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Rashid Sayyid: Hello everyone, this is Rashid Sayyid. I'm a urologic oncology fellow at the University of Toronto, and along with Zach Klaassen, associate professor and program director at Augusta University, we'll be discussing the recent ATLAS publication that looked at the treatment of low-grade intermediate-risk, non-muscle-invasive bladder cancer with UGN-102, with or without TURBT, compared to TURBT monotherapy, within the context of a randomized, controlled, phase III trial. This trial was recently published in The Journal of Urology, with Dr. Sandip Prasad as the first author. We know that low-grade non-muscle-invasive bladder cancer accounts for approximately 50% of the aggregate bladder cancer disease burden in the USA as of 2023. The current paradigm for low-grade intermediate-risk patients... Here, I'll make a distinction between the low-risk and intermediate-risk. The current paradigm includes TURBT plus adjuvant intravesical immunotherapy or chemotherapy. And this is based on the AUA guidelines, and the NCCN guidelines as well. But recurrence rates in this disease space are high. And it's due to a number of factors.

First and foremost, the underlying disease biology, but also potential incomplete surgical resection of visible tumor, and that's where the blue light comes into play, and also poor compliance with recommendations for adjuvant therapy. And as such, it becomes clear that novel agents to improve disease eradication, reduce subsequent recurrence rates for this patient population are sorely needed. UGN-102, what is it? Essentially, it's a mitomycin-containing reverse thermal gel. And within the context of the OPTIMA II trial, it was tested for patients with low-grade non-muscle-invasive disease, who were deemed, AUA, intermediate-risk. And in this small trial, this included 63 patients with non-muscle-invasive bladder cancer, these patients were treated with UGN-102, instilled intravesically, and demonstrated that patients who received it had a complete response rate of 65% in three months, with 61% maintaining this response at 12 months. And as such, there's enough evidence to further explore this within the context of a phase III trial. The study objective of the ATLAS trial was to evaluate the efficacy and safety of primary chemoablation using this UGN-102, the mitomycin gel, with or without subsequent TURBT, compared to TURBT alone, to treat these patients with low-grade intermediate-risk, non-muscle-invasive bladder cancer.

The ATLAS trial was an open-label, phase III RCT that was conducted between January 2021 and March 2023, at 72 sites in the USA Europe and Israel. And the eligibility criteria for this trial included patients with low-grade TA disease that were diagnosed using cold cup biopsy. Patients have visible tumor left in situ, and patients had a negative voided cytology for high-grade disease. Essentially, it's the low-grade TA, intermediate-risk patients. And what is intermediate-risk? It's, per the AUA definition, defined as having one to two of the following risk criteria. Presence of multiple tumors, a solitary tumor greater than three centimeters, or recurrence of low-grade non-muscle-invasive bladder cancer within one year of the current diagnosis. If you had one or two of the following, along with disease left in the bladder, then you were eligible for this trial. In this trial, patients underwent randomization, in a one-to-one fashion, to either UGN-102, with or without TURBT. And patients in this arm received six once-weekly intravesical instillations.

They received it the first day of the week, for example, and then again one week later, for six doses, which is, essentially, the induction course, similar to what we see with BCG. Or, patients were randomized to TURBT alone. And it's important to note here, that patients did not receive adjuvant chemotherapy or immunotherapy, which is discordant with what the current guideline recommendations are. Patients underwent reassessment every three months after treatment initiation for the determination of the response to treatment. And that included having a cytology, a cystoscopy, and biopsies were only performed if there were lesions. There was no mandate for biopsy in this trial if everything looked good. Now, with patients who had a complete response, no further treatment, and they entered the follow-up period. And if there was no complete response with residual low-grade disease in either arm, patients had TURBT for any of the remaining lesions, and then entered the follow-up period. When we say that patients received UGN-102, plus or minus TURBT, that's for patients who had no complete response, and required the TUR for the residual lesions.

Now, during the follow-up period, patients had quarterly clinic visits every three months, which is standard of care. Patients that were determined to be disease-free remained on study until completion of all follow-up visits, or until they had evidence of recurrence, progression or death. And then, patients who were deemed to have protocol-defined recurrence or progression, at any follow-up, or an unscheduled visit, were considered to have completed the study, and were released to the care of the treating physicians. Here, we see the study design for the trial. Again, as we spoke about earlier, if you had intermediate-risk low-grade TA, with residual cancer, and a negative cytology for high-grade disease, you were randomized, one-to-one, to either the UGN-102 or TURBT. And then, again, based on whether you had a complete response or no complete response, you underwent the additional TURBT and entered the surveillance follow-up period. The primary study outcome was disease-free survival that was defined as the time from randomization until treatment failure or death.

