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Open AccessJournal of UrologyAdult Urology1 Oct 2023

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)

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    Abstract

    Purpose:

    Low-grade intermediate-risk nonmuscle-invasive bladder cancer is a chronic illness commonly treated by repetitive transurethral resection of bladder tumor. We compared the efficacy and safety of intravesical chemoablation with UGN-102 (a reverse thermal gel containing mitomycin), with or without subsequent transurethral resection of bladder tumor, to transurethral resection of bladder tumor alone in patients with low-grade intermediate-risk nonmuscle-invasive bladder cancer.

    Materials and Methods:

    This prospective, randomized, phase 3 trial recruited patients with new or recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer to receive initial treatment with either UGN-102 once weekly for 6 weeks or transurethral resection of bladder tumor. Patients were followed quarterly by endoscopy, cytology, and for-cause biopsy. The primary end point was disease-free survival. All patients were followed for adverse events.

    Results:

    Trial enrollment was halted by the sponsor to pursue an alternative development strategy after 282 of a planned 632 patients were randomized to UGN-102 ± subsequent transurethral resection of bladder tumor (n=142) or transurethral resection of bladder tumor monotherapy (n=140), rendering the trial underpowered to perform hypothesis testing. Patients were predominantly male and ≥65 years of age. Tumor-free complete response 3 months after initial treatment was achieved by 92 patients (65%) who received UGN-102 and 89 patients (64%) treated by transurethral resection of bladder tumor. The estimated probability of disease-free survival 15 months after randomization was 72% for UGN-102 ± transurethral resection of bladder tumor and 50% for transurethral resection of bladder tumor (hazard ratio 0.45). The most common adverse events (incidence ≥10%) in the UGN-102 group were dysuria, micturition urgency, nocturia, and pollakiuria.

    Conclusions:

    Primary, nonsurgical chemoablation with UGN-102 for the management of low-grade intermediate-risk nonmuscle-invasive bladder cancer offers a potential therapeutic alternative to immediate transurethral resection of bladder tumor monotherapy and warrants further investigation.

    In 2023 low-grade (LG) nonmuscle-invasive bladder cancer (NMIBC) will account for approximately 50% of the aggregate bladder cancer disease burden in the United States.1 Management of LG NMIBC is performed primarily by endoscopic surgical resection under anesthesia.2 Recurrence of disease following transurethral resection of bladder tumor (TURBT) is common, particularly for patients with intermediate-risk (IR) cancer. This is due to multiple factors, including the biology of urothelial cancers with asynchronous malignant transformation of normal-appearing urothelium and incomplete surgical removal of visible tumor.3-5 Both the AUA and the National Comprehensive Cancer Network recommend adjuvant immunotherapy or chemotherapy following TURBT for IR NMIBC patients, but real-world evidence suggests that compliance with this recommendation is modest in the U.S.6-8

    Since risk of disease progression is low but risk of recurrence is high in LG NMIBC, improved methods aimed at optimizing disease clearance and forestalling recurrence to avoid risks of repetitive surgery and anesthesia are needed.5,9,10 A phase 2b trial (OPTIMA II; NCT03558503) of primary chemoablation using UGN-102 (an investigational mitomycin-containing reverse thermal gel) in patients with new or recurrent LG IR NMIBC suggested favorable rates of complete response (CR) and durability of response (DOR).11 In this report, we describe efficacy and safety of primary chemoablation using UGN-102 with or without subsequent TURBT compared to TURBT alone to treat patients with LG IR NMIBC.

    MATERIALS AND METHODS

    Study Design and Population

    This prospective, phase 3, randomized, open-label, controlled study was conducted from January 12, 2021, to March 17, 2023, at 72 sites in the U.S., Europe, and Israel. Eligible patients were ≥18 years of age with LG NMIBC (Ta) diagnosed using cold cup biopsy (with visible tumor left in situ) and negative voiding cytology for high-grade (HG) disease. IR disease was defined as having 1 or 2 of the following: presence of multiple tumors, solitary tumor >3 cm, and/or recurrence of LG NMIBC within 1 year of the current diagnosis. Eligible patients were randomized in a 1:1 ratio (stratified by the presence of previous LG NMIBC episodes within 1 year of the current diagnosis) to UGN-102 with or without TURBT or TURBT alone (Figure 1).

