Modern BCG outperforms historic benchmarks in high-risk NMIBC

BCG monotherapy remains the preferred first-line treatment for BCG-naive high-risk non–muscle-invasive bladder cancer (NMIBC), with gemcitabine plus docetaxel as a strong alternative, according to Vignesh T. Packiam, MD.¹ Packiam, an associate professor of surgery at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, presented “First Move Matters: Optimizing the BCG-Naïve Patient” at the 2026 LUGPA Annual Meeting.¹

First-line options now include BCG plus mitomycin, gemcitabine plus docetaxel, BCG plus a checkpoint inhibitor, and clinical trials, alongside BCG.^1,2 Packiam reviewed the evidence for each, along with treatment selection, biomarkers, and the role of transurethral resection of bladder tumor (TURBT) in achieving durable outcomes.¹ The space has many novel therapeutics but also important evidence gaps, he said.¹

2026 AUA risk stratification and modern BCG efficacy in high-risk NMIBC

The 2024 American Urological Association (AUA) risk stratification classified solitary high-grade Ta tumors 3 cm or smaller as intermediate risk.¹ Packiam noted high-grade Ta tumors behave alike whether or not they have these favorable features. He cited a study by Bree et al in which time to progression on BCG overlapped for intermediate- and high-risk high-grade Ta tumors.³

Many urologists therefore already treated any high-grade disease as high risk, and the 2026 AUA risk stratification reflects this practice.^1,2 High-risk disease now includes any high-grade tumor or carcinoma in situ (CIS), any subtype histology, any lymphovascular invasion, and any high-grade prostatic urethral involvement.² AUA, European Association of Urology, National Comprehensive Cancer Network, and other guidelines recommend BCG as first-line treatment for high-risk disease.¹

Historic data set a benchmark of 60% to 65% for 2-year recurrence-free survival (RFS) with BCG.⁴ Modern trials report substantially better results. Two-year RFS was 85% in the standard-frequency arm of NIMBUS and about 80% in the BCG-alone arm of CREST (NCT04165317).^5,6

Packiam attributed the improvement partly to better TURBT technology and routine re-resection of high-grade T1 disease.¹ He also credited blue light cystoscopy with maximal CIS resection, plus improved staging with timely imaging and biomarkers.¹

BCG supply, strains, and comparisons with intravesical chemotherapy

Only one BCG strain, Tice, is in standard use in the United States, since production of the Connaught strain ended in 2012, according to Packiam.¹ The Tokyo strain may be approved in the near future. Use of recombinant BCG has been increasing, although more data are needed.¹ Intermittent shortages, including major ones in 2019 and in 2024 and 2025, have kept some practices from delivering induction or maintenance.¹

In a meta-analysis by Chou et al, BCG induction alone was associated with higher recurrence than mitomycin C (relative risk [RR], 1.27; 95% CI, 1.01-1.61).⁷ BCG induction plus maintenance reduced recurrence compared with mitomycin C (RR, 0.79; 95% CI, 0.71-0.87).⁷

Most of these comparisons were conducted in Europe roughly 20 years ago, Packiam noted.¹ Together, they show BCG induction plus maintenance outperforms single-agent chemotherapy.¹

Gemcitabine plus docetaxel as a first-line alternative to BCG in high-risk NMIBC

Sequential intravesical gemcitabine and docetaxel was historically used after recurrence on BCG, but some urologists began using it first line during BCG shortages.¹ In a retrospective study led by Packiam at the University of Iowa, 312 patients with AUA high-risk, treatment-naive NMIBC received BCG (n = 174) or gemcitabine plus docetaxel (n = 138) between 2011 and 2021.⁸ Approximately 40% of patients had CIS, and more than 50% had T1 disease.⁸

The BCG arm received full-dose BCG when available, or one-third dose, with or without interferon alfa, plus maintenance at 3, 9, and 15 months.⁸ The gemcitabine plus docetaxel arm received monthly maintenance for 2 years.⁸ High-grade RFS was similar between arms, and slightly better with gemcitabine plus docetaxel. Packiam said the result gives him confidence in the regimen despite the retrospective design.^1,8

In a prospective study by Patel et al of 25 patients with AUA high-risk NMIBC, gemcitabine plus docetaxel achieved a 3-month complete response (CR) rate of 100% and a 1-year CR rate of 92% at a median follow-up of 19 months.⁹ Packiam described the 1-year result as essentially identical to modern BCG outcomes.¹

The phase 3 BRIDGE trial (ECOG-ACRIN EA8212) randomly assigned patients with BCG-naive high-grade NMIBC 1:1 to 1 of 2 arms.¹⁰ One arm received 6 weekly instillations of gemcitabine plus docetaxel with monthly maintenance. The other received 6 weekly BCG instillations with SWOG maintenance.¹⁰

