Rethinking BCG Failure and The Bladder-Sparing Boom in NMIBC

The treatment paradigm for non–muscle invasive bladder cancer (NMIBC) has shifted considerably since the FDA established a formal definition of Bacillus Calmette-Guérin (BCG)–unresponsive disease, opening the door to a wave of new intravesical and gene therapies, according to Saum Ghodoussipour, MD.

In a conversation with CancerNetwork® on the Oncology On the Go podcast, Ghodoussipour, director of the Bladder and Urothelial Cancer Program at Rutgers Cancer Institute and associate professor of surgery at Robert Wood Johnson Medical School, discussed the distinction between real-world “BCG-exposed” disease and the FDA’s stricter, trial-oriented definition of BCG unresponsiveness. The agency’s definition accounts for persistent papillary disease, carcinoma in situ, or stage progression within specific timeframes following adequate BCG induction and maintenance.

Ghodoussipour walked through how the bladder-sparing armamentarium has expanded since 2020, when pembrolizumab (Keytruda) became the first novel agent approved for BCG-unresponsive disease. He detailed how nadofaragene firadenovec (Adstiladrin), nogapendekin alfa inbakicept-pmln (Anktiva), and TAR-200 (Inlexzo) have since given patients and clinicians a broader menu of options beyond radical cystectomy, each with distinct dosing schedules, response rates, and durability data drawn from single-arm trials.

He also addressed how a persistent global BCG shortage is reshaping treatment decisions, noting that some centers, including his own, have adopted third-dose maintenance schedules rather than full-dose, 3-year courses, informed by EORTC data showing no difference in progression or overall survival despite a modest reduction in recurrence prevention. Ghodoussipour further discussed how emerging comparative trials, such as the ECOG-led EA8212/BRIDGE trial (NCT05538663) evaluating BCG against gemcitabine/docetaxel combination therapy, may help resolve open questions around sequencing and allocation.¹

On the surgical side, Ghodoussipour emphasized that radical cystectomy remains a guideline-recommended option for BCG-unresponsive disease and pointed to data from the CISTO trial (NCT03933826) suggesting that patient-reported quality of life may actually improve after cystectomy compared with prolonged bladder-sparing attempts.² Still, he noted that improving risk stratification, using biomarkers such as circulating tumor DNA and the AI-driven Vesta Bladder test, may help identify which patients are the best candidates for continued bladder preservation.

“[NMIBC] has been booming the last few years,” Ghodoussipour said. “I'm fortunate to have been in such an exciting space because…it's getting better for our patients. But in order for us to reach the point where we can confidently and consistently cure these patients, we really got to get down to tumor biology.”

Throughout the conversation, Ghodoussipour underscored the importance of multidisciplinary collaboration among urologists, medical oncologists, and radiation oncologists as systemic therapies and checkpoint inhibitor combinations, including regimens studied in the phase 3 CREST (NCT04165317) and POTOMAC trials (NCT03528694), increasingly enter the BCG-naive and BCG-unresponsive settings.^3,4 He also stressed that shared decision-making, better patient-reported outcome data, and continued discovery work into tumor biology will be essential to bring greater consistency to treatment sequencing in the years ahead.

References

1. Intravesical BCG vs GEMDOCE in NMIBC (BRIDGE). Clinicaltrials.gov. Updated July 17, 2026. Accessed September 9, 2026. https://tinyurl.com/w9axbzks
2. Gore JL, Wolff EM, Nash MG, et al. Twelve-month results from the CISTO study comparing radical cystectomy versus bladder-sparing therapy for recurrent high-grade non-muscle-invasive bladder cancer. J Clin Oncol. 2025;44(4):274-285. doi:10.1200/JCO-25-01324
3. Powles T, Shore N, Galsky M, et al. Sasanlimab in combination with bacillus Calmette-Guérin (BCG) in BCG-naive, high-risk non–muscle-invasive bladder cancer (NMIBC): Event-free survival (EFS) subgroup analyses based on disease stage from the CREST study. J Clin Oncol. 2025;43(suppl 17):4517. doi:10.1200/JCO.2025.43.16_suppl.4517
4. De Santis M, Redorta J, 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. The Lancet. 2025;406(10516):2221-2234. doi:10.1016/S0140-6736(25)01897-5