Analysis of real-world re-induction outcomes with nadofaragene firadenovec in patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer
Brief Report

Analysis of real-world re-induction outcomes with nadofaragene firadenovec in patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer

Chad Reichard1, Andrew Trainer2, Katie Grant3, Parisa Asgarisabet3, Angele Kotomale3, Nadia Foskett4, Daniel Shoskes5,6

1Urology of Indiana, Greenwood, IN, USA; 2Nebraska Medicine, Omaha, NE, USA; 3Cardinal Health Specialty Solutions, Dublin, OH, USA; 4Ferring SAS, Gentilly, France; 5Ferring Pharmaceuticals Inc., Parsippany, NJ, USA; 6Cleveland Clinic, Cleveland, OH, USA

Correspondence to: Chad Reichard, MD. Urology of Indiana, 679 East County Line Road, Greenwood, IN 46143, USA. Email: chadalan@me.com.

Abstract: Nadofaragene firadenovec is an intravesical gene therapy approved for use in patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer who have carcinoma in situ (CIS) with/without papillary disease (Ta or T1). It is administered every 3 months for as long as the patient maintains a complete response (CR). In the phase 2 and 3 clinical trial program, patients without CR at 3 months were not re-treated with nadofaragene firadenovec; however, many immune therapies do benefit from re-induction of this kind. We report findings from an observational cohort study of patients who underwent re-induction with nadofaragene firadenovec in a real-world setting. Electronic health records from US Specialty Networks private urology practices were used to identify patients with urothelial CIS with/without papillary disease (Ta or T1) who (I) underwent induction with intravesical nadofaragene firadenovec therapy; (II) failed to achieve a CR 3 months after the first dose but subsequently received ≥1 re-induction dose; and (III) had ≥1 follow-up cystoscopy examination. In total, 13 male patients [CIS alone (n=8), CIS + Ta (n=2), CIS + T1 (n=3)], aged (mean) 77.5 years, satisfied the study eligibility criteria. Patients had received a mean of 11 prior BCG doses; other prior therapy included gemcitabine (n=4) and pembrolizumab (n=5). Median follow-up was 379 (range, 135–519) days. After the first re-induction dose (Dose 2) of nadofaragene firadenovec, four patients (30.8%) achieved a CR, including two patients with CIS + T1. Of the patients with a CR, three received subsequent maintenance doses: one patient maintained a CR after Doses 3 and 4; one patient showed disease persistence/recurrence after Dose 4, and one patient progressed to T2a disease 15 months after re-induction. Nine patients experienced treatment failure after first re-induction with nadofaragene firadenovec; two received a second re-induction dose without response. In this real-world cohort, approximately 30% of patients achieved a CR after re-induction with nadofaragene firadenovec, supporting the proof of concept of this approach.

Keywords: Non-muscle-invasive bladder cancer (NMIBC); nadofaragene firadenovec; gene therapy; induction therapy

Submitted Jan 17, 2026. Accepted for publication Mar 06, 2026. Published online May 25, 2026.

doi: 10.21037/tau-2026-1-0053

Introduction

For patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC), the guideline-preferred treatment option is radical cystectomy (1). However, radical cystectomy is associated with significant morbidity and mortality, particularly among elderly patients, who commonly have BCG-unresponsive disease (2-4). Furthermore, the procedure impacts multiple dimensions of patients’ quality of life (5).

Nadofaragene firadenovec, an intravesical gene therapy, is approved by the Food and Drug Administration (FDA) for use in adults with BCG-unresponsive NMIBC who have carcinoma in situ (CIS) with or without papillary disease (Ta or T1) (6). Nadofaragene firadenovec is administered once every 3 months as long as the patient maintains a complete response (CR) to treatment, with no recurrence of high-grade disease (7). In the pivotal Phase 3 trial of nadofaragene firadenovec in BCG-unresponsive NMIBC, patients with CIS ± Ta/T1 disease received nadofaragene firadenovec once every 3 months for up to 12 months (4 doses) or until high-grade NMIBC recurrence or unacceptable toxicity occurred; in the absence of disease recurrence, patients were allowed to continue treatment for a further 4 years (8). If a CR was not attained after the first dose, patients were ruled treatment failures and did not receive further nadofaragene firadenovec therapy (8). This is in contrast to studies of nogapendekin alfa inbakicept and cretostimogene in this patient population, which have permitted re-induction in the absence of an initial response (9-11). Although the ongoing ABLE-22 trial of nadofaragene firadenovec in BCG-unresponsive NMIBC (NCT06545955) allows re-induction for patients with persistent NMIBC (any CIS and high-grade Ta) at 3 months after the first dose (12), there is a lack of data regarding the benefit of nadofaragene firadenovec re-induction.

