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Zachary Klaassen: Hi, my name is Zachary Klaassen. I’m a urologic oncologist at the Georgia Cancer Center. I’m delighted to be joined on your show today by Dr. Sandip Prasad, who is a urologic oncologist at the Morristown Medical Center and Atlantic Health System. Sandip, thanks so much for joining us on UroToday.

Sandip Prasad: Zach, thank you so much for having me. I’m excited to be here.

Zachary Klaassen: So we’re going to talk today about an SUO 2024 presentation that you gave about the ENVISION trial. And just for our listeners, this is primary chemo ablation of recurrent low grade, intermediate non-muscle invasive bladder cancer with UGN-102. So I’d love for you to walk our listeners through some of the slides that you presented at SUO.

Sandip Prasad: Well, Zach, thank you again for the introduction. And this was presented at the SUO in 2024, looking really at a novel concept in urologic oncology—that is the idea of primary chemo ablation of bladder cancer. So again, this is really in contrast to what we typically do, which is transurethral resection of bladder tumors, or TURBT, and then we typically use medications, but really in an adjuvant setting for bladder instillation. And so this is really a novel concept where we’re instilling a compound into the bladder, and the investigational agent is called UGN-102.

And this actually primarily treats the tumor. And so this is really as a competitor to TURBT rather than as an adjuvant treatment. And again, we’re looking at a very specific space—this is recurrent low grade, intermediate risk non-muscle invasive bladder cancer. So again, just as a definition reminder, intermediate risk non-muscle invasive bladder cancer that’s low grade is either large, meaning greater than 3 centimeters; it’s multifocal; or it’s recurrent, meaning recurrence within one year. In the ENVISION study, all patients satisfied the recurrence criteria. So these are all patients that recurred within the past year.

And so again, this is sort of a population that we see fairly frequently in our practices. They’re not necessarily a nuisance in the sense that they progress, but they recur frequently, and despite the use of TURBT and adjuvant therapies, we really don’t have great control over these recurrent low grade tumors. So I think this is something that really is relevant to all urologists.

So we’ll talk a bit about ENVISION, which is a single-arm, open-label phase III study, looking specifically at this investigational UGN-102. UGN-102 is a reverse thermal gel; it’s actually been studied in two prior large studies: a phase II study called OPTIMA, and a phase III randomized controlled trial called ATLAS, which randomized patients 1:1 between UGN-102 and TURBT. UGN-102 essentially is an instillation that goes into the bladder; it goes in as a liquid form when it’s chilled, and then at body temperature it warms and becomes a gel.

It typically coats the lining of the urothelium for anywhere from 6 to 8 hours, providing a longer contact time than aqueous chemotherapy could do. The actual active compound is mitomycin, so it’s something that we’ve used in the bladder for many decades. And again, we’re looking specifically at low grade, intermediate risk, recurrent patients. And again, we talked a bit about this patient population—it’s really a recurrent kind of nuisance population, but one that TURBT, which is our standard of care, doesn’t really do a great job addressing in this patient population because of the recurrences.

And again, when we talk about bladder cancer, we’re talking about older patients—older than the age of 75, patients who often have cardiopulmonary disease, patients who are on blood thinners because of this. And again, putting these patients to sleep under general anesthesia to do the resections over and over again really is not in the best interest of these patients. So an additional alternative that’s non-surgical is fairly appealing.

This is the study schema for ENVISION. There are 240 patients enrolled in the study. Again, all patients had a viable tumor left behind at the beginning of the study. And so all 240 patients had a tumor that was left untreated. Then they received once a week for six weekly instillations of UGN-102—this can just be done in the office with a traditional urethral catheter. And again, the design is really similar to what we see in most urothelial cancer studies, mimicking the BCG schedule of six once-weekly instillations.

