Modern frameworks for treating high-risk non–muscle invasive bladder cancer

A recent Urology Times Clinical Forum brought together clinicians from diverse practice environments to examine the rapidly changing landscape of treatment for non–muscle invasive bladder cancer (NMIBC), especially for patients with BCG-unresponsive disease. Moderator Stephen Boorjian, MD, the Carl Rosen Professor of Urology and David and Anne Luther Chair of the Department of Urology and director of the Urologic Oncology Fellowship at Mayo Clinic in Rochester, Minnesota, guided the group through a practical, case-based exchange that reflected real-world challenges, operational hurdles, and emerging enthusiasm for new drug-delivery technologies, including the gemcitabine intravesical system (Inlexzo, formerly TAR-200).

The ongoing challenge of BCG-unresponsive disease

Participants agreed that managing BCG-unresponsive disease has become increasingly complex. Although radical cystectomy remains the definitive standard for eligible patients, most individuals strongly prefer bladder preservation strategies when possible. Several clinicians noted that many patients are older or medically fragile, further diminishing cystectomy eligibility.

Across practices, the most common first-line bladder-sparing strategy after meeting criteria for BCG-unresponsive disease remains intravesical gemcitabine plus docetaxel (Gem/Doce). Clinicians repeatedly emphasized its favorable tolerability, accessibility, and cost profile. However, they also highlighted logistical difficulties—especially the long dwell time, prolonged room occupation, and need for certified staff when delivered outside operating rooms or infusion centers.

Despite widespread use, participants recognized that Gem/Doce is still off-label, lacks prospective randomized validation in BCG-unresponsive disease, and may not meet the needs of all patients. As a result, many rely on a “1 good salvage attempt” philosophy before escalating to more advanced therapies.

Real-world barriers in identifying disease status

An early theme was the inconsistent identification of carcinoma in situ (CIS) across practice settings. Some clinicians benefit from dedicated genitourinary pathologists; others face variability in pathology quality, specimen handling, or the use of enhanced cystoscopic technologies.

This variability affects treatment eligibility for agents restricted to BCG-unresponsive CIS. In some practices, missing CIS has caused delays in accessing therapy, whereas in others, even small foci of CIS can disqualify patients from clinical trial arms designed for papillary-only disease. The group agreed that standardizing pathology communication—particularly by explicitly labeling specimens “rule out CIS”—can improve diagnostic accuracy.

The expanding therapeutic landscape

The group moved through the major FDA-approved and emerging therapies—each with distinct mechanisms, logistics, and limitations.

Intravesical Gene Therapy (nadofaragene firadenovec)

Many practices have adopted nadofaragene firadenovec (Adstiladrin), especially after Gem/Doce failure. Its quarterly dosing schedule offers meaningful workflow advantages for both clinicians and patients. Clinicians noted, however, that financial barriers can be significant and highly variable depending on practice setting, buy-and-bill capacity, or 340B pricing.

Immunotherapy (pembrolizumab [Keytruda])

Most clinicians reported minimal use of systemic immunotherapy for NMIBC. Operational concerns, toxicity risks, and the modest long-term durability observed in trials have limited enthusiasm. Several noted reluctance from medical oncologists as well, emphasizing that checkpoint inhibitor toxicities feel disproportionate for a non-muscle invasive setting.

Subcutaneous checkpoint inhibitors generated mixed reactions. Some clinicians felt that easier delivery could enhance uptake; others believed that the immune toxicity profile—not the route of administration—remains the real barrier.

Anktiva (nogapendekin alfa) with BCG

The need for concurrent BCG has significantly limited uptake. Practices experiencing BCG scarcity have largely reserved supply for BCG-naive patients rather than for combination regimens.

The Gemcitabine Intravesical System (TAR-200)

Discussion intensified around the recently approved gemcitabine intravesical system, often referred to as the pretzel device. Many clinicians have used it in clinical trials and are now beginning to integrate it into routine care.

Participants highlighted several advantages:

• Short placement time, performed similarly to a routine cystoscopy.

• Sustained high-concentration gemcitabine exposure without prolonged room occupation.

• Applicability across a range of disease states, including BCG-unresponsive CIS, papillary-only cohorts, and BCG-naive disease in ongoing trials.

• Potential patient preference, particularly among those who struggled with tolerance or logistics of Gem/Doce.

However, concerns remain:

• Possibility of retained devices, particularly among older patients or those who miss follow-up appointments.

• Increased cystoscopy volume for placement, surveillance, and removal.

• Uncertain sequencing—especially when patients relapse with CIS after prior Gem/Doce.

This sequencing dilemma prompted discussion on mechanism-driven treatment patterns. Some clinicians noted that selecting another chemotherapy-based agent after Gem/Doce failure requires justification, whereas others argue that the prolonged dwell time and delivery mechanism fundamentally differentiate the gemcitabine intravesical system.

Despite variation in practice, most participants anticipate substantial clinical adoption due to workflow efficiencies and strong early efficacy signals.

Operational realities: The “hidden” determinants of care

A major theme was the impact of logistics on therapy choice. These include:

• Room availability for prolonged instillations

• Certification requirements for handling chemotherapies

• Nursing bandwidth and training

• Use of APPs in cystoscopic procedures

• Availability of single-use cystoscopes for rapid room turnover

• Financial risk associated with expensive agents in buy-and-bill settings

Many noted that a therapy’s clinical performance matters only if it can be operationalized. This is one reason many predicted rapid uptake of the gemcitabine intravesical system: it fits naturally into a urology clinic’s existing cystoscopy workflow.

Looking forward: Personalization, biomarkers, and cost

The group agreed that the future of NMIBC treatment depends on biomarkers that can direct patients toward the therapy most likely to work. Early AI-driven pathology tools—such as digital slide-based classifiers—were seen as promising.

Cost was a major concern. Some agents may approach hundreds of thousands of dollars per year. Several clinicians expressed discomfort with the idea of “delaying the inevitable” cystectomy at enormous financial cost, especially in a healthcare system already under severe economic strain.

Despite these concerns, there was strong optimism. Participants recognized that patients now have more promising bladder-sparing tools than ever before, including the gemcitabine intravesical system, which many expect to become a central component of future NMIBC care.