FDA’s ODAC Votes Against Risk/Benefit Profile of UGN-102 in Recurrent, Low-Grade, Intermediate-Risk NMIBC

FDA

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 5 to 4 against the risk/benefit profile of UGN-102 (mitomycin for intravesical solution) for the treatment of patients with recurrent, low-grade, intermediate-risk non–muscle-invasive bladder cancer (NMIBC).1

In August 2024, UroGen Pharma—the developer of UGN-102—submitted a new drug application (NDA) to the FDA seeking the approval of UGN-102 for the treatment of patients with low-grade, intermediate-risk NMIBC.2 Data from the phase 3 ENVISION (NCT05243550) and ATLAS (NCT04688931) supported the NDA submission.1,2

“I voted no. Without a full randomized trial—I do want to commend and give kudos to the applicant for showing it's feasible to conduct a randomized trial—it is hard to determine the true benefit of [UGN-102],” Daniel Spratt, MD, of Case Comprehensive Cancer Center in Cleveland, Ohio, said following the vote. “I understand from experts that the 3-month complete response [CR] end point is a standard in [the NMIBC] field, but for an indolent disease, that is an unbelievably short end point for me to demonstrate clinical benefit. There is very limited long-term follow-up.”

During the ODAC meeting, the FDA sought input from the committee on whether randomized trials should be required in the future to assess the effectiveness of therapies in the low-grade, intermediate-risk NMIBC setting. They also discussed whether the overall risk/benefit profile of UGN-102 was favorable for this patient population in the recurrent setting.

“I voted yes. This is a very important option for select patients who have significant comorbidity and who are not ideal surgical candidates," Isla Garraway, MD, PhD, of UCLA Health, said after the vote. "Anytime you can delay a surgery or prevent a surgery, it’s a win for everyone, especially given that our time [as clinicians] is [also] a limited resource. [NMIBC] is usually an indolent disease in the majority of patients. I agreed with my colleague Mark W. Ball, MD, FACS, [of the National Cancer Institute], that the toxicities that were reported are difficult to compare out of context since the study design was not meant to compare the toxicities with transurethral resection of bladder tumor [TURBT]. In general, patients in this age group often develop urinary symptoms regardless, so it’s hard to put that in complete context. I think the drug is safe and promising for delaying and avoiding TURBT."

Given the split nature of the vote, the FDA will meet with UroGen Pharma to discuss future directions for UGN-102.

“While we are disappointed by today’s outcome, we continue to believe our clinical data support UGN-102 for the treatment of recurrent low-grade, intermediate-risk NMIBC, a disease with no FDA-approved therapies,” Liz Barrett, president and chief executive officer of UroGen, stated in a news release.3 “The FDA carefully considers the independent advice from ODAC, and we look forward to working with the FDA as they complete their review of the application for UGN-102.”

ENVISION Overview

The single-arm, multicenter, international ENVISION trial included patients with low-grade, intermediate-risk NMIBC, where all patients received UGN-102 once per week for 6 total doses.2 CR rate at 3 months following the first dose of UGN-102 served as the trial’s primary end point. Durability of CR was a secondary end point.

Data submitted to the FDA in the NDA showed UGN-102 (n = 191) generated a 3-month CR rate of 79.6%, meeting the primary end point.2,4 Patients who achieved a CR at 3 months achieved a 12-month duration of response (DOR) rate of 82.3% (95% CI, 75.9%-87.1%). The estimated 15-month and 18-month DOR rates were both 80.9%.

Regarding safety, the most common treatment-emergent adverse effects (TEAEs) included dysuria, hematuria, urinary tract infection, pollakiuria, fatigue, and urinary retention.2 Most TEAEs were mild to moderate, and they had resolved or were resolving at data cutoff. Safety findings for UGN-102 were consistent with data from prior studies.

ATLAS Overview

ATLAS was a randomized, open-label, controlled study that evaluated UGN-102 vs TUBRT in patients at least 18 years of age with low-grade NMIBC (Ta).5 Patients were randomly assigned to receive 6 weekly instillations of UGN-102 or standard-of-care TURBT. Patients who achieved a CR at 3 months received no additional treatment and entered follow-up. Patients who had recurrence or disease progression at any point completed the study and received further care from their treating physicians.

Disease-free survival (DFS) served as the trial’s primary end point. However, the study enrollment was ended early by UroGen Pharma after the company elected to pursue an alternative development strategy for UGN-102 in bladder cancer. Follow-up was terminated after the last patient had been followed for 15 months. All analyses of the trial were classified as descriptive since no interim efficacy analysis was performed, and the early termination prevented the study from being powered to test the hypothesis.