    Figure 1.Study design. *Screening procedures were performed to provide evidence of low-grade disease and exclude high-grade disease. **Patients randomized to either treatment arm with residual low-grade disease at the 3-month assessment were eligible for treatment with transurethral resection of bladder tumor (TURBT). CR indicates complete response; CT, computed tomography; DFS, disease-free survival; EOS, end of study; EOT, end of treatment; MRI, magnetic resonance imaging; NCR, noncomplete response; TURBT, transurethral resection of bladder tumor.

    Figure 1. Study design. *Screening procedures were performed to provide evidence of low-grade disease and exclude high-grade disease. **Patients randomized to either treatment arm with residual low-grade disease at the 3-month assessment were eligible for treatment with transurethral resection of bladder tumor (TURBT). CR indicates complete response; CT, computed tomography; DFS, disease-free survival; EOS, end of study; EOT, end of treatment; MRI, magnetic resonance imaging; NCR, noncomplete response; TURBT, transurethral resection of bladder tumor.

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    Patients randomized to the UGN-102 group received 6 weekly intravesical instillations, and patients randomized to the TURBT alone group received TURBT. All patients were scheduled to return to the clinic approximately 3 months after start of treatment for determination of response. Patients confirmed to have CR received no further treatment and entered the follow-up period of the study. Patients confirmed to have noncomplete response with residual LG disease in either treatment arm were treated by TURBT for any remaining lesions and then entered the follow-up period. During the follow-up period, patients were scheduled to return to the clinic quarterly, and patients determined to be disease-free remained on study until completion of all follow-up visits or until disease recurrence, disease progression, or death was documented. Patients determined to have had a protocol-defined recurrence or progression at any follow-up or unscheduled visit were considered to have completed the study and were released to the care of their treating physicians. Disease-free survival (DFS) was the primary end point.

    The trial protocol, amendments, and informed consent form were approved by the Institutional Review Board at each participating site (IRB No. BL006). The trial was conducted in compliance with the Declaration of Helsinki, International Council for Harmonization guidelines, and the U.S. Code of Federal Regulations Title 21, parts 50, 56, and 312. The study is registered with ClinicalTrials.gov (NCT04688931).

    Procedures

    Eligible patients received either 6 once-weekly intravesical instillations of UGN-102 (75 mg mitomycin in 56 mL admixture with reverse thermal hydrogel to equal 1.33 mg/mL) or TURBT. Patients randomized to TURBT did not receive adjuvant immunotherapy or chemotherapy. The ablative effect of UGN-102 or TURBT was evaluated 3 months after start of treatment. Response was determined based on visual assessment (cystoscopy), biopsy of remaining lesions (if applicable), and voided urine cytology. If cystoscopy indicated no remaining tumors and urine cytology was negative, the patient had no detectable disease and was considered CR. If the bladder was free of tumor endoscopically but cytology was positive, the investigator was required to exclude upper tract urothelial carcinoma (UTUC) and occult carcinoma of the bladder or urethra. If any lesions were detected, even if they appeared necrotic, a biopsy was taken for further evaluation.

    Outcomes

    The primary efficacy end point of DFS was defined as the time from randomization until treatment failure or death from any cause. Treatment failure comprised residual LG disease at the 3-month assessment (TURBT arm only), recurrence of LG disease at any time after the 3-month assessment, or progression to HG disease at any time. Residual LG disease at the 3-month assessment in the UGN-102 ± TURBT arm was not counted as a DFS event since such an outcome would not be considered treatment failure following neoadjuvant therapy. DFS was analyzed based on the intent-to-treat population, defined as all patients who were randomized to treatment. Key secondary end points included CR rate and DOR.

