EAU 2026: Case-Based Panel Discussion High-Risk NMIBC Post-BCG Failure: Spare the Bladder? Bladder Sparing: Trial Overview ICB (Combinations)

(UroToday.com) The 2026 European Association of Urology (EAU) Annual Meeting held in London, U.K., was host to the Urothelial Cancer: Towards Integrated Therapeutic Strategies: Plenary Session. Dr. Trinity Bivalacqua, in a case-based panel discussion, presented a bladder-sparing trial overview.

Dr. Yasmin Abu Ghanem then presented a clinical case of a 68-year-old male with a history of former tobacco use, hypertension, and type 2 diabetes who initially presented with recurrent painless visible hematuria over a three-month period. The patient had no prior history of bladder cancer and maintained an ECOG performance status of 0.

Initial TURBT revealed multifocal high grade G3 pTa disease with three tumors, the largest measuring approximately 3.5 cm. Cross sectional imaging with CT urography and chest imaging showed no evidence of metastatic disease. A repeat TURBT demonstrated residual high grade G3 pTa disease along with concomitant CIS. The patient subsequently initiated BCG induction therapy and expressed a strong preference for bladder preservation.

The patient subsequently received BCG induction followed by maintenance according to the SWOG protocol, for a total of 11 instillations, fulfilling the EAU criteria for adequate BCG exposure. Following induction therapy, he achieved a complete response with negative cystoscopy and negative cytology. Maintenance therapy was initiated with three instillations at the three-month mark, although the third dose during the six month maintenance cycle was held due to grade 3 hematuria and cystitis, and he developed a recurrence at the 9-month mark. The timeline of the patient’s treatment course is illustrated below.

Subsequent TURBT pathology revealed a papillary tumor classified as high grade T1 measuring 1.5 cm. Random bladder biopsies demonstrated CIS in multiple sites, including involvement of the prostatic urethra. Detrusor muscle was present in the specimen with no evidence of muscle invasive disease, and no variant histology was identified. Based on these findings, the patient met EAU criteria for very high risk NMIBC and was considered to have BCG unresponsive disease despite having received adequate BCG exposure

Dr. Bivalacqua began by noting that the presence of prostatic urethral involvement in this patient would exclude him from the major trials evaluating immune checkpoint inhibitors in combination with BCG. He then reviewed the evidence from three large randomized trials investigating the addition of immune checkpoint inhibition to BCG in BCG naïve high risk NMIBC, including the CREST, POTOMAC, and ALBAN studies, all of which evaluated combination strategies of ICI plus BCG in patients with high risk disease.^1-3 The trials are summarized below.

He highlighted two key takeaways from these trials. First, level 1 evidence now supports the addition of immune checkpoint inhibition to intravesical BCG in the treatment of BCG naïve high risk NMIBC. Second, the combination of immune checkpoint inhibitors with BCG appears to provide meaningful clinical benefit with an acceptable safety profile in patients with BCG naïve high-risk disease who are at the greatest risk of progression and metastasis. He noted, however, that the patient discussed in this case would not fall into this category, as he has BCG unresponsive disease.^1-3

Notably, these three trials were well designed, randomized, international studies that collectively enrolled more than 2,500 patients. Importantly, differences in trial design and patient populations mean that each study addressed slightly different clinical questions. The CREST and POTOMAC trials enrolled a higher risk NMIBC population, with approximately 58 percent of patients having T1 disease, and a control arm that included adequate BCG maintenance. Both trials demonstrated nearly identical improvements in high grade event free or disease-free survival, supporting the addition of PD-1 inhibition to adequate BCG therapy in this higher risk population. In contrast, the ALBAN trial enrolled a lower risk high risk population, with only 39 percent of patients having T1 disease and a truncated BCG maintenance schedule of 12 months. This study did not demonstrate an event free survival benefit and included low grade recurrences as events, highlighting how differences in study design and patient selection can influence trial outcomes.^1-3

He also reviewed the biological rationale underlying BCG unresponsive disease, highlighting the concept of adaptive immune resistance following intravesical BCG therapy. Studies have demonstrated that BCG exposure can lead to increased PD-L1 expression within the tumor microenvironment, particularly among nonresponders. This adaptive upregulation of immune checkpoint pathways may contribute to resistance to BCG (As shown below), providing a biological rationale for investigating immune checkpoint inhibition in this disease setting.

