Nadofaragene Firadenovec May Propel Advances in Intermediate-Risk NMIBC Management

Neal D. Shore, MD, FACS

The treatment paradigm for patients with intermediate-risk non–muscle-invasive bladder cancer (NMIBC) continues to evolve as new therapeutic strategies aim to address high recurrence rates and the limitations of current interventions, according to Neal D. Shore, MD, FACS.

Historically, treatment for this patient population has relied on Bacillus Calmette-Guérin (BCG) and intravesical chemotherapy—including gemcitabine, gemcitabine/docetaxel, and mitomycin C. However, with ongoing BCG shortages and the lack of an FDA-approved standard therapy for intermediate-risk NMIBC, there remains a significant unmet need for effective, evidence-based treatment options. Shore emphasized that although recurrence is a primary challenge, progression to higher-risk disease, though less common, remains a concern in clinical decision-making.

The phase 3 ABLE-32 trial (NCT06510374) is currently investigating nadofaragene firadenovec-vncg (Adstiladrin)—a gene therapy currently FDA approved for patients with high-risk, BCG-unresponsive NMIBC—in patients with intermediate-risk NMIBC.1,2 If positive, Shore noted that these findings could establish nadofaragene firadenovec as the first FDA-approved therapy for this intermediate-risk patient population.

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

In the interview, Shore discussed the rationale for ABLE-32, the role of nadofaragene firadenovec in NMIBC management, and ongoing research evaluating novel intravesical and systemic approaches in this disease. Shore is the medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

OncLive: How do you currently approach the treatment of patients with intermediate-risk NIMBC? What are the key challenges in determining the optimal therapy following recurrence in this population?

Shore: Patients with intermediate-risk disease fall between low risk and high risk. [This population] includes patients with more than 1 low-grade papillary lesion, recurrence within 1 year [of prior treatment], and/or a high-grade solitary lesion smaller than 3 cm. [Patients with] T1, low-grade [disease may also be included in this population].

The intermediate-risk group, historically, has a significant amount of recurrence. The likelihood of [these patients progressing] is low, [although progression] can [occur]. However, recurrence becomes a significant problem and a challenge for patients. Blood testing also becomes an issue [because it adds an additional] cost to the health care system.

We’ve historically treated these patients [with BCG] when we were abundant in BCG. Some patients [have been able to get BCG with the shortage, [however, BCG access has] become a problem. Other patients—if we choose to do interventional treatment—will receive intravesical chemotherapy. The intravesical chemotherapies that have [been] used in my practice and elsewhere include gemcitabine [with or without] docetaxel, as well as mitomycin C.

What are the objectives, rationale, and design of the ABLE-32 trial?

[In the] ABLE-32 [study], patients will be randomly assigned to receive nadofaragene firadenovec —which is approved in the United States for patients who have BCG-unresponsive, high-risk NIMBC with carcinoma in situ, with or without papillary disease—vs observation on the comparator arm.1 [Nadofaragene firadenovec will be] given once every 3 months intravesically, as it is administered in its BCG-unresponsive, high-risk NMIBC indication. [Patients may be given] up to 8 treatments for [a maximum of] 2 years of treatment. The [primary] end point will be recurrence[-free survival].

What distinguishes nadofaragene firadenovec from other approved drugs for patients with NIMBC?

Nadofaragene firadenovechas an intravesical application. We have lots of 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.

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

What other ongoing research is evaluating nadofaragene firadenovec in patients with bladder cancer?

[Beyond] ABLE-32 that is enrolling intermediate-risk patients, an important large phase 2 study, the ABLE-22 [study (NCT06545955)], is combining nadofaragene firadenovec by itself or [in combination with] either pembrolizumab [Keytruda] or gemcitabine and docetaxel in patients with high-risk NMIBC.3 Both these studies may allow for consideration [of nadofaragene firadenovec–based] combination options as well as [the use of this therapy in] different stages of disease.

References

1. Trial of nadofaragene firadenovec vs. observation in participants with intermediate risk non-muscle invasive bladder cancer (ABLE-32). ClinicalTrials.gov. Updated March 11, 2025. Accessed March 13, 2025. https://www.clinicaltrials.gov/study/NCT06510374?term=ABLE-32&rank=1
2. FDA approves first adenoviral vector-based gene therapy for high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer. FDA. December 16, 2022. Accessed March 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-first-adenoviral-vector-based-gene-therapy-high-risk-bacillus-calmette-guerin
3. 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 March 11, 2025. Accessed March 13, 2025. https://www.clinicaltrials.gov/study/NCT06545955?term=ABLE-22&rank=1