    The safety population comprised all patients who received ≥1 instillation of UGN-102 or underwent primary TURBT. Adverse events were assessed via verbal questioning during study visits or (for the TURBT alone arm) telephone follow-up and were coded using the Medical Dictionary for Regulatory Activities version 23.1, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Treatment effects on disease-related symptoms, functioning, and health-related quality of life were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Non-muscle Invasive Bladder Cancer patients (EORTC-QLQ-NMIBC24).12

    Statistical Analysis

    The trial was designed with a target sample size of 632 patients to observe an estimated 470 DFS events which would provide 80% power to detect a hazard ratio of 0.77 in the UGN-102 group compared to the TURBT group, using a 1-sided log-rank test at a significance level of 0.025 (type 1 error). The hazard ratio was based on an assumed median DFS of 12 months for the TURBT alone arm and 15.6 months for the UGN-102 arm. Patients were to be followed for 24 months. Two interim efficacy analyses of DFS based on 50% and 75% information fractions were planned.

    A stratified log-rank test was planned for testing superiority of the UGN-102 arm compared to the TURBT alone arm for DFS. A stratified Cox regression model was used to estimate the hazard ratio of DFS, along with 95% confidence intervals. Patients who did not have a DFS event were censored at the date of last adequate disease assessment. The distribution function of DFS was estimated using the Kaplan-Meier method. Similar time-to-event statistical methodology was used for the secondary end point of DOR. The secondary end point of 3-month CR rate was summarized along with nominal 95% exact CI using the Clopper-Pearson method. A mixed effect model for repeated measures was planned to evaluate changes in the EORTC-QLQ-NMIBC24 measures. SAS software was used to perform all data analyses.

    Study enrollment was stopped early by the sponsor to pursue an alternative development strategy for UGN-102 in the treatment of bladder cancer. Patients who had consented at the time the trial terminated were permitted to continue, but follow-up was terminated once the last patient had been followed for 15 months after start of treatment. No interim efficacy analyses were performed, and early termination rendered the trial underpowered to perform hypothesis testing. Thus, all analyses are descriptive.

    RESULTS

    A total of 282 patients were enrolled in the trial and randomized to receive UGN-102 ± TURBT (n=142) or to undergo primary TURBT (n=140), representing the intent-to-treat analysis set (Figure 2). Most participants were ≥65 years and male in both study arms. The median age was 68 years in the UGN-102 arm and 67 years in the TURBT arm. Fifty-four patients (38%) randomized to the UGN-102 arm and 65 patients (46%) in the surgery arm had prior history of LG NMIBC (Table 1), and 29% of patients in both groups had prior history of LG NMIBC within 1 year of study entry (stratification variable). Fifty-two patients (37%) in the UGN-102 arm and 64 patients (46%) in the TURBT arm had prior TURBT. Multifocal tumor was identified at baseline in 82 patients (58%) randomized to the UGN-102 arm and 94 surgery patients (67%). Tumors >3 cm were identified in 67 UGN-102 patients (47%) and 59 surgery patients (42%).

    Figure 2.Patient flow diagram. AE indicates adverse event; CR, complete response; DFS, disease-free survival; EOS, end of study; HG, high-grade; ITT, intent-to-treat; LG, low-grade; TURBT, transurethral resection of bladder tumor.

    Figure 2. Patient flow diagram. AE indicates adverse event; CR, complete response; DFS, disease-free survival; EOS, end of study; HG, high-grade; ITT, intent-to-treat; LG, low-grade; TURBT, transurethral resection of bladder tumor.