He also emphasized several important considerations when interpreting clinical trials in BCG unresponsive NMIBC. Differences in the mechanism of action of immune checkpoint inhibitors, particularly between PD 1 and PD-L1 targeting agents, may influence outcomes. In addition, trial design elements such as the use of mandatory biopsies at six or twelve months can lead to differences in reported results. The patient populations included in these studies are also heterogeneous, ranging from patients with CIS alone to those with multifocal papillary tumors or CIS combined with papillary disease. He further noted that trial outcomes are reported using several endpoints, including complete response rates at any time point, complete response at 12 and 24 months, and complete response at twelve and 24 months among patients who were disease free at three months. More objective endpoints, such as the risk of progression and cystectomy free survival, should also be considered when evaluating the clinical relevance of these therapies.

Dr. Bivalacqua reviewed the role of immune checkpoint inhibitor monotherapy in BCG unresponsive NMIBC with CIS. Several studies have evaluated this approach, including KEYNOTE 057 with pembrolizumab,⁴ SWOG S1605 with atezolizumab and cetrelimab,⁵ and the GU16 243 ADOPT BLADDER trial with durvalumab. Across these trials, the complete response rate at twelve months in the CIS population has been approximately 20 percent. He also reviewed currently available FDA approved therapies for BCG unresponsive CIS with or without papillary disease, including systemic pembrolizumab, intravesical nadofaragene firadenovec, and the combination of N 803 with BCG. In addition, newer intravesical therapies such as TAR 200 delivering gemcitabine are emerging as potential treatment options in this space.

He also noted that one ongoing study is currently evaluating this strategy in the BCG unresponsive setting. The phase 3 KEYNOTE 676 trial is investigating systemic pembrolizumab in combination with intravesical BCG in patients with high risk NMIBC that is persistent or recurrent following BCG induction. In this study, patients are randomized to receive pembrolizumab plus BCG or BCG alone, with complete response as the primary endpoint for the BCG unresponsive cohort. This trial is still recruiting, and results are not yet available. The trial design is shown below.

Notably, the SunRIse-1 study evaluating TAR-200 in BCG-unresponsive NMIBC assessed immune checkpoint inhibition. In Cohort 1, which evaluated TAR-200 in combination with the immune checkpoint inhibitor cetrelimab (n=53), the complete response rate at 12 months was 55%. However, although the initial trial design included the combination arm with cetrelimab, further development has primarily focused on the TAR-200 monotherapy strategy.⁶

He also reviewed the ADOPT-BLADDER phase 1 trial, which evaluated durvalumab-based strategies in patients with BCG-unresponsive CIS ± papillary disease and notably allowed inclusion of patients with prostatic urethral involvement. The study included three arms: durvalumab alone, durvalumab + BCG, and durvalumab + external beam radiation therapy, with a mandatory biopsy at 6 months. Although the combination of durvalumab + BCG showed some activity, the results did not meet the level of efficacy that would be considered clinically meaningful in this setting.⁷

Moreover, he went on to discuss the phase 2 CORE-001 trial evaluating cretostimogene grenadenorepvec in combination with pembrolizumab in patients with high-risk BCG-unresponsive NMIBC with CIS ± papillary disease.⁸ The study enrolled 35 patients, the majority with CIS, and required mandatory biopsies at the 12-month assessment. The treatment regimen included intravesical cretostimogene administered weekly for six weeks as induction, with a second induction for non-responders, followed by maintenance therapy, together with pembrolizumab given every six weeks for up to two years. The primary endpoint of the study was complete response at 12 months. The study design is shown below.⁸

He then reviewed results from studies evaluating cretostimogene. In the BOND-003 trial, which assessed cretostimogene monotherapy in BCG-unresponsive NMIBC (n=112), the CR rate was 46% at 12 months and 42% at 24 months. In comparison, the phase 2 CORE-001 trial evaluating cretostimogene combined with pembrolizumab (n=35) reported a 12-month CR rate of 57%. Overall, this represents roughly a 10% improvement with the addition of pembrolizumab, although whether this difference is clinically meaningful remains open for debate.⁸

Dr. Bivalacqua concluded with several key points:

Combination intravesical + ICI strategies, which may have synergistic effects, are likely needed to achieve more durable responses and meaningfully impact quality of life and bladder preservation in patients with NMIBC.
When evaluating new therapies, attention should be placed on complete response rates at 24 months and durability of response rather than early response alone.
Cost considerations, along with the overall risk–benefit profile of these emerging combination approaches, will also be critical when selecting future treatment strategies.

Presented by: Trinity Bivalacqua, MD, PhD, Director of Urologic Oncology, Co-Director of the Genitourinary Cancer Service Line, Abramson Cancer Center, Professor of Surgery at the Hospital of the University of Pennsylvania, Philadelphia, PA

Written by: Julian Chavarriaga, MD, Assistant Professor, Urologic Oncologist, Department of Urology at Penn State Health. @chavarriagaj on X during the 2026 European Association of Urology (EAU) Annual Meeting, London, United Kingdom, Fri, Mar 13 – Mon, Mar 16, 2026.

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