Re-induction with nadofaragene firadenovec: a fragile signal that should not influence clinical practice

The recently published real-world case series evaluating re-induction with nadofaragene firadenovec (ADSTILADRIN^®) in Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) is of interest, but its interpretation requires caution. The authors report a 31% complete response (CR) rate among initial non-responders (1). While intriguing, this finding is insufficient to support any modification of current practice.

The limitations of the study are substantial. The cohort is extremely small (n=13), exclusively male, and derived from private urology practices with heterogeneous documentation. More importantly, the population is characterized by high comorbidity: over half of the patients had a Charlson Comorbidity Index ≥3, indicating moderate-to-severe systemic disease. This strongly suggests that re-induction was preferentially offered to individuals medically unfit for cystectomy, introducing a profound selection bias that undermines any generalizability.

Equally problematic is the lack of comparability with the pivotal phase 3 trial of nadofaragene firadenovec (2), and with the authors’ own prior abstract-level report of re-induction outcomes (3). Patients in the present series were older (mean age 77.5 years), heavily pretreated (mean 11 prior BCG instillations; frequent prior gemcitabine or pembrolizumab), and likely enriched for individuals unwilling or unable to undergo cystectomy. This population differs markedly from the trial population on which regulatory approval and guideline recommendations are based. Extrapolating real-world outcomes from such a selected cohort to the broader BCG-unresponsive population is therefore inappropriate.

The timing of non-response assessment further complicates interpretation. In the pivotal trial, patients without CR at 3 months discontinued therapy, consistent with guideline recommendations to avoid delaying cystectomy in BCG-unresponsive carcinoma in situ (CIS) (4,5). The present study instead extends intravesical therapy beyond this point. Without a predefined 3-month landmark, without MIBC-free or cystectomy-free survival analyses, and without a matched control group, the apparent benefit of re-induction may simply reflect immortal time bias or therapeutic drift, rather than a true therapeutic effect (6-12).

The biological plausibility of re-induction—based on interferon-mediated immune activation—does not compensate for the absence of robust evidence. A historical parallel from the pre-immunotherapy era of metastatic melanoma is instructive: a minority of patients exhibited unexpectedly durable responses despite limited treatment efficacy (13,14). These “long survivors” were ultimately understood as reflecting an intrinsically favorable immunobiological phenotype, not treatment potency. The CRs observed after nadofaragene re-induction may similarly represent a rare subgroup with preserved immunologic responsiveness, rather than a reproducible effect applicable to the broader BCG-unresponsive population.

The broader therapeutic landscape also requires nuance. While no competing intravesical gene therapy has published real-world re-induction outcomes, several pivotal trials—such as QUILT-3.032 (nogapendekin alfa inbakicept) and BOND-003 (cretostimogene grenadenorepvec)—did allow protocol-defined re-induction at 3 months. The issue is therefore not the concept of re-induction itself, but the off-protocol, off-label use of nadofaragene firadenovec in a context where its pivotal trial explicitly prohibited it. This distinction is essential to avoid conflating mechanistic plausibility with evidence-based practice.

Furthermore, the present study is not entirely isolated: a separate academic cohort (Schmidt et al., n=17) reported a 38% CR rate after re-induction. However, this remains a small, uncontrolled dataset, insufficient to justify any change in clinical practice—particularly in a disease where delayed cystectomy carries a well-documented risk of progression.

The appropriate next step is not to incorporate re-induction into routine practice, but to formally evaluate its value. This could be achieved through a pragmatic randomized trial allocating 3-month non-responders to re-induction versus standard management (including early cystectomy), or through a rigorously designed target trial emulation using non-responders from the pivotal phase 3 study as an external control.

Until such data are available, the reported CRs after re-induction should be interpreted as exploratory observations—not as justification to delay cystectomy in BCG-unresponsive CIS, where timely definitive management remains critical. Given the off-label nature of nadofaragene re-induction and the industry-funded context of the present study, caution is not only scientifically warranted but ethically necessary to avoid exposing patients to avoidable progression risk.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0493/coif). P.P. is CEO and shareholder of Shiroito Co. Ltd., a for-profit company, and owns stocks of Takeda Pharmaceuticals Co. Ltd. P.P. served as SVP Global Research & Medical Affairs at Ferring Pharmaceuticals (Kastrup) until May 2026, and held a fiduciary role as a member of the Board of Directors of PharmaBiome AG (Zurich) until April 2026. P.P. has received honoraria for invited presentations from KONECT (South Korea) and PwC Denmark. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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.

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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