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    Table 1. Baseline Demographic and Clinical Characteristics (Intent-to-Treat Analysis Set)

    Characteristic UGN-102 ± TURBT (N=142)a TURBT alone (N=140)
    Age, y
     Mean (SD) 66.7 (10.6) 66.3 (10.5)
     Median (range) 68.0 (23-85) 67.0 (29-88)
    Age ≥65 y, No. (%) 91 (64) 77 (55)
    Male sex, No. (%) 105 (74) 93 (66)
    White race, No. (%) 140 (99) 139 (99)
    Non-Hispanic/non-Latino ethnicity, No. (%) 140 (99) 137 (98)
    Body mass index, kg/m2
     Mean (SD) 27.8 (5.0) 27.3 (4.7)
     Median (range) 26.9 (18.2-47.0) 26.7 (17.3-41.9)
    Tumor >3 cm, No. (%)b 67 (47) 59 (42)
    Multiple tumors number, No. (%)c 82 (58) 94 (67)
    Prior LG NMIBC episode, No. (%) 54 (38) 65 (46)
    Prior LG NMIBC episode within 1 y of current diagnosis, No. (%) 41 (29) 40 (29)
    Prior TURBT, No. (%) 52 (37) 64 (46)
    Smoking history, No. (%) 79 (56) 67 (48)

    Abbreviations: LG NMIBC, low-grade nonmuscle-invasive bladder cancer; TURBT, transurethral resection of bladder tumor.

    Patients randomized to initial treatment with UGN-102 were eligible to be treated with TURBT if they had noncomplete response at 3 months with residual LG NMIBC.

    Measured in 136 patients in UGN-102 ± TURBT arm and 132 patients in TURBT alone arm.

    Measured in 136 patients in UGN-102 ± TURBT arm and 134 patients in TURBT alone arm.

    At the first disease assessment 3 months after start of treatment, CR was achieved by 92 UGN-102 patients (65% [95% CI: 56.3, 72.6]) and 89 TURBT patients (64% [95% CI: 55.0, 71.5]; Table 2). Disease progression at the 3-month assessment was noted in 12 UGN-102 patients and 9 surgery patients. Among patients with residual LG disease at the 3-month assessment, 24/26 treated with UGN-102 and 18/22 treated with primary TURBT underwent TURBT. Median follow-up time for DFS among those remaining event-free was similar between the treatment arms: 15.4 (95% CI: 15.2, 16.0) and 15.3 (95% CI: 15.1, 15.9) months in the UGN-102 ± TURBT and TURBT monotherapy groups, respectively. DFS 15 months after randomization was estimated to be 72% for patients in the UGN-102 ± TURBT arm and 50% for patients in the TURBT monotherapy arm by Kaplan-Meier analysis (Figure 3). Among patients achieving CR at the 3-month assessment, estimated DOR at 12 months post-CR was 80% after induction treatment with UGN-102 and 68% after primary TURBT (Figure 4). In the CR analysis set, 67 patients treated with UGN-102 and 49 treated with TURBT remained disease-free at end of study. Overall hazard ratios for DFS and DOR were 0.45 and 0.46, respectively. Estimates of DFS remained favorable for the UGN-102 ± TURBT group in a post hoc sensitivity analysis that excluded as DFS events residual LG disease at the 3-month assessment in the TURBT alone group (HR=0.59 [95% CI: 0.38, 0.91]).

    Table 2. Complete Response Rates at the 3-month Visit Following Treatment (Intent-to-Treat Analysis Set)

    UGN-102 ± TURBT (N=142)aNo. (%) TURBT alone (N=140) No. (%)
    Complete response 92 (65) [95% CI 56.3, 72.6]b 89 (64) [95% CI 55.0, 71.5]b
    Noncomplete response 50 (35) 51 (36)
     Residual disease 26 (18) 22 (16)
     Progression to high grade disease 12 (8.5) 9 (6.4)
      Indeterminate 3 (2.1) 0
      Missingc 9 (6.3) 20 (14)

    Abbreviations: CI, confidence interval; TURBT, transurethral resection of bladder tumor.

    Patients randomized to initial treatment with UGN-102 were eligible to be treated with TURBT if they had noncomplete response at 3 months with residual low-grade nonmuscle-invasive bladder cancer.

    Exact 95% CI for complete response rate was computed using the Clopper-Pearson method.

