Bivalacqua, Trinity

755 Background: Patients with High-Risk BCG-Unresponsive Non-Muscle Invasive Bladder Cancer have limited treatment options. The US FDA approved treatments for BCG-UR patients with CIS, but additional bladder-sparing therapies are needed, especially for the BCG-UR papillary-only population. Cretostimogene is an oncolytic immunotherapy with dual mechanisms of action. It replicates in and lyses cancer cells with Rb-E2F pathway alterations. This releases tumor-specific antigens, initiating an anti-tumor immune response, further amplified by the GM-CSF transgene. The BOND-003 Cohort P study (NCT04452591) is a single-arm clinical trial assessing the efficacy and safety of intravesical cretostimogene in HR, papillary-only, BCG-UR NMIBC patients. Methods: Eligibility criteria include age ≥18 years, ECOG PS of 0-2, and histologically confirmed BCG-UR HG Ta/T1 papillary disease without CIS within 90 days of study enrollment as verified per central pathology review. Patients had no visible evidence of residual bladder cancer before treatment. Intravesical cretostimogene is instilled for six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through Month 12, then every six months through Month 36. Re-induction is permitted at 3 months for patients with HG Ta or CIS. Primary disease assessments include serial cystoscopy, urine cytology, axial imaging, and mandatory biopsy directed at prior tumor locations at Month 12, with centralized review of pathologic samples. Endpoints include HG-RFS, HG-EFS, PFS, and safety. The study has completed enrollment. Results: A total of 56 patients who received treatment with cretostimogene are evaluated based on data from September 1, 2025 cut off. At baseline, 76.7% of patients are 65 years or older, 21.4% are female, 64.3% have HG Ta, and 35.7% have HG T1 papillary NMIBC. Kaplan-Meier estimates of HG-RFS at 6- and 9-months are 84.6% (95% CI 73.1 - 96.1%) and 80.4% (95% CI 66.8-94.0%), respectively. No patients have undergone a radical cystectomy. One patient progressed to metastatic disease despite a clinical complete response in the bladder. Cretostimogene demonstrates a favorable safety profile, with most adverse events localized to low grade bladder symptoms. There are no serious treatment-related adverse events and no discontinuations related to cretostimogene. To date, no patients have required a dose delay or missed a dose due to a related adverse event. There have been no deaths related to study treatment. Further, updated data will be presented. Conclusions: These results demonstrate consistent efficacy and a well-tolerated safety profile. Mature data with longer term follow-up will build upon these promising findings and will inform future treatment approaches with cretostimogene. Clinical trial information: NCT04452591 .

741 Background: A significant treatment gap exists for efficacious, well-tolerated bladder-sparing options for patients with HR BCG-UR NMIBC with CIS. Cretostimogene is an oncolytic immunotherapy with dual mechanisms of action. It replicates in and lyses cancer cells with Rb-E2F pathway alterations, while simultaneously amplifying an anti-tumor immune response, further mediated by the GM-CSF transgene. BOND-003 (NCT04452591) is a phase-3 study evaluating the efficacy and safety of cretostimogene in patients with HR BCG-UR NMIBC with CIS +/- HG Ta/T1 (Cohort C) and HG Ta/T1 only (Cohort P). We report data on radical cystectomy performed post-recurrence or progression on Cohort C. Methods: 112 patients were enrolled. Participants had previously received adequate BCG and were considered BCG-UR by the FDA definition. Cretostimogene treatment consisted of a 6 weekly induction course, followed by 3 weekly maintenance cycles every 3 months at year one and every 6 months during years 2-3. Repeat induction was permitted at Month 3, if persistent HG Ta or CIS. Response assessments included serial cystoscopy, urine cytology, and mandatory mapping biopsy at 12 mo, with centralized review of all pathology. The primary endpoint was Complete Response (CR) at any time. Cystectomy-Free Survival (CFS) and Progression-Free Survival (PFS) were key secondary endpoints. Results: As of the June 23, 2025 data cutoff (median follow-up of 25.8 months), the CR rate at any time is 75.5% (83/110) (95% CI 66.3-83.2%). Kaplan-Meier estimates of 12- and 24-month DoR are 64.2% (95% CI 52.5-73.8%) and 60.1% (95% CI 48.2-70.0%), respectively, with a median DoR of 27.9 months (95% CI 14.3-NE%) and ongoing. The 12- and 24- month CR rate is 46.4% (51/110) (95% CI 36.8-56.1%) and 41.8% (46/110) (95% CI 32.5-51.6%), respectively. The 12- and 24-month CFS rates are 89.2 (95% CI 81.3-93.9) and 81.3% (71.8-87.8), respectively, with median CFS not reached. Among 18 patients who underwent radical cystectomy post-disease recurrence or progression; 15 (83.3%) had NMIBC or pT0 on final pathology. At 12- and 24- months, 96.6% are free from ≥T2 progression. Cretostimogene has a well-tolerated safety profile, with no grade ≥3 treatment-related adverse events. Conclusions: Cretostimogene offers distinct advantages with its mechanism of action, efficacy, durability and safety profile for the treatment of HR BCG-UR NMIBC. Furthermore, a significant proportion of patients receiving cretostimogene remained progression-free and avoided radical cystectomy. Most patients who underwent radical cystectomy had NMIBC or pT0 on final pathology maintaining a window of opportunity. Ongoing and future investigations of cretostimogene, as monotherapy and in rational combinations, may address the considerable unmet need for patients with bladder cancer. Clinical trial information: NCT04452591 .

TPS888 Background: There is currently no Food and Drug Administration (FDA)-approved treatment for intermediate-risk non–muscle-invasive bladder cancer (IR NMIBC), defined by the AUA as recurrence of low-grade (LG) Ta within 1 year, solitary LG Ta >3 cm, multifocal LG Ta, high-grade (HG) Ta (≤3 cm), and/or LG T1. Nadofaragene firadenovec-vncg is the first FDA-approved intravesical nonreplicating gene therapy for the treatment of adult patients with high-risk Bacillus Calmette Guérin (BCG)-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors. In a nonrandomized, multicenter, open-label, repeat-dose, phase 3 study, 53.4% of participants (55/103) with CIS ± HG Ta/T1 achieved complete response 3 months after the first instillation. Nadofaragene firadenovec was well tolerated, with no grade 4/5 study drug-related AEs. Because maintenance treatment with nadofaragene firadenovec following tumor resection may improve clinical outcomes in patients with IR NMIBC, the ABLE-32 open-label randomized study is being conducted to evaluate the efficacy of nadofaragene firadenovec administered every 3 months versus observation in participants with IR NMIBC. Methods: This phase 3 study includes approximately 100 global sites with 454 anticipated participants. Adults diagnosed with new or recurrent IR NMIBC and having undergone transurethral resection of bladder tumor within 60 days prior to randomization are eligible. Participants will be randomly assigned 1:1 to receive nadofaragene firadenovec or continue observation. The nadofaragene firadenovec group will receive quarterly doses unless disease recurs or progresses. The observation group will be followed quarterly and may receive nadofaragene firadenovec if IR NMIBC recurs within 24 months. All participants will be evaluated for recurrence and progression using cytology, cystoscopy, and for-cause biopsy for up to 5 years. The primary endpoint is recurrence-free survival (RFS), from randomization to first documented recurrence, progression, or death. Secondary endpoints include RFS at 12 and 24 months and safety. Exploratory endpoints include effect on potential biomarkers and health-related quality of life. Final results are expected in 2031. Clinical trial information: NCT06510374 .