FDA Approval of Intravesical Mitomycin in NMIBC Follows ODAC Debate on Need for Randomized Data

In an era of evolving regulatory standards and heightened focus on patient-centered care, the FDA’s June 2025 full approval of intravesical mitomycin (UGN-102; Zusduri) for adult patients with low-grade, intermediate-risk, non–muscle-invasive bladder cancer (NMIBC) marked a pivotal development in the management of this disease, representing the first nonsurgical, intravesical therapy option for this patient population.1

Although the regulatory decision marked a milestone, it followed a spirited debate and a narrowly split 5-to-4 decision from the FDA’s Oncologic Drugs Advisory Committee (ODAC), which voted against the risk:benefit profile of the agent in this patient population.2

During the ODAC meeting in May 2025, committee members raised concerns about the adequacy of single-arm trial results to guide regulatory decisions, with the FDA seeking input from the committee on whether randomized trials should be required in the future to assess the effectiveness of therapies for patients with low-grade, intermediate-risk NMIBC. Findings from the single-arm phase 3 ENVISION trial (NCT05243550) supported the regulatory decision.1

“[We] heard a number of critiques of the data presented [at the ODAC meeting] that could have perhaps been mitigated by having a randomized trial,” Mark W. Ball, MD, FACS, commented during the ODAC meeting.2

“That being said, there seems to be precedent in this disease space to use a single-arm trial design. [Although] it’s always the highest degree of evidence to have a randomized trial, saying it should be required is up to interpretation. I wouldn’t say it’s required, but it is preferable.” Ball is an attending surgeon in the urologic oncology branch of the National Cancer Institute and associate program director of the urologic oncology fellowship program in Bethesda, Maryland.

Although the ODAC committee did not vote on the necessity of randomized clinical trials to support future approvals in low-grade, intermediate-risk NMIBC, points of the discussion continued to highlight the value of randomized data. “A single-arm study gives you a response rate…. [There were] a large number of patients enrolled in [ENVISION], and all those additional patients give you is precision around a response rate,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said during the discussion. “[Single-arm studies] do not allow you to look at time-to-event end points, such as disease-free survival, time to progression, overall survival, [along with] an adequate assessment of duration of response [DOR], toxicity, and patient-reported outcomes. We get so much more from a randomized trial, and that’s why the emphasis [was on] where we want to go in the future with [low-grade, intermediate-risk NMIBC].” Although the FDA’s decision to approve mitomycin differed from the split vote of ODAC, members also pointed out the need to look at applications on an individual basis.

Navigating the Evidence from Envision

ENVISION enrolled 240 patients with low-grade NMIBC whose disease recurred after prior transurethral resection of bladder tumor (TURBT).1 Patients needed to meet 1 or 2 of the following criteria: multiple tumors, a solitary tumor of more than 3 cm, and/or recurrence within 1 year. UGN-102 was administered at 75 mg once per week for 6 weeks via urinary catheter in an outpatient setting. The study’s primary end point was complete response (CR) rate at 3 months; a key secondary end point was DOR in patients achieving CR. Findings supporting the approval showed that evaluable patients (n = 223) achieved a CR rate of 78% (95% CI, 72%-83%) at 3 months. The 12-month DOR rate was 79%, and DORs ranged from 0 to 25-plus months.

The most frequently reported adverse effects (AEs) occurring in at least 10% of patients were elevated creatinine levels, increased potassium levels, increased aspartate aminotransferase levels, elevated alanine aminotransferase levels, increased eosinophil levels, decreased lymphocyte counts, decreased neutrophil counts, dysuria, urinary tract infection, and hematuria.

Serious AEs occurred in 12% of patients, with urinary retention reported in 0.8% and urethral stenosis in 0.4%. One patient experienced a fatal AE due to cardiac failure. Updated data announced following the June approval showed that at a median follow-up of 23.7 months, patients who achieved a CR experienced a 24-month DOR rate of 72.2% (95% CI, 64.1%-78.8%), with a median DOR that was not reached.3 The ODAC meeting also examined findings from the phase 3 ATLAS trial (NCT04688931), which was a randomized, open-label, controlled study that evaluated mitomycin vs TURBT in patients with low-grade NMIBC.1

Patients were randomly assigned to receive 6 weekly instillations of mitomycin or standardof-care TURBT. Those who achieved a CR at 3 months received no additional treatment and entered follow-up, and patients who had recurrence or progression completed the study and returned to physician-directed care.

Although disease-free survival served as the trial’s primary end point, the study was closed early by UroGen Pharma, which opted to pursue an alternative development strategy.4 As a result, no interim efficacy analysis was conducted, and all analyses were considered descriptive.1

Investigator Insights on the Approval

William C. Huang, MD, chief of the urology service at Tisch Hospital of NYU Langone Health in New York, New York, highlighted why the FDA’s approval of this mitomycin intravesical solution represents a novel shift in the management of low-grade, intermediate-risk NMIBC. It offers an alternative to repeated TURBTs, which have long been the standard of care, Huang said.

“The greatest implication of [this approval] is that, for the first time, we’re going to have a completely novel way of treating patients with low-grade, intermediate- risk [NMIBC],” Huang said. “It’s going to be a paradigm shift for many patients, from something that’s primarily been surgical to something that is nonsurgical and chemoablative.”

Within the low-grade, intermediate-risk NMIBC population, Huang said a proportion of patients will experience regular recurrences, leading to repeat visits to the operating room for TURBTs. Along with potentially providing patients with a disease-free interval, intravesical mitomycin may also be an alternative for patients who may not tolerate surgical procedures well, he noted.

“Another important subset includes patients who are medically frail, [such as] those on blood thinners or those who may not tolerate even infrequent trips to the operating room,” Huang said. “For them, this [strategy] offers a way to avoid the risks associated with general anesthesia and surgical intervention. I believe there are multiple subsets of patients for whom this could serve as a highly appropriate alternative.”

References

1. FDA approves mitomycin intravesical solution for recurrent low-grade intermediate-risk non-muscle invasive bladder cancer. FDA. June 12, 2025. Accessed August 5, 2025. https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-approves-mitomycin-intravesical-solution-recurrent-low-grade-intermediate-risknon-muscle

2. May 21, 2025, meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. Accessed August 5, 2025. bit.ly/4nce3As

3. UroGen announces 24-month duration of response of 72.2% from the pivotal phase 3 ENVISION trial of Zusduri, the first and only FDA-approved medicine for recurrent low-grade intermediate-risk non-muscle invasive bladder cancer. News release. UroGen. August 5, 2025. Accessed August 5, 2025. bit.ly/42a3XIj

4. A phase 3 study of UGN-102 for low-grade intermediate-risk non-muscle invasive bladder cancer (ATLAS). ClinicalTrials.gov. Updated June 6, 2024. Accessed August 5, 2025. https://clinicaltrials.gov/study/ NCT04688931