    Of the 9 patients with a missing 3-month disease assessment in the UGN-102 ± TURBT arm, 4 were randomized but not treated, 2 discontinued due to adverse events, and 1 patient each violated entry criteria (did not have intermediate-risk disease), withdrew consent, or sought treatment at another medical center. Of the 20 patients with a missing 3-month disease assessment in the TURBT alone arm, 8 were randomized but not treated, 5 violated entry criteria (eg, had T1 or high-grade Ta disease), 4 withdrew consent, and 1 patient each discontinued due to investigator discretion, noncompliance, or loss to follow-up.

    Figure 3.Kaplan-Meier estimates of disease-free survival (intent-to-treat analysis set). TURBT indicates transurethral resection of bladder tumor.

    Figure 3. Kaplan-Meier estimates of disease-free survival (intent-to-treat analysis set). TURBT indicates transurethral resection of bladder tumor.

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    Figure 4.Kaplan-Meier estimates of duration of response (3-month complete response [CR] analysis set). The 3-month CR analysis set includes those patients randomized to initial treatment with UGN-102 or transurethral resection of bladder tumor (TURBT) who were disease-free at the 3-month assessment.

    Figure 4. Kaplan-Meier estimates of duration of response (3-month complete response [CR] analysis set). The 3-month CR analysis set includes those patients randomized to initial treatment with UGN-102 or transurethral resection of bladder tumor (TURBT) who were disease-free at the 3-month assessment.

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    The safety analysis set comprised 138 patients who received ≥1 dose of UGN-102 in the primary chemoablation treatment arm and 132 patients who were treated by primary TURBT. Of those treated with UGN-102, 132 patients (96%) completed 6 instillations. Treatment-emergent adverse events (TEAEs) occurred more commonly in patients treated with UGN-102 (75% vs 48%). Fifty-four patients (39%) in the UGN-102 ± TURBT arm and 15 (11%) in the TURBT monotherapy arm experienced TEAEs related to study treatment. Serious TEAEs occurred in 12 patients (8.7%) who received UGN-102 and 7 patients (5.3%) in the surgery arm; however, no serious TEAEs in the UGN-102 group and 1 in the TURBT monotherapy group (postoperative hematuria) were considered by the investigator to be related to treatment. Treatment discontinuation and study discontinuation due to adverse events occurred in 5 (3.6%) and 4 (2.9%) patients receiving UGN-102. The most commonly reported adverse events in the UGN-102 ± TURBT arm of the study were dysuria (30%), micturition urgency (18%), nocturia (18%), and pollakiuria (16%; Table 3). One death occurred during the study (in the TURBT arm) which was attributed to infection with COVID-19. Patient-reported symptoms, functioning, and quality-of-life—as measured by changes from baseline in the EORTC-QLQ-NMIBC24—either were improved or not worsened in those treated with UGN-102 ± TURBT or TURBT alone (Table 4).

    Table 3. Summary of Treatment-emergent Adverse Events (Safety Analysis Set)

    UGN-102 ± TURBT (N=138)a TURBT alone (N=132)
    TEAEs, No. (%)
     Any TEAE 104 (75) 63 (48)
     Treatment discontinuation due to TEAE 5 (3.6) NA
     Serious TEAE 12 (8.7) 7 (5.3)
     Treatment-relatedb serious TEAEs 0 1 (0.8)
    TEAEs ≥5% in any treatment group
     Dysuria 42 (30) 6 (4.5)
     Micturition urgency 25 (18) 10 (7.6)
     Nocturia 25 (18) 9 (6.8)
     Pollakiuria 22 (16) 8 (6.1)
     Flatulence 13 (9.4) 4 (3.0)
     COVID-19 11 (8.0) 8 (6.1)
     Erectile dysfunction 9 (6.5) 4 (3.0)
     Hematuria 9 (6.5) 6 (4.5)
     Malaise 8 (5.8) 2 (1.5)

    Abbreviations: NA, not applicable; TEAE, treatment-emergent adverse event; TURBT, transurethral resection of bladder tumor.

    Patients randomized to initial treatment with UGN-102 were eligible to be treated with TURBT if they had noncomplete response at 3 months with residual low-grade nonmuscle-invasive bladder cancer.