Treatment failure was defined as one of the following three. Either residual low-grade disease at the three month assessment... And this was only for the TURBT arm patients. Again, remember, when we talked about the UGN-102 arm, if they had residual disease at the first evaluation, they could have undergone a TURBT alone. Residual disease, at three months, in this arm was not considered a failure, because you would not consider neoadjuvantly treated patients, having residual disease, having failed therapy. The authors rationalized that, if you give neoadjuvant therapy, had residual disease, that isn't really treatment failure. And TURBT is justified in the setting, and not really a treatment failure. Again, a bit of a difference in the definition of what defined treatment, based on the arm patients were randomized to.

Alternatively, another definition of treatment failure was recurrence of low-grade disease at any time after the three month assessment in either arm, or progression to high-grade disease at any time. Other secondary endpoints included the complete response rate, the duration of response, safety events, adverse events, and then disease-related symptoms, functioning, and health-related quality of life. The target sample size for this trial was 632 patients, with 470 disease-free survival events, giving enough power, at 80%, to detect a hazard ratio improvement of 0.77, in favor of the UGN-102 group, assuming that your median disease-free survival would be one year in the TURBT arm, and slightly better, at, almost, 16 months, in the UGN-102 group. Time-to-event outcomes were analyzed using Kaplan-Meier curves. And then, the outcomes between the study arms, in the classic fashion, were compared using the stratified log-rank tests.

And they also used stratified Cox regression models to generate hazard ratio, and the corresponding 95% confidence intervals, when comparing the two treatment arms. One important thing to note in this trial, that it was terminated early. The study enrollment was stopped because the sponsor decided to pursue an alternative development strategy for this product, UGN-102, in the treatment of bladder cancer. Patients who had been consented at the time the trial was terminated were allowed to continue. And then, follow-up was terminated once the last patient had been followed for 15 months after the start of treatment. No interim efficacy analyses were performed. And the early termination of the study rendered the trial underpowered to perform hypothesis testing. And as such, all analyses were considered descriptive, and not analytic, for the purposes of this report. And at this point, I'll turn it over to Zach to go over the results and discussion for this trial.

Zach Klaassen: Thanks so much, Rashid, for that great introduction of ATLAS. This is the patient flow diagram. There were 396 patients that were screened. Ultimately, 285 met eligibility criteria. And 282 patients were randomized, comprising the intention to treat population. This included 142 patients to UGN-102, and 140 patients to the TURBT arm. Ultimately, 138 patients in the UGN-102 arm received treatment, and 132 patients in the TURBT arm received treatment. If we look down here, and we'll go through these results in the next couple of slides, 92 patients had a complete response at three months in the UGN-102 arm, and 89 patients with a complete response at three months in the TURBT alone arm. This is the baseline demographic and clinical characteristics, divided up into a couple of slides. You can see here, the median age was in the late sixties in this group. Roughly, three quarters were male in the UGN-102 arm, and two thirds were male in the TURBT alone arm. Essentially, all patients were white in this trial, mean body mass index was 26.9 in the UGN-102 arm, and 26.7 in the TURBT alone arm.

With regards to some of the tumor characteristics, in terms of greater than three centimeters, just under 50% for each group. In terms of multiple tumors, 58% in the UGN-102 arm, and 67% in the TURBT alone arm. In terms of any previous low-grade non-muscle invasive bladder cancer, just over one third in the UGN-102 arm, and almost 50% in the TURBT alone arm. And previous low-grade non-muscle-invasive bladder cancer, within one year of diagnosis, 29% in both arms. In terms of smoking history, roughly 50% had a smoking history in each of these arms. This is the complete response rates at the three-month visit following treatment, in the intention to treat population. We can see here, the complete response rate was 65% in the UGN-102 arm, and 64% in the TURBT alone arm. When we look at the non-complete responses, we see very similar data between these two arms. In terms of residual disease, 18% in the UGN-102 arm, 16% in the TURBT alone. Progression to high-grade disease, 8.5% in UGN-102, and 6.4% in TURBT alone. We see very similar outcomes in the 282 patients that were randomized. This is the Kaplan-Meier estimate of disease-free survival.

