patients in the reduced-frequency arm vs 15% in the standard-frequency arm (HR, 0.40; 95% CI, 0.24-0.68), with restaging transurethral resection required in the trial.² Jayram argued the reduced-frequency arm resembles real-world community practice, where patients may receive 3 or 4 instillations and may or may not complete induction.¹

He suggested many BCG failures reflect suboptimal resection and BCG delivery rather than biologically aggressive disease.¹ A high volume of patients moving to BCG-unresponsive therapies each month may signal gaps in upfront care, he said.¹

“You can’t really throw a checkpoint inhibitor on top of BCG and make bad medicine good,” Jayram said.¹

Practice steps to improve first-line BCG outcomes in high-risk NMIBC

Jayram outlined several measures he described as the minimum standard before considering intensification.¹ These include a complete transurethral resection of bladder tumor (TURBT) and a high-quality restaging TURBT for high-grade disease, particularly T1. He also called for standardized pathology reporting to support confident risk stratification, noting outcomes will suffer if muscle-invasive disease is misclassified as T1.¹

Enhanced cystoscopy with blue light or narrow-band imaging remains underutilized in community practice, and incorporating it into pathways and surveillance improves outcomes, according to Jayram.¹ He advised strict adherence to BCG induction and at least 2 years of maintenance, along with attention to risk, cost, and treatment burden.¹ These steps will help patients more than simply adding a checkpoint inhibitor, he said.¹

POTOMAC trial results for durvalumab plus BCG in BCG-naive high-risk NMIBC

POTOMAC (NCT03528694) is a randomized, open-label, global phase 3 trial enrolling 1018 patients with BCG-naive high-risk NMIBC, randomly assigned 1:1:1.³ Eligible tumors included T1, high-grade/G3, carcinoma in situ (CIS), or multiple, recurrent, and large (≥3 cm) disease. Patients received durvalumab 1500 mg intravenously every 4 weeks for 13 cycles plus BCG induction and maintenance (n = 339), durvalumab plus BCG induction only (n = 339), or BCG induction and maintenance alone (n = 340).³

The trial met its primary end point of disease-free survival (DFS) for durvalumab plus BCG induction and maintenance vs BCG alone (HR, 0.68; 95% CI, 0.50-0.93; P = .0154).³ At a median follow-up of 60.7 months, DFS events occurred in 67 of 339 patients (20%) vs 98 of 340 patients (29%). DFS rates were 92% vs 87% at 12 months, 87% vs 82% at 24 months, and 82% vs 77% at 36 months.³

Jayram, who served as lead author of PATAPSCO (NCT05943106), a 100-patient US safety study he described as a sister trial to POTOMAC, characterized the topline absolute benefit of 5 to 6 percentage points as modest.¹ He highlighted the strong performance of the BCG comparator arm, consistent with NIMBUS, as evidence protocol-driven BCG is difficult to beat.¹ Approximately 60% of POTOMAC participants had high-grade T1 disease, a higher-risk population than a typical high-risk NMIBC cohort, which may make each recurrence more clinically meaningful, he said.¹

Longer-term POTOMAC analyses point to benefit in high-grade T1 disease

Updated analyses presented by Neal D. Shore, MD, at the 2026 American Urological Association Annual Meeting showed high-risk disease events within the first year in 53 of 339 patients (16%) receiving durvalumab plus BCG vs 69 of 340 (20%) receiving BCG alone.⁴ Median time to a high-risk event was 14.1 months vs 8.3 months. Among patients with events, 45% (24/53) vs 61% (42/69) occurred within 12 months and 26% (14/53) vs 42% (29/69) within 6 months.⁴

BCG-unresponsive criteria were met by 11% of patients in the durvalumab arm vs 16% in the BCG-alone arm, with adequate BCG delivery achieved in 87% vs 93%, respectively.⁴ Cystectomy occurred in 13 of 339 patients (4%) vs 21 of 340 (6%; HR, 0.63; 95% CI, 0.31-1.24), and the cystectomy-free survival HR was 0.69 (95% CI, 0.48-0.99).⁴ Jayram acknowledged the small number of cystectomy events.¹