    Relationship of TEAE to study treatment as assessed by the investigator.

    Table 4. Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Non-muscle Invasive Bladder Cancer (Safety Analysis Set)

    UGN-102 ± TURBT (N=138)a TURBT alone (N=132)
    EORTC-QLQ-NMIBC24 subscale and item scoresb No. Mean baseline score Mean change No. Mean baseline score Mean change
    Urinary symptoms 134 19.1 125 17.4
     1 wk 118 −4.2 85 −3.4
     3 mo 125 −10.7 116 −4.5
     12 mo 89 −15.3 59 −9.4
    Malaise 134 7.5 −2.3 125 6.7
     1 wk 118 −4.4 85 −0.6
     3 mo 125 −5.8 116 −1.1
     12 mo 89 59 −5.9
    Intravesical treatment issues 134 12.7 125 15.2
     1 wk 118 0.6 85 −3.9
     3 mo 125 −4.0 116 −2.9
     12 mo 89 −3.0 59 −7.3
    Future worries 134 41.7 125 43.1
     1 wk 118 −3.3 85 −0.9
     3 mo 125 −12.7 116 −8.3
     12 mo 89 −18.0 59 −21.2
    Bloating and flatulence 134 12.8 125 9.7
     1 wk 118 −2.7 85 −0.8
     3 mo 125 −7.7 116 −3.0
     12 mo 89 −6.6 59 −3.7
    Male sexual problems 98 17.0 84 23.8
     1 wk 85 0.8 60 −5.3
     3 mo 91 0.9 80 −0.6
     12 mo 65 −1.8 40 −5.4
    Sexual intimacy 90 10.4 82 8.9
     1 wk 65 0.0 50 0.7
     3 mo 63 0.0 65 3.6
     12 mo 42 −6.3 27 −2.5
    Risk of contaminating partner 87 10.0 82 6.9
     1 wk 66 2.0 50 2.0
     3 mo 61 1.6 64 0.0
     12 mo 41 −8.1 27 −2.5
    Female sexual problems 17 17.6 22 10.6
     1 wk 15 −4.4 13 −2.6
     3 mo 10 −10.0 15 −8.9
     12 mo 4 −16.7 5 0.0
    Sexual function 134 80.5 125 80.8
     1 wk 118 1.1 85 3.5
     3 mo 125 0.4 116 −1.6
     12 mo 89 0.6 59 −1.7
    Sexual enjoyment 87 58.2 82 63.0
     1 wk 63 1.6 49 −4.8
     3 mo 61 8.7 65 −1.0
     12 mo 40 10.8 27 2.5

    Abbreviations: EORTC-QLQ-NMIBC24, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Non-muscle Invasive Bladder Cancer; TURBT, transurethral resection of bladder tumor.

    Patients randomized to initial treatment with UGN-102 were eligible to be treated with TURBT if they had noncomplete response at 3 months with residual low-grade nonmuscle-invasive bladder cancer.

    The EORTC-QLQ-NMIBC24 consists of 24 items organized into 6 scales (urinary symptoms, malaise, future worries, bloating and flatulence, sexual functioning, and male sexual problems) and 5 single items (intravesical treatment issues, sexual intimacy, risk of contaminating partner, sexual enjoyment, and female sexual problems). Higher scores on functioning scales represent better functioning, while higher scores on symptom scales indicate more symptom burden.

    DISCUSSION

    LG NMIBC is the most common form of urothelial bladder cancer accounting for approximately 50% of the 82,000 incident bladder cancers in the U.S. in 2023 and much of the prevalent national disease burden which approaches 800,000 cases. Most patients experience recurrence after endoscopic surgical treatment and repeat TURBT is the current standard of care for patients who experience noninvasive intravesical relapse. TURBT is associated with well-known risks.13 Repetitive surgical procedures under anesthesia carry additional risk, particularly for those of advanced age.4,14

