Chris Wallis: Hello, and thank you for joining us for a UroToday Journal club discussion. Today we're discussing a recent publication of the OLYMPUS trial entitled Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel. This is the final report of the OLYMPUS trial. I'm Chris Wallis, an assistant professor in the division of urology at the University of Toronto. With me today is Zach Klaassen, an assistant professor in the division of urology at the Medical College of Georgia. This is the citation for this recent publication in the Journal of Urology led by Dr. Surena Matin and Seth Lerner.

Upper tract urothelial carcinoma represents a relatively small set of urothelial cancers, perhaps between five and 10%. There is a significant geographic variation in its incidence around the world due to the differing prevalence of risk factors for this condition. Like bladder cancer, there's a male predominance of upper tract disease, in part due to shared risk factors, including smoking. However, there are unique risk factors for upper urothelial disease, including environmental exposures.

Treatment approaches in this condition, in part due to its scarcity, are poorly supported by prospective data. The gold standard for patients with high-grade disease is open radical nephrouterectomy with bladder cuff excision, although minimally invasive approaches have been shown to be oncologically equivalent. For patients with low-grade disease, kidney sparing treatment is recommended, and this is particularly true for those with low-grade disease and small favorably located tumors. Endoscopic ablation, as you can see pictured here on the right, has been often employed. And while topical therapies are used frequently in the bladder as adjuvant treatment, these have been limited for upper tract disease by the inability to get sufficient drug concentration and dwell time due to the passage of urine.

To adjust this, UGN-101 was produced, and this contains mitomycin in a reverse thermal gel. And as a result, the exposure to the upper tract is prolonged. Based on the initial results of the OLYMPUS trial, UGN-101 is indicated for primary chemoablative treatment of low-grade upper tract urothelial carcinoma based on results showing a 59% complete response rate. However, at the time of this primary analysis published in Lancet Oncology, less than one-half of patients who had a complete response had a year of follow-up or more. And so as a result, a planned follow-up analysis was performed.

To remind you, this is an open-label, single-arm phase three trial that enrolled adult patients with primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma. Patients were treated with an initial induction course of once weekly installations of UGN-101 for six treatments. At this point, they underwent primary disease evaluation four to six weeks after their last installation. Those who had a complete response at the time of primary disease evaluation subsequently underwent monthly maintenance therapy each month for out to 12 months. Follow-up visits for disease evaluation were performed at three, six, nine, and 12 months.

A key secondary outcome of the OLYMPUS trial, which is the primary endpoint of this report, is the long-term durability of response. And this was assessed among the subset of patients who had a complete response at their initial primary disease evaluation. This is measured based on ureteroscopically observed complete response out to 12 months after the initial visit. The duration of response was calculated using the Kaplan-Meier method, and those without recurrence or who died prior to recurrence were censored at the time of their last assessment or death. The authors further assessed toxicity using laboratory investigations, physical examination, and adverse event monitoring throughout the duration of follow-up. I'm going to hand it over to Zach to walk us through the results of this final report of the OLYMPUS trial.

Zachary Klaassen: Chris, thanks very much for the introduction. This is a patient flow diagram to sort of highlight what was included in the original publication in that there were 74 patients that were enrolled. Ultimately 71 patients were treated with the UGN-101. 61 patients completed treatment, 42 patients with complete response at primary disease evaluation. And then subsequently, 41 patients that encompassed follow-up after that. And so those 41 patients will be the ones that we focus on in this discussion.

So this table is a summary of baseline demographics and clinical characteristics among these 41 patients that had complete response at the time of primary disease evaluation. You can see on the right that the authors have stratified this between those that received no maintenance treatment and those that received one or more maintenance treatments. And so in these 41, 12 patients received no maintenance and 29 received maintenance. You can see that the age for those receiving no maintenance was slightly older at 74.7 years versus 69.4. And just generally looking at the rest of these characteristics, including race, body mass index, and different previous treatments, these are relatively similar between those that received maintenance therapy and those that did not receive maintenance therapy.

