 and the director of research in the department of urology at the University of Cincinnati

Dr Martini on the Mechanism of Action of Cretostimogene Grenadenorepvec in Urothelial Carcinoma

“Cretostimogene is a gene therapy [that uses] a viral vector which is an adenovirus which is oncolytic.”

Alberto Martini, MD, a urologic oncologist at the University of Cincinnati Medical Center and an assistant professor of clinical urology at the University of Cincinnati College of Medicine, discussed the investigational oncolytic therapy cretostimogene grenadenorepvec for the treatment of patients with urothelial carcinoma.

Cretostimogene is a gene therapy which uses an oncolytic adenovirus viral vector, Martini began. This virus is able to selectively replicate in RB-E2F–altered bladder cancer cells, resulting in subsequent tumor cell lysis, he added. This mechanism of action also activates the transgene of the granulocyte colony-stimulating factor, which in turn triggers an immune response, he concluded.

Cretostimogene was evaluated in patients with intermediate-risk non–muscle-invasive bladder cancer (NMIBC) following transurethral resection of bladder tumor (TURBT) in the phase 3 PIVOT-006 trial (NCT06111235). The study randomly assigned patients 1:1 to receive either cretostimogene after TURBT or surveillance after TURBT. The primary end point is recurrence-free survival (RFS). RFS at 12 and 24 months represents a secondary end point of the study; safety is also a secondary end point. In September 2025, the study completed enrollment.

Cretostimogene was also examined in patients with BCG-unresponsive NMIBC in the phase 3 BOND-003 trial (NCT04452591). Findings presented during the 2025 American Urological Association Annual Meeting revealed that cretostimogene monotherapy produced an any-time complete response (CR) rate of 75.5%. The 12- and 24-month CR rates were 46.4% (95% CI, 36.9%-56.1%) and 33.7% (95% CI, 24.8%-43.8%), respectively. At the data cutoff of March 14, 2025, the median duration of response was 28 months and was ongoing. Most patients (97.3%) were free from progression to muscle-invasive disease at 24 months. Thirty-four patients had confirmed CRs at 24 months; 24-month assessments were pending for 9 patients at the data cutoff.

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Alberto Martini, MD, discusses cretostimogene grenadenorepvec in urothelial carcinoma.

Alberto Martini, MD

“There was no biopsy [required] in the [QUILT-3.032 trial], whereas there was a mandated biopsy at the end of the [CS-003 trial], which found that nearly 1 out of 10 patients had occult disease in the absence of visible disease on cystoscopy.”

Alberto Martini, MD, a urologic oncologist at the University of Cincinnati Medical Center, discussed the clinical significance of nadofaragene firadenovec-vncg (Adstiladrin), the first FDA-approved gene therapy for patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC). *I would just add this to the lower third

Nadofaragene firadenovec was FDA approved for this indication in 2022 based on findings from the open-label, multicenter, single-arm phase 3 Study CS-003 (NCT02773849). In this trial, intravesical nadofaragene firadenovec elicited a complete response (CR) rate of 51% (n = 50/98; 95% CI, 41%-61%) in patients with carcinoma in situ (CIS) with or without concomitant high-grade Ta or T1 disease.

In the per-protocol analysis of the broader study population (n = 151), 59.6% of patients (95% CI, 51.3%-67.5%) achieved a CR at 3 months, with approximately half of these responses maintained at 12 months. Importantly, all patients underwent bladder biopsy at 12 months, and 10% of those without visible disease on cystoscopy were found to have occult disease, underscoring the importance of pathologic confirmation in NMIBC trials, according to Martini.

Martini placed these data in the context of outcomes from research with nogapendekin alfa inbakicept-pmln (Anktiva), an interleukin-15 superagonist evaluated in the phase 2/3 QUILT-3.032 trial (NCT03022825). In this single-arm, multicenter study of 77 patients with BCG-unresponsive, high-risk NMIBC with CIS with or without Ta/T1 papillary disease following transurethral resection, the CR rate was 62% (95% CI, 51%-73%). Among those who achieved a CR, 58% maintained a duration of response (DOR) of at least 12 months, and 40% maintained a DOR of at least 24 months.

Martini noted that although these QUILT-3.032 results suggest encouraging durability, trial design differences complicate direct comparison with the CS-003 study. Specifically, the QUILT-3.032 trial allowed reinduction for patients with early treatment progression and did not mandate 12-month biopsy, whereas the CS-003 study included a mandatory biopsy, which identified subclinical disease in approximately 1 of 10 patients considered disease free by cystoscopy.

According to Martini, nadofaragene firadenovec represents an important advance in bladder-preserving therapy for patients with BCG-unresponsive NMIBC, a historically challenging clinical setting with limited alternatives. However, he emphasized that although both nadofaragene firadenovec and nogapendekin alfa inbakicept have demonstrated meaningful clinical activity, interpretation of efficacy must be grounded in differences in trial design, methodology, and biopsy requirements.

Alberto Martini, MD, discusses the current optimal role of nadofaragene firadenovec in the BCG-unresponsive NMIBC treatment paradigm.

Dr Martini on the Clinical Significance of Nadofaragene Firadenovec in BCG–Unresponsive NMIBC

Martini

"[The use of intravesical therapies] are dependent on the patient's stage and also their risk category."

Alberto Martini, MD, a urologic oncologist at University of Cincinnati Medical Center, outlined the current treatment paradigm for localized urothelial carcinoma, emphasizing the evolving role of intravesical therapies, particularly in patients with high-risk, non–muscle-invasive bladder cancer (NMIBC).

Standard management for high-risk NMIBC continues to rely on intravesical BCG as the first-line treatment. According to Martini, the initial course of BCG is typically followed by maintenance therapy in patients who do not experience recurrence. However, disease relapse or BCG failure necessitates consideration of second-line treatment options, a clinical challenge that has prompted investigation into alternative intravesical regimens and novel agents, he said.

 presentation focused on emerging approaches for BCG-unresponsive NMIBC, Martini discussed the use of intravesical chemotherapy with gemcitabine and docetaxel. This combination, delivered on a schedule similar to BCG, has demonstrated encouraging efficacy in the salvage setting. Although not currently considered standard of care, gemcitabine/docetaxel may offer a bladder-preserving strategy for patients who are not candidates for or wish to delay radical cystectomy.

Martini noted that several novel therapies are also under investigation in this space, including immune checkpoint inhibitors and other agents designed to enhance local immune activation or directly target urothelial carcinoma cells. Although these agents remain investigational, their incorporation into ongoing clinical trials reflects an increasing focus on expanding intravesical treatment options beyond traditional chemotherapy or BCG.

Martini concluded that taken together, these strategies highlight the importance of a nuanced approach to managing NMIBC. BCG remains foundational in high-risk disease, but alternatives such as gemcitabine/docetaxel are gaining traction, he said, adding that ongoing research into novel intravesical agents may further diversify the therapeutic armamentarium in this setting.

Alberto Martini, MD, discusses the evolving role of intravesical therapies in patients with high-risk non–muscle-invasive bladder cancer. 

Alberto Martini, MD

Articles

Dr Martini on the Mechanism of Action of Cretostimogene Grenadenorepvec in Urothelial Carcinoma

Dr Martini on the Clinical Significance of Nadofaragene Firadenovec in BCG–Unresponsive NMIBC

Dr Martini on the Evolving Role of Intravesical Therapies in High-Risk NMIBC