UGN-102 Shows Favorable Risk-Benefit Profile, Sustained CR Rates in Low-Grade, Intermediate-Risk NMIBC

Treatment with UGN-102 (mitomycin) elicited a high complete response (CR) rate at 3 months in patients with low-grade, intermediate-risk non–muscle-invasive bladder cancer (LG-IR-NMIBC) and increased their likelihood of remaining disease free 1 year later, according to findings from the phase 3 ENVISION trial (NCT05243550) published in the Journal of Urology.1,2

Among patients treated with UGN-102 (n = 240), the 3-month CR rate after initial treatment was 79.6% (95% CI, 73.9%-84.5%), meeting the study’s primary end point.2 Moreover, 61% (95% CI, 54%-67%) of patients maintained a CR for 15 months after starting treatment.

For patients who achieved CRs, the probability of remaining in response 12 months after the 3-month assessment was 82% (95% CI, 75.9%-87.1%) by Kaplan-Meier analysis. The median duration of response (DOR) estimates after the 3-month CR were 81% (95% CI, 73.9%-86.2%) at both 15 months (n = 43) and 18 months (n = 9). However, the median DOR was not estimable at a median follow-up of 13.9 months due to the lack of recurrence during the follow-up period. The Kaplan-Meier estimated disease-free survival rate was 76% (95% CI, 69.7%-81.1%) at 15 months.

Notably, multifocality, tumor size, and recurrence less than or more than 1 year prior to study enrollment did not seem to affect CR rates with UGN-102 or DORs for patients who achieved a CR.

“These data from the ENVISION trial provide compelling evidence that treatment with UGN-102 achieves a clinically meaningful CR rate and also demonstrates remarkable durability in patients with LG-IR-NMIBC,” Sandip Prasad, MD, MPhil, director of Genitourinary Surgical Oncology at Morristown Medical Center/Atlantic Health System in New Jersey and principal investigator of the ENVISION trial, stated in a news release.1 “The long-term results…further strengthen UGN-102’s potential as a nonsurgical, effective treatment for patients facing the recurrent and challenging nature of LG-IR-NMIBC.”

Previously reported findings from ENVISION supported the submission of a new drug application to the FDA for UGN-102 in LG-IR-NMIBC, which was accepted and assigned a Prescription Drug User Fee Act goal date of June 13, 2025.

“The impressive DOR data from the ENVISION trial further highlight UGN-102’s potential to transform the treatment landscape for patients with LG-IR-NMIBC,” Mark Schoenberg, MD, chief medical officer of UroGen, added in the news release. “Many of these patients are elderly and face the burden of repeated surgeries under general anesthesia, so there is a critical need for innovative treatment options for this patient population. We believe that, if approved, UGN-102’s ability to achieve durable CRs and potentially reduce recurrence rates while extending treatment-free intervals will represent a significant advance in managing LG-IR-NMIBC.”

Background and Study Design

LG-IR-NMIBC is a recurrent malignancy insufficiently managed with the standard approach of transurethral resection of bladder tumors (TURBT).2 Due to the persistent nature of LG-IR-NMIBC, patients often undergo multiple TURBTs under general anesthesia, which is associated with significant morbidity and risks.

UGN-102 is an investigational reverse thermal gel containing mitomycin, administered intravesically via a urethral catheter in an outpatient setting. This minimally invasive treatment utilizes a sustained-release, hydrogel-based formulation of mitomycin, which enhances bladder tissue exposure to the drug. This design enables nonsurgical tumor management, potentially addressing the unmet need for alternative therapeutic approaches in LG-IR-NMIBC.

The ongoing, multinational, single-arm ENVISION trial evaluated the efficacy and safety of chemoablation with UGN-102 as the primary treatment approach for patients with biopsy-proven recurrence of treatment-naive LG-IR-NMIBC. The study was designed to validate prior results from the phase 2b study OPTIMA II trial (NCT03558503), a similar study conducted in 63 patients with LG-IR-NMIBC.

To be included in the study, patients must have had LG-NMIBC histologically confirmed by cold cup biopsy at or within 8 weeks before screening; a history of 1 or more prior episodes of LG-NMIBC requiring treatment with TURBT; negative voiding cytology for high-grade disease within 8 weeks prior to screening; and an anticipated life expectancy of at least the trial duration. Intermediate-risk disease was defined as having 1 or 2 of the following criteria: the presence of multiple tumors, a single tumor larger than 3 cm, and/or early or frequent recurrence.