The primary end point is event-free survival, and randomization was stratified by pure CIS, pure papillary, or mixed disease.¹⁰ Packiam said the trial will provide a definitive answer in the next few years.¹

BCG plus checkpoint inhibitors and BCG plus mitomycin in BCG-naive NMIBC

The phase 3 CREST and POTOMAC (NCT03528694) trials each showed a benefit from adding a checkpoint inhibitor to BCG induction and maintenance.^1,6 In CREST, event-free survival at 24 months was 84.7% with sasanlimab plus BCG vs 79.9% with BCG alone (HR, 0.68; 95% CI, 0.49-0.94; 1-sided P = .0095).⁶ In POTOMAC, disease-free survival at 24 months was 86.5% with durvalumab (Imfinzi) plus BCG vs 81.6% with BCG alone (HR, 0.68).¹

Packiam summarized the checkpoint inhibitor benefit as about 5% at 2 years in all comers, with approximately 20% more grade 3 or higher adverse events.¹ He noted neither trial had shown a difference in progression, cancer-specific survival, or overall survival.¹

In the ANZUP trial reported by Hayne et al, 2-year high-grade RFS was 79% with BCG vs 82% with BCG plus mitomycin.¹¹ Patients in the BCG arm received 16 BCG doses over 1 year, whereas the combination arm received nine BCG and nine mitomycin doses.¹¹ Packiam said he viewed the trial as negative and noted combination patients receive fewer active BCG doses plus additional mitomycin exposure, which can be toxic to the bladder.¹

“To me, it isn’t worth it to give a combination therapy if you’re going to have the same recurrence as just BCG alone,” Packiam said.¹

A treatment-naive philosophy and AI biomarker-directed therapy selection

Packiam outlined 5 goals for first-line treatment: a strong response, limited toxicity, preserved drug supply during BCG shortages, preserved eligibility for salvage therapies, and avoiding combination therapy when it adds no benefit.¹ All newly approved therapies in this space are indicated for BCG-unresponsive disease. Patients must therefore receive some BCG to qualify for them, he noted.¹

Measured against these goals, BCG monotherapy delivers a strong response and deserves to remain the level 1 standard, according to Packiam.¹ Given its toxicity, adding a checkpoint inhibitor may warrant a second look for every patient. Gemcitabine plus docetaxel preserves BCG supply for patients facing a shortage.¹

“BCG monotherapy still works very, very well,” he said.¹

Beyond clinicopathologic features, Packiam highlighted Vesta/CHAI, an artificial intelligence-augmented digital histopathology biomarker. It analyzes more than 600 microscopic features on hematoxylin and eosin slides at 40x magnification.¹ In a retrospective study, about 30% of patients were biomarker positive, and in this group 2-year high-grade RFS was 90% with gemcitabine plus docetaxel vs 56% with BCG.^1,12

Among biomarker-negative patients, outcomes did not differ significantly between treatments.¹² A prospective validation study is underway.¹

TURBT quality, repeat resection, and enhanced cystoscopy in high-risk NMIBC

Packiam described TURBT as one of the most important and most difficult surgeries urologists perform for these patients, calling it underrated.¹ In the randomized JCOG 1019 trial, 263 patients with high-grade T1 disease re-resected to T0 received BCG induction or active surveillance.¹ Active surveillance led to about 20% more recurrence, but progression and survival did not differ between arms.¹

Packiam described the trial as provocative though not practice-changing, suggesting an excellent TURBT may drive many of the good outcomes seen in these patients.¹ He pointed to a 10-item checklist shown to improve reporting of critical procedural elements during TURBT, including visually complete resection and visualization of detrusor muscle.¹³ He suggested adding enhanced cystoscopy findings to the checklist.¹

AUA guidelines recommend repeat resection within 6 weeks for T1 disease (strong recommendation; evidence strength grade B) and suggest considering it for high-risk, high-grade Ta tumors (moderate recommendation; grade C).¹⁴ Repeat resection is diagnostic, prognostic, therapeutic, and predictive. In data from Herr, a second resection improved RFS and progression-free survival in patients with T1 disease.¹⁵

Packiam acknowledged he does not always repeat resection for very focal T1 involvement with deep resection.¹ He does perform it for T1 and extensive high-grade Ta disease.¹

He uses blue light cystoscopy in almost all of his TURBTs.¹ A meta-analysis of 12 randomized trials involving 2288 patients found blue light cystoscopy improved detection of Ta/T1 tumors by about 15% and CIS by more than 40%. It also decreased recurrence by about 10% to 15%.¹⁶

AUA guidelines recommend offering blue light cystoscopy at TURBT when available (moderate recommendation; grade B).¹⁴ Enhanced cystoscopy also matters during surveillance of patients undergoing multiple lines of bladder-sparing therapy.¹

