Nadofaragene Firadenovec Trial Looks to Prove Efficacy in Intermediate-Risk NMIBC

The ongoing phase 3b ABLE-32 trial (NCT06510374) evaluating nadofaragene firadenovec-vncg (Adstiladrin) is looking to see efficacy with the agent in patients with intermediate-risk non–muscle-invasive bladder cancer (NMIBC) and fill an unmet need as there are currently no FDA-approved maintenance therapies for this patient population who will experience disease recurrence at a rate of approximately 50%.1

In December 2022, the drug became the first FDA-approved intravesical gene therapy for patients with NMIBC, and those with high-risk BCG-unresponsive disease with carcinoma in situ with or without papillary tumors were included in the approval.2,3 In February 2024, Fox Chase Cancer Center announced they were the first cancer center in the region offering access to the therapy as standard of care.3 With a dosing of once every 3 months via catheter into the bladder, nadofaragene firadenovec stands out compared with available treatment options which require 6 weekly administrations plus maintenance therapy.

A trial in progress poster on the agent presented at the 2025 Genitourinary Cancers Symposium noted that the randomized, controlled, ABLE-32 study is currently enrolling an anticipated 454 patients with intermediate-risk NMIBC to receive the intravesical gene therapy vs observation across approximately 100 locations globally.1 The trial started in the fourth quarter of 2024 and its estimated primary completion date is the third quarter of 2028, with a last patient/last visit through the full length of the trial anticipated for quarter 1 of 2031.

The open-label trial’s interim analysis will evaluate early stopping and if it is decided the trial should continue, a sample size reassessment will be performed to evaluate population expansion.

Details of Enrollment for ABLE-32

Patients are eligible for ABLE-32 if they have newly diagnosed or recurrent intermediate-risk NMIBC, defined by the 2020 AUA/SUO guideline, at screening. They must have a life expectancy of more than 2 years and undergo transurethral resection of bladder tumor (TURBT) within the 60-day period prior to random assignment. Those with evidence of muscle-invasive/metastatic disease at screening or those who have low- or high-risk NMIBC are not eligible. Patients will be observed for up to 60 months in the study.

Following TURBT with or without perioperative chemotherapy, 1:1 random assignment will occur to the nadofaragene firadenovec arm and observation arm, and crossover is allowed at recurrence within 24 months. Patients will receive 75 mL (3 × 1011 vp/mL) of nadofaragene firadenovec instilled quarterly with up to 8 intravesical instillations. During the 24-month treatment period follow-up will occur based on the AUA/SUO guideline surveillance schedule.

The primary end point of ABLE-32 is recurrence-free survival (RFS), and key secondary end points include RFS at 12 and 24 months as well as safety. Exploratory end points are RFS up to 5 years from random assignment and changes in the expression of potential urine and blood biomarkers.

Additional Trials Examining Nadofaragene Firadenovec

Nadofaragene firadenovec is a nonreplicating and nonintegrating adenoviral vector-based gene therapy that delivers the human IFNa2b gene to urothelial cells and Syn3; this enhances viral transduction of the urothelium. Notably, further explorations of the drug are ongoing in the observational ABLE-41 trial (NCT06026332), which is examining real-world outcomes with the agent, and the phase 2 ABLE-22 trial (NCT06545955) evaluating nadofaragene firadenovec as monotherapy or in combination with chemotherapy or immunotherapy in patients with high-grade BCG-unresponsive NIMBC.4,5 The phase 1/2 LUNAR study (NCT06668493) has also been initiated but is not yet recruiting patients; it will examine the agent in those with low-grade upper tract urothelial carcinoma.6

References

1. Shore N, Dickstein R, Tyson M, et al. ABLE-32: a randomized, controlled, phase 3b clinical trial of nadofaragene firadenovec-vncg versus observation in patients with intermediate-risk non–muscle-invasive bladder cancer. J Clin Oncol. 2025;43(suppl 5):TPS888. doi:10.1200/JCO.2025.43.5_suppl.TPS888
2. FDA D.I.S.C.O. Burst Edition: FDA approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors. FDA. January 20, 2023. Accessed February 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-adstiladrin-nadofaragene-firadenovec-vncg-patients-high-risk#:~:text=On%20December%2016%2C%202022%2C%20the,with%20or%20without%20papillary%20tumors
3. Adstiladrin (nadofaragene firadenovec-vncg): the first intravesical gene therapy for bladder cancer now available at Fox Chase. Fox Chase Cancer Center Temple Health. February 13, 2024. Accessed February 17, 2025. https://physicianresources.foxchase.org/news/adstiladrin-nadofaragene-firadenovec-vncg-the-first-intravesical-gene-therapy-for-bladder-cancer-now-available-at-fox-chase
4. Adstiladrin early utilization and outcomes in the real world setting (ABLE-41). ClinicalTrials.gov. Updated November 13, 2024. Accessed February 17, 2025. https://clinicaltrials.gov/study/NCT06026332?term=nadofaragene%20firadenovec&rank=5
5. A trial to evaluate intravesical nadofaragene firadenovec alone or in combination with chemotherapy or immunotherapy in participants with high-grade BCG unresponsive non-muscle invasive bladder cancer (ABLE-22). ClinicalTrials.gov. Updated February 19, 2025. Accessed February 19, 2025. https://clinicaltrials.gov/study/NCT06545955?term=nadofaragene%20firadenovec&rank=4
6. Low-grade UTUC treated with nadofaragene firadenovec administered to renal pelvis (LUNAR). ClinicalTrials.gov. Updated February 10, 2025. Accessed February 17, 2025. https://clinicaltrials.gov/study/NCT06668493?term=nadofaragene%20firadenovec&rank=3