The primary endpoint was complete response at three months, and so all patients underwent a cystoscopy and cytology and then a biopsy for cause at three months. If those patients were complete responders, they were then followed for a period of time with cystoscopy, cytology, and then again for-cause biopsy. So we’re going to present both the complete response rate and the 12-month durability of response rate for those complete responders. That will really be the focus of this discussion, the SUO presentation, as well as a recent publication in The Journal of Urology at the end of last year.

So the main takeaway here is that the primary endpoint for primary chemo ablation of low grade, intermediate risk recurrent tumors at three months was 79.6%. So almost four out of five patients who had an existing tumor that was not addressed by TURBT subsequently had no tumor seen at the three-month cystoscopy. Interestingly, we also get a sense of the natural history of this disease process. We looked to see what happened for those patients that were not complete responders. Some of these patients were partial responders, and I had several of these on study, where they may have gone from 10 or 15 tumors down to 2, and again made resection a more viable and palatable option.

And then we saw that overall, the rate of progression to high grade disease was low in this patient population, which is reassuring that if we use a nonsurgical approach, really only 3% of patients here showed progression to high grade disease. Which means that if you were not a responder in that minority of patients, very likely you remained in the low grade state for a salvage TURBT if needed down the road. So again, that provides some reassurance that a very robust CR rate of almost 80% is really coupled by a low risk of progression for those patients that would not be a complete responder.

And I think potentially even more importantly, when we look at those patients who were complete responders at three months, they were then followed regularly with cystoscopy. And you saw at the one-year mark, Kaplan-Meier analysis anticipates that there’s a predicted likelihood of remaining in complete response of 82.3% at 12 months. Remember, all of these patients were recurrent, which means by definition they had recurred within the past 12 months. So these are patients for whom the norm is recurring within a year.

And you can see here that with the very robust complete response rate of 79.2%, even for those patients who achieved initial complete response, a very significant proportion of them maintained a durability of response up to 12 months, really defying their natural history. On the right, you can see the swimmer’s plot for all complete responders. And again, you can see very few events, with many patients having duration of responses even beyond 12 months on this swimmer’s plot. We looked at the safety profile of these patients. In general, overall 29 patients experienced a serious adverse event; only two of these were actually assessed as being related to treatment. One was urinary retention, the second was urethral stenosis, and both of these resolved spontaneously.

When we look at the type of adverse events that patients reported on study, it was the sorts of things that we typically expect to see in a study with urothelial cancer catheterization/instillation, such as dysuria, hematuria, UTI—all things that I think urologists are very comfortable handling with a very low rate of serious adverse events. So really, in summary, we found that primary chemo ablation with UGN-102 in this patient population with recurrent, low grade, intermediate risk non-muscle invasive bladder cancer had a very robust CR of 79.6%.

And again, for those patients that achieved a CR at three months, the likelihood that they remained with the CR at one year by Kaplan-Meier analysis was 82.3%. I think this durability of response is really what, to me, is proof of principle of chemo ablation. And we’ll talk about maybe why we’re seeing such robust durability of response in patients who otherwise recur based on their natural history. And again, the overall benefit-risk profile was very favorable. Two out of 240 patients had a treatment-related adverse event that was serious; both of these were self-resolved.

And again, this supports—along with OPTIMA and ATLAS—the notion that UGN-102 may be a viable nonsurgical alternative for TURBT in this patient population. I think when we talk about limitations, one of the important factors is that tumor size would have been very helpful to give as a baseline. I’ve often been asked by other urologists about what patient volume is appropriate for topical chemo ablation versus going right to a TURBT. And again, I would say that this patient population in general has larger tumors, in general has multifocal tumors, and so we’re typically seeing a larger burden of disease. But again, this was not quantified in the study, which is an important limitation.

Our take-home message here really is: when we look at the complete response, the durability of response, and the side effect profile of UGN-102, they’re all very favorable. This really supports the further investigation and application to the FDA for UGN-102 as a nonsurgical alternative for this patient population. Thanks so much for allowing me to present these slides today. I’m happy to have a little more of a conversation about the study in more detail.