In this retrospective analysis, we studied the outcome of patients who received a re-induction dose of nadofaragene firadenovec for treatment of BCG-unresponsive NMIBC in a private practice setting. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0053/rc).

Methods

This retrospective observational cohort study was based on an analysis of Specialty NetworksTM Urology electronic health record (EHR) data covering the period from September 2023 through May 2025 from US private urology practices. Specialty NetworksTM Urology’s UroGPO network represents ~800 independent urology physician practices in 49 states, and its SoNaR Registry Platform provides access to administrative claims data, EHRs, radiology and pathology reports, treatment and clinical outcomes data, and patient demographics (13). The study was performed using EHR data de-identified at source in compliance with the Health Insurance Portability and Accountability Act of 1996 and was determined to be exempt from Institutional Review Board approval. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent was waived as the study used existing fully de-identified data, with de-identification performed at source.

The EHR dataset was screened to identify clinical practice patients who (I) received nadofaragene firadenovec for treatment of CIS ± Ta or T1 NMIBC between September 2023 and January 2025, (II) did not achieve CR at month 3, (III) received at least one additional (re-induction) dose of nadofaragene firadenovec, and (IV) had a follow-up cystoscopy. Administration of any dose, regardless of duration of retention in the bladder, was considered to meet the definition of treatment.

Data on all eligible patients were extracted from their medical records available through May 2025. Patient demographic and clinical characteristics at the time of diagnosis and outcome data were collected on this cohort as available. Outcomes of interest included cystoscopy findings, pathology reports for transurethral resection of bladder tumor (TURBT), if performed, post-re-induction treatments, disease progression, and mortality.

In this non-comparative exploratory study, outcomes were summarized using descriptive statistics. No formal, predetermined sample size requirements were set for the study.

Results

In total, 13 patients were identified in the Specialty Networks database as fulfilling the study inclusion criteria of receiving nadofaragene firadenovec between September 2023 and January 2025 for treatment of CIS ± Ta or T1 NMIBC and, in addition, receiving a re-induction dose of nadofaragene firadenovec after failing to achieve a CR to the initial dose. The patient cohort was exclusively male and had a mean age of 77.5 (range, 66–87) years. Eleven patients were White; information on race was missing for the other two patients. The 13 patients came from a total of eight clinics included within the Specialty Networks database.

At initial staging, patients had CIS alone (n=8), CIS + Ta (n=2), and CIS + T1 (n=3). The study cohort had significant comorbidity, as reflected in a Charlson Comorbidity Index (CCI) score of 1–2 (mild) in six patients (46.2%), 3–4 (moderate) in four patients (30.8%), and ≥5 (severe) in three patients (23.1%). The median time from first bladder cancer diagnosis to first dose of nadofaragene firadenovec was 159 weeks (interquartile range, 139–532 weeks).

The median follow-up from the first nadofaragene firadenovec dose was 54 weeks (range, 19–74 weeks), and patients received a median of 3 doses (range, 2–4 doses). After the re-induction (second) dose of nadofaragene firadenovec, four patients had a CR (30.8%), including two patients whose initial pathology was CIS + T1. Of the four patients with a CR, one patient had no further follow-up, and three patients received a third and fourth dose of nadofaragene firadenovec. Among the latter, one patient maintained a CR after the third and fourth doses, and one patient (whose initial pathology was CIS + T1 disease) maintained a CR after the third dose before eventually progressing to T2a disease 15 months after re-induction; the third patient had no assessment after the third dose but showed disease persistence/recurrence after the fourth dose.

Of the nine patients who experienced treatment failure after the re-induction dose of nadofaragene firadenovec, two were assessed for response after receiving a second re-induction dose, with both showing disease persistence/recurrence. To date, no patients have died. One patient initially presenting with CIS + T1 disease underwent cystectomy for invasive high-grade urothelial carcinoma (stage 2b) approximately 51 weeks after starting nadofaragene firadenovec treatment. Individual patient responses to the re-induction doses of nadofaragene firadenovec are depicted in Figure 1.

Figure 1 Plot depicting tumor responses in individual patients with CIS ± Ta or T1 undergoing re-induction therapy with nadofaragene firadenovec. Dose 1 represents the initial induction dose; Doses 2, 3, and 4 represent subsequent re-induction doses. CIS, carcinoma in situ.

Discussion

Nadofaragene firadenovec has emerged as an FDA-approved and guideline-recommended therapy for BCG-unresponsive high-risk NMIBC in patients with CIS with or without papillary disease. Its approval and recommendations for use were based on findings from clinical trials that did not permit treatment re-induction after the first dose, even if the patient showed a partial response.