This is a simple table, but shows the number of UGN-101 maintenance installations. So we can see, as I mentioned, there was 12 patients that did not have any maintenance. And then we see a distribution of patients all the way from one maintenance dose to 11 maintenance doses. And you can see here at the bottom of this table, there was about 25 to 30% of patients that received between eight and 11 maintenance doses of UGN-101. This is the Kaplan-Meier analysis for durability of complete response among these 41 patients. And the estimated complete response rate at 12 months was 82% with a 95% confidence interval of 66% to 91%.

This is a table looking at the subgroup analysis of the durable, complete responders at 12 months. And basically what this table is looking at is to assess if there was any factors such as gender, treatment, age, body mass index, country, that would significantly differ between response rates. And essentially, to summarize this table, there was no individual parameter that appeared to affect durability of response.

Interestingly, I've highlighted here at the bottom with the asterisks looking at maintenance doses yes or no. And then the patients that had no maintenance doses, 50% of these had a complete response, and those that had maintenance doses, 59% complete response. So not a lot of difference between those with maintenance versus those without maintenance in the 12 month evaluation of complete response.

This is the swimmer plot for these patients. And we can see here that the patients in blue have no documented disease recurrence. Whereas the patients in red do have a documented disease recurrence. And to sort of summarize this swimmer plot, there were eight patients with disease recurrence, three patients that recurred within about three months after the primary disease evaluation visit, and then five patients that recurred later in the follow-up.

This table highlights the patients that underwent radical nephroureterectomy. And you can see that out of the 71 patients only eight patients or 11% underwent radical neph u. Two of these patients were complete responders, but they had the radical neph u because of ureteric stenosis. And one of these patients had maintenance installations. Both of these patients on final pathology were PT zero. The other six patients were non-responders and went underwent radical neph u for disease control purposes.

This table looks at the treatment-emergent adverse events occurring in more than or equal to 10 patients. You could see here at the top, this is again stratified by number of patients with more than or equal to seven installations of UGN-101 compared to less than or equal to six installations. Not surprisingly, nearly every patient had some form of a treatment-emergent adverse event. In terms of serious adverse events, relatively stable as well, actually a little bit lower at 34% in the patients receiving more maintenance doses. What's of interest and has been of interest over the last couple years since the initial publication is the ureteric stenosis rates. As we can see here in the patients that received less maintenance doses, 29% versus 66% in the patients that received greater than or equal to seven insulation doses. So we see likely a cumulative effect with more doses leading to worsening incidence of ureteric stenosis.

So several important discussion points from this study, we know that from the interim report of OLYMPUS, which was published in Lancet Oncology in 2020, as Chris mentioned, there was a complete response rate of 59% after six weekly installations UGN-101. The current report has a Kaplan-Meier estimated durability of 82% complete response at 12 months of follow-up. And these durable responses are encouraging, given that some patients lesions at the time of randomization were deemed unresectable at baseline.

At 12 months of follow-up, durable, complete response was observed in 59% of patients receiving any maintenance doses versus 50% of patients with no maintenance doses. And thus, based on the percentages as listed here, were unable to draw conclusions about the value of maintenance therapy in sustaining a complete response. Increasing number of UGN-101 installations was associated with increased incidence and severity of ureteric stenosis, as I mentioned on the previous slides.

So in conclusion, installation of UGN-101 once weekly for six weeks has been shown to be effective and clinically meaningful for primary chemoablation of low-grade upper tract urothelial carcinoma. Results from this analysis suggest durability of response in a majority of patients for up to 12 months following induction therapy with or without maintenance therapy.

There were no new safety signals that were identified. And the overall safety profile in this analysis was consistent with the known safety profile of endoscopic administration of intravesical mitomycin. The benefit-risk profile of UGN-101 for induction treatment of low-grade upper tract disease appears favorable and suggests that kidney-sparing endoscopic treatment can be augmented in patients with multifocal disease in those with tumors that are difficult to treat endoscopically.

 And finally, the use of maintenance treatment for patients achieving complete response requires full consideration of the potential benefits and risks. We thank you very much for your attention, and we hope you enjoyed this discussion of the OLYMPUS trial final report.