ABLE-32 Looks to Expand the Use of Nadofaragene Firadenovec Into Intermediate-Risk NMIBC

Neal D. Shore, MD, FACS

Following its FDA approval in December 2022 as the first adenoviral vector–based gene therapy for patients with high-risk BCG-unresponsive non–muscleinvasive bladder cancer (NMIBC), investigators are now evaluating nadofaragene firadenovecvncg (Adstiladrin) in those with intermediaterisk disease.1 The agent is being compared with observation in patients with intermediate-risk NMIBC in the ongoing phase 3b ABLE-32 trial (NCT06510374).2

“In the intermediate-risk population, some oncologists have used BCG in the past, [and] some have used various intravesical chemotherapies,” Neal D. Shore, MD, FACS, said in an interview with OncologyLive. “We don’t have level 1 evidence or an FDA-approved therapy in the intermediate-risk population; therefore, [positive outcomes from ABLE-32 could] lead to a new indication for patients who have intermediate-risk disease.”

Shore is the medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

Nadofaragene firadenovec is a nonreplicating and nonintegrating adenoviral vector–based gene therapy. The agent delivers the human IFNa2b gene to urothelial cells and Syn3, enhancing viral transduction of the urothelium. The direct cytotoxic effects of IFNa2b promote tumor apoptosis and antiangiogenesis.

“Nadofaragene firadenovec has an intravesical application,” Shore explained. “We have [many] other intravesical applications, but this therapy combines interferon alfa-2b with an adenoviral component. It’s a viral gene vector [therapy], and ultimately, the mechanism of action is to stimulate the patients’ interferon production, which [makes it an effective] apoptotic agent [against] urothelial carcinoma.”

Data from the phase 3 CS-003 study (NCT02773849) supported the 2022 FDA approval of nadofaragene firadenovec in patients with BCG-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with or without papillary tumors.3 Findings from the study showed that response-evaluable patients with BCG-unresponsive CIS (n =98) achieved a complete response (CR) rate of 51% (95% CI, 41%-61%). The median duration of response (DOR) was 9.7 months (range, 3 to 52+). Forty-six percent of patients experienced a DOR of at least 12 months.

Additionally, data from an open-label phase 3 study (NCT02773849) demonstrated that patients with BCG-unresponsive NMIBC in the CIS with or without Ta/T1 cohort who received nadofaragene firadenovec (n =103) achieved a CR rate of 53.4% (95% CI, 43.3%-63.3%).4 The median high-grade recurrence-free survival (RFS) was 5.9 months (95% CI, 3.4-8.3).

ABLE-32 Launches to Examine Nadofaragene Firadenovec in Intermediate-Risk NMIBC

ABLE-32 is enrolling adult patients with intermediate-risk NMIBC per the 2020 American Urological Association (AUA)/Society of Urologic Oncology (SUO) Guidelines, which define intermediate-risk disease as recurrence of low-grade Ta within 1 year; solitary low-grade Ta above 3 cm; multifocal low-grade Ta; high-grade Ta of 3 cm or less; and/ or low-grade T1 disease (Figure).2,5 Within 60 days before random assignment, all patients are required to undergo complete transurethral resection of bladder tumor with or without perioperative chemotherapy. Patients with high- or low-risk NMIBC, as well as those with evidence of muscle-invasive or metastatic disease at screening, are excluded from the trial.2

Phase 3 ABLE-32 Trial Design

Eligible patients will be randomly assigned 1:1 to receive nadofaragene firadenovec or undergo observation. In the nadofaragene firadenovec arm, patients are receiving 75 mL (3 x 1011 viral particles/mL) of nadofaragene firadenovec quarterly for up to 8 intravesical instillations. Patients in the observation arm are being followed per the AUA/SUO Guidelines over the 24-month treatment period. Crossover from the observation to investigational arm is permitted if intermediate-risk NMIBC recurs within 24 months.

Disease recurrence and progression will be monitored in all patients via cytology, cytoscopy, and for-cause biopsy for up to 5 years. An interim analysis will be performed to evaluate early stopping of therapy. In the event the trial continues, investigators will perform a sample reassessment to consider population expansion.

"We know the unique mechanism of action [of nadofaragene firadenovec] from its approved indication," Shore explained. "[The agent] is given once every 3 months intravesically, whereas other approved intravesical therapies [have] much [more] intensive dosing schedules. [This therapy offers] a significant convenience for throughput for both the clinic and patients."

The primary end point of ABLE-32 is RFS.5 Secondary end points consist of 12- and 24-month RFS rates as well as safety. Exploratory end points are RFS up to 5 years from randomization, changes in the expression of potential urine and blood biomarkers, and quality of life measures.2

ABLE-32 was initiated in the fourth quarter of 2024 and is enrolling patients at approximately 100 centers worldwide. The estimated primary completion date is in the third quarter of 2028, and the study is anticipated to run through the first quarter of 2031.

"Beyond] ABLE-32, which is enrolling intermediate-risk patients, an important large phase 2 study, ABLE-22 [NCT06545955], is [examining] nadofaragene firadenovec [as] monotherapy or [in combination with] pembrolizumab [Keytruda] or gemcitabine and docetaxel in patients with high-risk NMIBC,” Shore said. “Both these studies may allow for consideration [of nadofaragene firadenovec–based] options, as well as [the use of this therapy in] different stages of disease.”

References

1. FDA approves first adenoviral vector-based gene therapy for high-risk Bacillus Calmette-Gu.rin unresponsive non-muscle invasive bladder cancer. FDA. Updated December 19, 2022. Accessed April 9, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-firstadenoviral-vector-based-gene-therapy-high-risk-bacilluscalmette-guerin
2. 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
3. Adstiladrin. Prescribing information. Ferring Pharmaceuticals; 2022. Accessed April 9, 2025. https://www.fda.gov/media/164029/download?attachment
4. Narayan VM, Boorjian SA, Alemozaffar M, et al. Efficacy of intravesical nadofaragene firadenovec for patients with Bacillus Calmette-Guérin-unresponsive nonmuscle-invasive bladder cancer: 5-year follow-up from a phase 3 trial. J Urol. 2024;212(1):74-86. doi:10.1097/JU.0000000000004020
5. Trial of nadofaragene firadenovec vs. observation in participants with intermediate risk non-muscle invasive bladder cancer (ABLE-32). ClinicalTrials.gov. Updated April 8, 2025. Accessed April 9, 2025. https://clinicaltrials.gov/study/NCT06510374