This is a 15-month disease-free survival estimation. You can see here, the UGN-102 15-month estimation was 72%, compared to TURBT alone, which was 50%, with a hazard ratio of 0.45. And then, if we flip to the next slide, this is Kaplan-Meier estimates of the duration of response, in the three-month complete response analysis set. And the 12-month duration of response estimation, post complete response, was 80% in the UGN-102 arm, and 68% in the TURBT alone arm. The hazard ratio was 0.46. With regard to treatment emergent adverse events, before going through this table, it's important to highlight that 96% of the UGN-102 patients completed all six instillations. Treatment compliance was excellent for these patients. Any treatment-related adverse event was 75% of the patients in the UGN-102 arm, compared to 48% in the TURBT alone arm. Only 3.6% of patients in the UGN-102 arm had treatment discontinuation due to adverse events. And with regards to serious adverse events, 8.7% in the UGN-102 arm, and 5.3% in the TURBT alone arm.

With regards to treatment emergent adverse events of interest, as you'd expect from an intravesical therapy, 30% had dysuria, 18% had micturition urgency, 18% had nocturia, and 16% had pollakiuria. This is the PROs from this trial. Basically, to summarize this table, and the following slide, which is the continuation, essentially, between urinary malaise and these other characteristics related to sexual function, future worries, bloating and flatulence, essentially, the UGN patients did, essentially, the same from baseline, slightly better. There was no significant decrease in patient-reported quality of life for this trial. By way of discussion, as Rashid mentioned, UGN-102 is a reverse thermal gel, containing mitomycin at a lower concentration than UGN-101, which is used for upper tract disease. Administration is simpler than UGN-101, since its delivery is by urethral catheter in an ambulatory setting. There are several notable findings from ATLAS, including that the UGN-102 arm achieved complete response rates comparable to the TURBT control group.

Secondly, treatment with UGN-102, plus or minus TURBT, resulted in a numerically greater probability of DFS versus TURBT monotherapy. Third, for patients with a three-month complete response after UGN-102, estimates of the duration of response suggest the response was maintained over time. And finally, the most common treatment emergent adverse events were dysuria, micturition frequency, nocturia, and pollakiuria, which is, essentially, what we'd expect in patients receiving intravesical therapy. Several limitations from this trial. First, patients randomized to TURBT monotherapy did not receive adjuvant intravesical therapy. And this may bias outcomes in favor of the UGN-102 arm. Secondly, the rate of residual low-grade disease in the TURBT monotherapy arm, at the three-month assessment, is somewhat higher than reported in other trials. But if we remember back to the baseline characteristics, there was a decent percentage of these patients that had tumors greater than three centimeters, as well as multifocal tumors, which may explain some of these low-grade disease at the three-month follow-up.

Thirdly, residual low-grade disease at the three month assessment was counted as a DFS event in the TURBT alone arm, but not in the UGN-102 TURBT arm, as Rashid explained in the introduction. And this could bias the estimate of DFS in favor of UGN-102, plus or minus TURBT. However, the authors did do a post hoc sensitivity analysis of DFS, that treated the control arm like the experimental arm, such as, they did not assign residual low-grade disease, at three months, as a DFS event in either arm. And this resulted in a hazard ratio of 0.59, and a 95% confidence interval of 0.38 to 0.91, in favor of primary chemoablation, with UGN-102 compared to TURBT alone. And finally, as mentioned, the trial closed to new enrollment at the request of the sponsor after 282 patients were randomized. The sponsor has initiated another phase III trial called the ENVISION trial, which is an open-label, single-arm study assessing efficacy and safety of UGN-102 for recurrent, intermediate-risk, non-muscle-invasive bladder cancer.

In conclusion, treatment with UGN-102, plus or minus TURBT, resulted in a numerically greater probability of DFS, and a favorable duration of response in patients with low-grade, intermediate-risk, non-muscle-invasive bladder cancer compared to TURBT monotherapy. Although treatment with UGN-102, plus or minus TURBT, was associated with more frequent adverse events, there were no serious treatment-related adverse events in the UGN-102 cohort. And finally, further study of primary chemoablation with UGN-102, for the initial treatment of patients with new or recurrent low-grade, intermediate-risk, non-muscle-invasive bladder cancer is warranted. We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club, discussing the recently published ATLAS trial in the Journal of Urology.