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.
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.
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.
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.
Caught in the middle: Exploring a different treatment strategy for low-grade intermediate risk NMIBC
Commentary by Dr. Laura Mertens
Patients diagnosed with non-muscle invasive bladder cancer (NMIBC) within the intermediate-risk category exhibit a low risk of disease progression. For these patients the EAU guidelines recommend a transurethral resection of the bladder tumour (TURBT) followed by a one-year full-dose of BCG treatment, or instillations of chemotherapy. Nevertheless, the intermediate-risk group encompasses a diverse range of patients with varying characteristics, including low-grade and high-grade tumours. In the case of low-grade NMIBC, while the risk of disease progression is indeed low, the risk of recurrence is notably high. Consequently, there is a need for enhanced methods primarily focused on reducing recurrence risk, all while carefully considering the potential of unnecessary overtreatment.
In this article, Prasad et al., report the results of their phase 3 trial (ATLAS) concerning the efficacy and safety of primary chemoablation using investigational drug UGN-102 (a mitomycin-containing reverse thermal gel which can be inserted with a transurethral catheter in an ambulatory setting) with or without subsequent TURBT compared to TURBT alone, for the treatment of patients with low-grade intermediate risk NMIBC.
This prospective, randomised, phase 3 trial included patients with a new or recurrent low-grade intermediate risk NMIBC at 72 sites in the US, Europe and Israel, between 2021 and 2023. Eligible patients were diagnosed through cold cup biopsy, and intermediate risk disease was defined as having 1 or 2 of the following: presence of multiple tumours, solitary tumour >3 cm, and/or recurrence of LG NMIBC within 1 year of the current diagnosis. Patients were randomised to receive treatment with either UGN-102 once weekly for 6 weeks with or without TURBT (depending on whether or not a complete response was achieved at the first check-up at three months) or TURBT alone. Patients were followed quarterly by endoscopy, cytology, and for-cause biopsy. The primary end point was disease-free survival (DFS).
The trial was designed with a target sample size of 632 patients. However, study enrolment was halted by the sponsor after enrolling a total of 282 patients for UGN-102 ± TURBT (n=142) or primary TURBT monotherapy (n=140). Therefore, the trial was underpowered to perform hypothesis testing.
The median age was 66 years, and 38-46% had a prior low-grade NMIBC. The authors describe that tumour-free complete response 3 months after the initial treatment was achieved by 92 patients (65%) who received UGN-102 and 89 patients (64%) treated by transurethral resection of bladder tumour – which means a considerable percentage of non-complete responders in both the UGN-102 and TURBT monotherapy group. The estimated probability of DFS 15 months after randomisation was 72% for UGN-102 ± transurethral resection of bladder tumour and 50% for transurethral resection of bladder tumour (hazard ratio 0.45). However, 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, which could bias the estimate of DFS in favour of UGN±TURBT.
The most common adverse events (incidence ≥10%) in the UGN-102 group were dysuria, urgency, nocturia, and pollakiuria. Although treatment with UGN-102 ± TURBT was associated with more frequent TEAEs, there were no serious treatment-related TEAEs in the UGN-102 cohort.
Since considerably fewer patients were randomised than initially planned, this study does not provide the evidence to conclude that UGN-102 is an effective treatment for patients with low-grade intermediate risk NMIBC. Further studies on chemoablation are anticipated, in this understudied category of NMIBC, where many aspects regarding the most suitable therapy remain unclear.