“I would argue cystectomy-free survival is probably the most meaningful end point for patients in this setting,” Jayram said.¹

Papillary tumors accounted for approximately 91% of patients.⁴ DFS HRs were 0.61 (95% CI, 0.43-0.84) for any papillary disease, 0.56 (95% CI, 0.37-0.84) for papillary disease without CIS, 0.48 (95% CI, 0.28-0.79) for T1 only, and 0.55 (95% CI, 0.31-0.95) for T1 high-grade/G3 only.⁴ Jayram anticipated the treatment will prove most meaningful for younger, motivated patients able to engage with systemic therapy.¹

Counseling patients on immune-mediated adverse events with checkpoint inhibitors

Adding durvalumab to BCG induction and maintenance had no major impact on patient-reported quality of life as measured by the EORTC QLQ-C30 global health status scale.³ Quality of life was also maintained with sasanlimab plus BCG induction and maintenance in the CREST trial (NCT04165317).¹ Jayram noted CREST used 2 years of sasanlimab, compared with approximately 1 year of durvalumab in POTOMAC.¹

Among 336 patients receiving durvalumab plus BCG induction and maintenance, immune-mediated adverse events (imAEs) occurred in 91 patients (27%), with grade 3 or 4 events in 27 (8%) and treatment discontinuation due to imAEs in 32 (10%).⁴ Hypothyroid events were the most common imAE, occurring in 36 patients (11%), followed by hepatic events in 17 (5%).⁴ Among patients with imAEs, 47% (43/91) had resolved, 16% (15/91) were resolving, 3% (3/91) resolved with sequelae, and 33% (30/91) had not resolved, with endocrine events accounting for most unresolved cases.⁴

Jayram tells patients roughly 30% of those receiving checkpoint inhibitors will experience an imAE, and about 10% of those events are severe.¹ He also advises patients 5% to 10% may require lifelong thyroid replacement.¹ He urged the urology community and industry partners to package safety data in ways clinicians can translate into clearer patient conversations.¹

ctDNA and biomarker selection for treatment intensification in NMIBC

Jayram said he expects circulating tumor DNA (ctDNA) and urine tumor DNA to play a central role in selecting patients for intensification.¹ He cited a Cleveland Clinic real-world report in which 35% of patients with NMIBC were ctDNA positive, ctDNA positivity predicted upstaging, and several ctDNA-positive patients had no cystoscopic or radiographic findings.⁵ Patients with ctDNA positivity and minimal or no visible disease represent an ideal population for checkpoint inhibitor intensification, he said.¹

Jayram is involved in SCORE-NMIBC (NCT07763197), a recruiting, Natera-sponsored prospective study evaluating the incidence of ctDNA positivity in high-risk NMIBC and its impact on outcomes.¹ He encouraged urologists running clinical trials to consider participation.¹

For practicing urologists, Jayram’s message centered on improving BCG fundamentals as the most immediate step toward better first-line outcomes.¹ He described BCG plus checkpoint inhibition as supported by level 1 evidence from large randomized trials with active comparators, uncommon in an NMIBC landscape largely built on single-arm studies.¹ A “first shot, best shot” approach is reasonable for patients seeking to reduce future treatment, he said, although overall survival data will take time to mature.¹

REFERENCES

1. Jayram T. Systemic therapy in BCG-naïve NMIBC: is it worth it? Presented at: 2026 LUGPA Annual Meeting; November 5-7, 2026, Chicago, Illinois.

2. Grimm MO, van der Heijden AG, Colombel M, et al. Treatment of high-grade non-muscle-invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: Results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial "NIMBUS.” Eur Urol. 2020;78(5):690-698. doi:10.1016/j.eururo.2020.04.066

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

4. 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

5. Wang B, Davis LE, Weight CJ, Abouassaly R, Bukavina L. Real-world experience with a commercial circulating tumor DNA assay in non-muscle-invasive bladder cancer. Eur Urol Oncol. 2025;8(4):883-887. doi:10.1016/j.euo.2025.05.019.