Findings from the study showed that the 3-month CR rate was 64.8% (95% CI, 56.3%-72.6%) for UGN-102 (n = 142) compared with 63.6% (95% CI, 55.0%-71.5%) for TURBT (n = 140).4,5 The estimated 12-month DOR rates were 79.7% (95% CI, 69.3%-86.9%) and 67.7% (95% CI, 55.8%-77.1%), respectively.4 The median DOR was not estimable in both arms (HR, 0.46; 95% CI, 0.24-0.86).

Dysuria was the most common AE reported in the UGN-102 arms of both the ENVISION and ATLAS studies, occurring at rates of 22.5% and 30.4%, respectively.

FDA’s Standpoint

Disease Setting

In their presentations during the ODAC meeting, the FDA noted that no drugs are currently approved specifically for adult patients with low-grade, intermediate-risk NMIBC.6

Sundeep Agrawal, MD, the clinical team lead of the Genitourinary Malignancies Division of Oncology in the Office of Oncologic Diseases at the FDA, highlighted that low-grade, intermediate-risk NMIBC is a heterogenous disease with a wide range of recurrence and progression probabilities.

“There is limited contemporary evidence to correlate [risk] categories with clinical outcomes, but the general [risk] categories are thought to broadly estimate the likelihood of recurrence and progression,” Agrawal said.1

Support of a Single-Arm Trial

Prior to 2021, UroGen Pharma and the FDA met to discuss various trial designs that could pave a pathway toward approval for UGN-102.6 This included the ATLAS study. Notably, the members of this meeting decided that a noninferiority trial with a primary end point of DFS would not be sufficient to support the regulatory approval of this agent.

In August 2021, the FDA stated that a single-arm trial could be acceptable to support approval, but an ODAC meeting would be needed. ATLAS was closed in November 2021, and ENVISION had its first patient consent in February 2022. The ENVISION data were the primary results to support the NDA, but the FDA determined that ATLAS data could be considered supportive.

The FDA provided input on the design of a single-arm trial, noting that it could serve as a major trial if it enrolled a large number of patients, had a sufficient duration of follow-up, and demonstrated sufficient efficacy and safety encompassing later outcomes with subsequent TURBTs. The regulatory agency also explained that demonstrating a treatment effect that was distinct from the natural history of the disease was critical.

Agrawal also detailed challenges associated with single-arm trial, and why the FDA recommended a randomized trial for UGN-102 on multiple occasions.

“Single-arm trials have supported FDA drug approvals when randomized trials are unethical or infeasible, Agrawal said.1 “For example, [these trials support approvals] when there are suboptimal or no available therapies to assign the control arm to, or in rare diseases or low-frequency populations [that power] a randomized trial for progression-free survival where an overall survival [end point] is not possible. However, single-arm trials have several limitations, which include the potential for selection bias and a concurrent control to provide context to the results. Without the control, it is unclear whether results in a single-arm trial can be replicated and extrapolated to the indicated patient population in practice.”

“We’ve heard a number of critiques of the data presented today that perhaps could have been mitigated by having a randomized trial,” Ball said during the discussion ahead of the committee’s vote. “That being said, there seems to be precedence in this disease space to use a single-arm trial design. While it’s always the highest degree of evidence to have a randomized trial, saying it should be required should be up to interpretation. I don’t know if it’s required, but it is preferable.”

References

1. May 21, 2025, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/live/5ecyDbK9ezc
2. UroGen submits completed UGN-102 NDA seeking approval as the first FDA-approved treatment for low-grade intermediate-risk non-muscle invasive bladder cancer. News release. UroGen Pharma. August 14, 2024. Accessed May 21, 2025. https://investors.urogen.com/news-releases/news-release-details/urogen-submits-completed-ugn-102-nda-seeking-approval-first-fda
3. UroGen announces outcome of Oncologic Drugs Advisory Committee for UGN-102 for the treatment of recurrent low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC). News release. UroGen Pharma. May 21, 2025. Accessed May 21, 2025. https://investors.urogen.com/news-releases/news-release-details/urogen-announces-outcome-oncologic-drugs-advisory-committee-ugn
4. Prasad S, Hu B, Bjurlin M, et al. Treatment of low-grade intermediate-risk non-muscle-invasive bladder cancer with UGN-102: results of the phase 3 ATLAS and ENVISION studies. J Clin Oncol. 2025;43(suppl 5):777. doi:10.1200/JCO.2025.43.5_suppl.777
5. Prasad SM, Huang WC, Shore ND, et al. Treatment of low-grade intermediate-risk nonmuscle-invasive bladder cancer with UGN-102 ± transurethral resection of bladder tumor compared to transurethral resection of bladder tumor monotherapy: a randomized, controlled, phase 3 trial (ATLAS). J Urol. 2023;210(4):619-629. doi:10.1097/JU.0000000000003645
6. UGN-102 (Mitomycin). FDA. May 21, 2025. Accessed May 21, 2025. https://www.fda.gov/media/186561/download