Blue light cystoscopy alone detected cancer in 19% of patients with 3 or more prior intravesical treatments, compared with 6% after 1 and 7% after 2 prior treatments.¹ Packiam performs surveillance under blue light in the operating room for patients who have received 2 or 3 prior intravesical therapies.¹

For urologists managing BCG-naive high-risk NMIBC, Packiam’s message centered on fundamentals: a meticulous TURBT, repeat resection when indicated, enhanced cystoscopy, and BCG induction plus maintenance.¹ Gemcitabine plus docetaxel offers a BCG-sparing option, and BRIDGE and prospective biomarker studies may further refine first-line selection.^1,10,12

REFERENCES

1. Packiam VT. First move matters: optimizing the BCG-naïve patient. Presented at: 2026 LUGPA Annual Meeting; November 5-7, 2026, Chicago, Illinois

2. Clark PE, Holzbeierlein J, Chang SS, et al. 2026 updates to the diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO Guideline. J Urol. 2026 Sep 4:10.1097/JU.0000000000005280. doi:10.1097/JU.0000000000005280.

3. Bree KK, Hensley PJ, Lobo N, et al. All high-grade Ta tumors should be classified as high risk: bacillus Calmette-Guérin response in high-grade Ta tumors. J Urol. 2022;208(2):284-291. doi:10.1097/JU.0000000000002678

4. Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013;63(3):462-472. doi:10.1016/j.eururo.2012.10.039

5. 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

6. 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;31(8):2806-2814. doi:10.1038/s41591-025-03738-z

7. Chou R, Selph S, Buckley DI, et al. Intravesical therapy for the treatment of nonmuscle invasive bladder cancer: a systematic review and meta-analysis. J Urol. 2017;197(5):1189-1199. doi:10.1016/j.juro.2016.12.09

8. McElree IM, Steinberg RL, Mott SL, O’Donnell MA, Packiam VT. Comparison of sequential intravesical gemcitabine and docetaxel vs bacillus Calmette-Guérin for the treatment of patients with high-risk non–muscle-invasive bladder cancer. JAMA Netw Open. 2023;6(2):e230849. doi:10.1001/jamanetworkopen.2023.0849

9. Patel SH, Gabrielson AT, Chan S, et al. A phase 2 trial of intravesical gemcitabine and docetaxel in the treatment of bacillus Calmette-Guérin‒naïve nonmuscle-invasive urothelial carcinoma of the bladder. J Urol. 2024;212(1):95-103. doi:10.1097/JU.0000000000003977

10 Kates M, Chu X, Hahn N, et al. Background and update for ECOG-ACRIN EA8212: a randomized phase 3 trial of intravesical bacillus Calmette-Guérin (BCG) versus intravesical docetaxel and gemcitabine treatment in BCG-naïve high-grade non–muscle-invasive bladder cancer (BRIDGE). Eur Urol Focus. 2023;9(4):561-563. doi:10.1016/j.euf.2023.06.006.

11. Hayne D, Zhang AY, Thomas H, et al. Bacillus Calmette-Guérin plus mitomycin versus bacillus Calmette-Guérin alone for bacillus Calmette-Guérin-naïve non-muscle-invasive bladder cancer: A randomised phase 3 trial (ANZUP 1301). Eur Urol. 2026;89(5):446-453. doi:10.1016/j.eururo.2026.01.009

12. Packiam VT, McElree IM, Ghodoussipour S, et al. Presence of an artificial intelligence-powered predictive biomarker is associated with a poor response to intravesical bacillus Calmette-Guerin but not to intravesical sequential gemcitabine/docetaxel in patients with high-grade non-muscle-invasive bladder cancer. Eur Urol Oncol. 2025;8(6):1461-1465. doi:10.1016/j.euo.2025.04.006

13. Anderson C, Weber R, Patel D, et al. A 10-item checklist improves reporting of critical procedural elements during transurethral resection of bladder tumor. J Urol. 2016;196(4):1014-20. doi:10.1016/j.juro.2016.03.151.

14. American Urological Association; Society of Urologic Oncology. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline (published 2016; amended 2020, 2024). American Urological Association; 2024. Accessed November 6, 2026. https://www.auanet.org/guidelines-and-quality/guidelines/bladder-cancer-non-muscle-invasive-guideline

15. Herr HW. Role of repeat resection in non–muscle-invasive bladder cancer. J Natl Compr Canc Netw. 2015;13(8):1041-1046. doi:10.6004/jnccn.2015.0123

16. Veeratterapillay R, Gravestock P, Nambiar A, et al. Time to turn on the blue lights: a systematic review and meta-analysis of photodynamic diagnosis for bladder cancer. Eur Urol Open Sci. 2021:31:17-27. doi:10.1016/j.euros.2021.06.011.