    The search for alternatives to TURBT has evolved over the past several decades. Electromotive drug administration and chemothermotherapy have been explored with early success in the treatment of refractory HG NMIBC but have not been successfully applied to IR papillary disease.15,16 Au et al and others have shown that the efficacy of intravesical drug treatment of urothelial cancer is directly related to increasing drug concentration and dwell time.17-21 Recent studies employing dose-intensive administration of aqueous mitomycin as primary therapy for LG NMIBC demonstrate the validity of this observation, achieving CR rates ranging from 50%-60%, but required frequent drug administration at short intervals that are cumbersome and impractical for routine patient care.22-24

    Reverse thermal gels are useful for drug delivery and are particularly well suited for use in the urinary tract where dilution by continuous urine production and excretion by bladder contraction limit the therapeutic effect of aqueous medications. UGN-101, a reverse thermal gel containing mitomycin (4 mg/mL) is approved by the U.S. Food and Drug Administration for the treatment of LG UTUC,25 and has recently been incorporated into AUA UTUC guidelines to promote renal preservation.26 The extended dwell time for mitomycin of 6-8 hours facilitates primary chemoablation with initial CR rates ranging from 57% to 70%, good DOR, and an acceptable safety profile.27 UGN-101 is administered into the upper tract either retrograde under fluoroscopic guidance or antegrade via a nephrostomy tube.28,29

    UGN-102 is a similar reverse thermal gel containing mitomycin at a lower concentration (1.33 mg/mL). Its administration is simpler than UGN-101 since it can be delivered via urethral catheter in an ambulatory setting.11 The instilled volume of approximately 60 mL delivers twice the dose of mitomycin that is administered in aqueous solution for adjuvant therapy and disintegrates over a period of 6-8 hours with gel fragments excreted during normal voiding.

    In the current trial, patients receiving induction treatment with UGN-102 achieved CR rates comparable to the surgical control group. In addition, initial treatment with UGN-102 with or without subsequent TURBT resulted in numerically greater probability of DFS compared with TURBT monotherapy, although this observation must be interpreted cautiously as residual LG disease at the 3-month assessment was counted as a DFS event in the TURBT monotherapy arm but not in the UGN-102 ± TURBT arm. For patients achieving CR 3 months after initial treatment with UGN-102, Kaplan-Meier estimates of DOR suggest that response is maintained over time.

    Treatment with UGN-102 ± TURBT was associated with more TEAEs than TURBT monotherapy; however, patients in the drug treatment arm were queried weekly during induction therapy regarding adverse effects associated with treatment, whereas patients in the surgical arm were evaluated at monthly intervals via telephone contact up to the 3-month visit. This imbalance in evaluation may have introduced ascertainment bias into the study which in turn may underestimate TEAEs associated with TURBT. The most common TEAEs encountered with UGN-102 treatment were dysuria, micturition frequency, nocturia, and pollakiuria which are common side effects of local therapy for bladder cancer and often dissipate with time from the intervention.

    This study has limitations. First, patients randomized to TURBT monotherapy did not receive adjuvant intravesical therapy which may bias outcomes in favor of the UGN-102 ± TURBT treatment group. While use of post-TURBT chemotherapy occurs in fewer than 1 in 5 patients,6 among patients in the TURBT-only arm in the current study who might otherwise have received post-TURBT chemotherapy, benefit from the absolute reduction in recurrence of 20% at 4 years seen in the SWOG S0337 study30 was excluded and any potential effects on 3-month CR and DFS are unknown. Second, in this trial the rate of residual LG disease in the TURBT monotherapy arm at the 3-month assessment is somewhat higher than reported in other trials30; however, this may be explained in part by differences in study populations. For example, two-thirds of patients in SWOG S0337 had a single tumor whereas almost two-thirds of patients in the current trial had multiple tumors. Additionally, 30% of patients in this study had a recurrence within 1 year of study enrollment whereas SWOG S0337 excluded highly recurrent patients.