A repeat course of BCG induction therapy is recommended in the event of disease persistence or recurrence after a single course of BCG induction (14), and trials of other therapies for high-risk NMIBC have successfully employed re-induction. In the QUILT-3.032 trial of nogapendekin alfa inbakicept, conducted among patients with high-grade BCG-unresponsive NMIBC with CIS ± Ta/T1 disease (n=82), 24 underwent re-induction at 3 months, with 13 (54%) achieving CR (9). In the BOND-003 trial of cretostimogene grenadenorepvec in BCG-unresponsive NMIBC, among the cohort with CIS ± Ta/T1 disease (n=110), 28 patients (25% of total) underwent re-induction at 3 months and 50% achieved a CR (11).

Consistent with the immuno-stimulatory, anti-angiogenic, and apoptotic effects of interferon in bladder cancer (15), nadofaragene firadenovec re-induction might be anticipated to provide benefit through further stimulation from shed antigen and amplification of the immune response. In the present study, 30.8% of patients (4 of 13) undergoing re-induction with nadofaragene firadenovec had a CR at next assessment. As a theoretical exercise, assuming 30% of non-responders who undergo re-induction will achieve a CR, re-induction therapy could have improved the 3-month CR rate seen in the pivotal phase III CS-003 trial from the observed 53% to 67% and the CR anytime rate seen in the Japanese phase III trial (NCT05704244) from the observed 75% to 85% (8,16). These extrapolated CR rates may over- or under-estimate the true effect of nadofaragene firadenovec re-induction, for which we await the results of the prospective ABLE-22 trial (NCT06545955) (17). Indeed, recently published findings from a cohort of patients (n=17) receiving re-induction with nadofaragene firadenovec, mostly in academic centers, indicated that those with CIS ± papillary disease (n=13) had a CR rate following re-induction of 38%; of the patients with papillary-only disease (n=4), 75% were free of disease at 3 months after re-induction (18).

As a retrospective observational study of real-world data, this analysis has a number of limitations. The study was based on findings obtained from a small patient sample and real-world EHR data entry. Because all eligible patients were included, the study sample reflects real-world clinical practice and patient populations from private practices participating in the Specialty Networks database. However, findings may not be generalizable to clinical settings outside this network. In general, patients encountered in clinical practice tend to be more diverse demographically and clinically than patients enrolled in randomized clinical trials, which may impact the pretreatment likelihood of recurrence. Cystoscopy was performed with white light only, with the potential for under-detection of persistent CIS but it could also impact the completeness of resection of papillary lesions during TURBT. The small sample size limited our ability to explore the impact of individual prognostic factors on treatment response. Patient visits following re-induction were event-driven rather than time-driven, and duration of response data are lacking. Finally, there was limited information on longer-term follow-up.

Conclusions

In conclusion, in this real-world patient cohort, approximately 31% of patients who failed to achieve a CR after a single dose of nadofaragene firadenovec therapy responded with a CR to a second (re-induction) dose, demonstrating the feasibility and potential utility of this therapeutic approach in the setting of BCG-unresponsive NMIBC.

Acknowledgments

The authors acknowledge medical writing support provided by Andrew Fitton, PhD (ApotheCom, London, UK) and Robin Isaac, PharmD (ApotheCom, Yardley, PA, USA), which was conducted under the guidance of the authors.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0053/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0053/prf

Funding: This work was supported by Ferring Pharmaceuticals Inc. Medical writing support was funded by Ferring Pharmaceuticals, Parsippany, NJ, USA.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0053/coif). C.R. has received consulting/advisory board fees from AstraZeneca, Ferring, Johnson & Johnson, and Novartis; speakers bureau fees from AstraZeneca, Ferring, Johnson & Johnson, and Merck; and research funding from AstraZeneca, CG Oncology, Ferring, Johnson & Johnson, Merck, and Novartis. K.G., P.A., and A.K. are employees of Cardinal Health Specialty Solutions, which has a research consultancy agreement with Ferring Pharmaceuticals Inc. N.F. is an employee of Ferring SAS. D.S. is a full-time employee of Ferring Pharmaceuticals Inc. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was performed using EHR data de-identified at source in compliance with the Health Insurance Portability and Accountability Act of 1996 and was determined to be exempt from Institutional Review Board approval. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent was waived as the study used existing fully de-identified data, with de-identification performed at source.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Reichard C, Trainer A, Grant K, Asgarisabet P, Kotomale A, Foskett N, Shoskes D. Analysis of real-world re-induction outcomes with nadofaragene firadenovec in patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer. Transl Androl Urol 2026;15(5):180. doi: 10.21037/tau-2026-1-0053

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