Exclusion criteria comprised the presence of all 3 intermediate-risk criteria; a history of muscle-invasive or metastatic disease, or a history of high-grade NMIBC within the past 2 years; receipt of bacillus Calmette-Guérin (BCG) treatment for urothelial carcinoma within the past year; or treatment with an intravesical chemotherapeutic agent within the past 2 years other than a single dose immediately after prior TURBT.

The primary end point was CR rate at 3 months after the first instillation in the intention-to-treat patient population. Key secondary end points included the DOR in patients who achieved a CR at the 3-month assessment, and safety.

The data cutoff date for the current analysis was April 4, 2024. It comprises results through month 15 of treatment, or 12 months of follow-up after the 3-month CR mark. Notably, patients who remain disease-free will be followed for up to 5 years after the 3-month visit.

The study enrolled a total of 240 patients across 56 sites and 10 countries. All patients received at least 1 75-mg dose of UGN-102, and 95% of patients received all 6 once-weekly installations in an ambulatory setting. Of the 12 patients who did not complete treatment, 7, 2, 2, and 1 patient received 5, 4, 2, and 1 dose, respectively. Treatment was discontinued due to AEs (n = 7), withdrawal of consent (n = 1), or missing reason (n = 4). By the data cutoff date, all patients on the study who were disease free had completed their 15 months visit, and 71% of patients remained on the study.

At baseline, most patients were male (61%), White (98%), and 65 years of age or older (68%). A small subset of patients (n = 11) with no prior NMIBC history (3.3%) or a history limited to high-grade NMIBC (1.3%) were mistakenly included. The mean number of prior TURBT procedures was 2. Most patients (83%) presented with multifocal tumors, primarily 3 cm or smaller in dimension, with an average aggregate tumor burden of 2.5 cm. Most patients had 2 to 4 tumors at study entry, each ranging from 0.5 cm to 1 cm in size. Most patients had no concerns (37%) or some concerns (40%) about TURBT but were willing to undergo the procedure. If not enrolled in the study, 97% of patients would have undergone TURBT and 2.1% would have undergone fulguration.

Safety Analysis and Study Limitations

UGN-102 displayed a favorable safety profile, which was consistent with that seen in other studies. Treatment-emergent adverse effects (TEAEs) were observed in 57% of patients, with 14% of patients reporting grade 3 or higher events. TEAEs occurred in 50% of patients within the first 3 months and in 32% of patients beyond 3 months. Most TEAEs were mild to moderate, with 24% of TEAEs unresolved at the data cutoff date.

The most common TEAEs were dysuria (23.0%), hematuria (8.3%), urinary tract infection (7.1%), pollakiuria (6.7%), fatigue (5.4%), and urinary retention (5.0%). The TEAEs were typically mild-to-moderate in severity and either resolved or were resolving. The ENVISION trial demonstrated a similar safety profile to that observed in other studies of UGN-102.1

Treatment- or procedure-related TEAEs occurred in 40.4% of patients, predominantly within the first 3 months (39%).2 Seven patients (2.9%) discontinued treatment due to TEAEs, and 6 patients (2.5%) discontinued the study due to TEAEs unrelated to treatment. Serious TEAEs were varied, with urinary retention, atrial fibrillation, and COVID-19 each occurring in 2 patients. Two treatment-related serious TEAEs were reported and resolved: urinary retention and urethral stenosis.

Three deaths occurred during the study due to pneumonia, cardiac failure, and unknown cause, respectively, but none were attributed to the treatment.

Limitations of the study include its single-arm, open-label design; a lack of tumor sizing following diagnostic biopsy; a lack of racial diversity within the patient population; the exclusion of patients treated with induction BCG intravesical therapy within the past 2 years; and the absence of a provision for therapies to improve the tolerance of UGN-102.

Based on these data, study investigators concluded that, “UGN-102 is a minimally invasive, nonsurgical treatment that may represent an efficacious and well-tolerated alternative to TURBT for patients with recurrent LG-IR-NMIBC.”

References

1. ENVISION trial results published in the February issue of The Journal of Urology highlight UGN-102 achievement of 82.3% duration of response at 12 months paving the way for the potential first FDA-approved treatment for LG-IR-NMIBC in June 2025. News Release. UroGen. January 15, 2025. Accessed January 17, 2025. https://investors.urogen.com/news-releases/news-release-details/envision-trial-results-published-february-issue-journal-urology
2. Prasad SM, Shishkov D, Mihaylov NV, et al. Primary chemoablation of recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer with UGN-102: a single-arm, open-label, phase 3 trial (ENVISION). J Urol. 2025;213(2):205-216. doi:10.1097/JU.0000000000004296