    Third, residual LG disease at the 3-month assessment was counted as a DFS event in the TURBT alone arm but not in the UGN-102 ± TURBT arm, which could bias the estimate of DFS in favor of UGN±TURBT (though not 3-month CR rate or estimate of DOR in the CR analysis set). However, a post hoc sensitivity analysis of DFS that treated the control arm like the experimental arm (ie, did not assign residual LG disease at 3 months as a DFS event in either arm and gave both arms the opportunity for TURBT in case of residual disease after the primary intervention) resulted in a hazard ratio in favor of primary chemoablation with UGN-102 ± subsequent TURBT compared with primary TURBT ± subsequent TURBT. Finally, while planned as a test of UGN-102 superiority to TURBT with a goal of enrolling 632 patients, the trial was closed to new enrollment at the request of the sponsor after 282 patients were randomized. Patients were treated and followed, permitting the presentation of the data for this report; however, the present study reflects both the enrollment of a smaller cohort of patients than would have been required to satisfy the original statistical analysis plan and what was likely an excessively conservative estimate of the therapeutic benefit of UGN-102, as suggested by the considerable difference between the targeted and estimated hazard ratios as well as the precision of the estimated hazard ratio. The sponsor subsequently initiated another phase 3 trial (ENVISION, NCT05243550), an open-label, single-arm study of the efficacy and safety of UGN-102 in the treatment of recurrent IR NMIBC.

    CONCLUSIONS

    Treatment with UGN-102 ± TURBT resulted in numerically greater probability of DFS and favorable DOR in patients with LG IR NMIBC compared to TURBT monotherapy in this study. Although treatment with UGN-102 ± TURBT was associated with more frequent TEAEs, there were no serious treatment-related TEAEs in the UGN-102 cohort. Further study of primary chemoablation with UGN-102 for initial treatment of patients with new or recurrent LG IR NMIBC is warranted.

    Acknowledgments

    We thank the following ATLAS Study Group investigators who enrolled and treated patients in the ATLAS study: Giorgi Adeishvili, Andrejs Aleksandrovs, Ilya Alexandrov, Igor Antonyan, Heino-Enn Arpo, Georgi Atanasov, Jack Baniel, Hryhoriy Bardakov, Alexander Bardin, Yurii Bondarenko, Oleg Burlaka, Aleksander Bystrov, Konstantin Chibirov, Shalva Chovelidze, Lukasz Curylo, Ivan Dechev, Konstantin Dunets, Zoran Dzamic, Mitchell Efros, Oleksandr Fedoruk, Evgeny Fomin, Nikoloz Gogoladze, Iaroslav Gotsuliak, Vladislav Grigoriev, Stefan Kachev, Guram Karazanashvili, Nikolay Kolev, Dmitri Korotots, Oleksandr Kostiuk, Andrzej Kupilas, Zaal Kvirikashvili, Viktor Latypov, Vilnis Lietuvietis, Jaak Lind, Dzintra Litavniece, Sergey Mishugin, Boris Mladenov, Robert Molchanov, Taron Nalbandian, Roomet Ots, Kalpesh Patel, Sergey Petrov, Andriy Rusyn, Maksym Sabadash, Kadir Safiullin, Daniel Saltzstein, Maksym Shostak, Alexander Shvets, Viktor Stus, Toomas Tamm, Marlen Topuzov, Chulpan Valiakhmetova, Michael Verni, Egils Vjaters, Ihor Vynnychenko, Radovan Zaric. We also thank the patients and their families and caregivers for volunteering to participate in this trial. Editorial support for the manuscript was provided by Mary Susan Prescott of Prescott Medical Communications Group (Chicago, Illinois).

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    Support: This study was supported by UroGen Pharma (SMP, WCH, GB, DS, VZ, AN, DK).

    Conflict of Interest: GB: Astellas, Speakers Bureau, Consultancy; Janssen: Speakers Bureau, Consultancy; Bayer: Speakers Bureau, Consultancy, Ad Boards; Pfizer: Consultancy, Ad Boards, Lecture Bureau.

    Ethics Statement: This study received Institutional Review Board approval (IRB No. BL006).

    Data Availability: Data not publicly available.

    Trial Registration Number: NCT04688931.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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