Zachary Klaassen: Fantastic. Great presentation and have really laid it out nicely. I want to circle back just to that three-month complete response rate and subsequently that almost 83% Kaplan-Meier duration of complete response, especially in those responders. Just for our listeners, just reemphasize how impressive these results are, because we’re taking a true chemo ablation population with not only great response, but durability as well.

Sandip Prasad: So it’s really interesting. In ATLAS, which I referred to earlier, this was a randomized controlled trial that actually preceded ENVISION. This was a trial that randomized these same low grade, intermediate risk patients to TURBT or to topical chemo ablation. We found that really in that patient population, the CR rate was about 70% for TURBT alone. Now these patients did not, importantly, receive adjuvant chemotherapy, and that’s an important limitation of ATLAS.

But again, we’re seeing that the natural history for this patient population really has complete response rates at three months that may be even lower in some ways in TURBT alone. So again, just setting that up against TURBT, which is clearly the gold standard in this patient population, I think that CR rate is pretty impressive. I think when we start talking about why this CR looks so good, and why the durability of response especially looks good, we have to think about the way that topical chemo ablation works compared to TURBT.

We know that most of us are still doing white light cystoscopy for low grade tumors—I certainly do. I typically reserve Cysview blue light cystoscopy for high grade tumors, for carcinoma in situ. I don’t typically do it for low grade disease. And the reality of this is that we understand with enhanced visualization techniques—whether it’s narrow-band imaging, blue light Cysview—that we’re not perfect at white light TURBT. We just don’t see everything. And so the reality is, when you start selecting a patient population that’s recurrent and multifocal, for example, probably some of these failures at three months are just incompletely missed tumors at the first cystoscopy and first TURBT—we just didn’t see them yet. They were too small or they were occult, and then three months later we began to see them.

The unique thing about topical chemo ablation is it does not need to “see” the tumor. If you’re bathing the urothelial lining, you’re agnostic to where the tumors are. You’re literally instilling and covering every surface of the bladder. So some of what you’re seeing in the CR rate is actually that you’re treating some of these very small tumors that probably, as urologists—no matter how dedicated or detailed we are—we’re just missing on traditional white light TURBT, which remains the standard approach for low grade disease. I think that also explains why there’s durability. That small tumor that may have taken three months or six months or nine months to recur, to become visualized, is getting treated at the primary treatment setting.

And so again, the reason why you’re seeing durability is you’re seeing this very broad treatment profile at the initial treatment cycle. And so again, you’re competing with what we can see compared to what is essentially a urothelial field tumor defect—we all know this to be the case, especially in this patient population. So treating the field with your treatment is actually a really elegant way of addressing this, and that helps us to understand why we may be seeing the types of numbers that appear in ENVISION.

Zachary Klaassen: That’s a great response. And I think you nailed it. We all have these patients—15 tumors, 12 tumors less than a centimeter. If we miss one of those, in three to six months, that’s the recurrence, right? Treating the entire bladder, I really like that response. You mentioned the morbidity of TURBT—elderly population. We all know, depending on the study, 10% to 15% pretty serious morbidity within 30 to 90 days of a TURBT. If we can avoid some of those TURs, certainly that number goes way down, especially if we’re not operating and putting people to sleep. When you discuss this with your patient, what’s the uptake like, and how does that conversation go? It seems like it’s well received by them.

Sandip Prasad: Yeah, so again, I’ve been a participant and the PI on several of these studies. I can tell you that for patients who’ve undergone TURBT in the past—especially those patients that have had catheters post-op, those patients that have had to hold their blood thinners, either had a bleeding event or have had the anxiety of holding a blood thinner until they can resume it—those patients were jumping at the chance to sign up for these clinical trials. So I think certainly those patients that are recurrent, that have already experienced what traditional bladder cancer management looks like, I think those patients are extremely eager for a nonsurgical alternative.

None of them really like this inherent process. They don’t like the general anesthesia, they don’t like the discontinuation of blood thinners, they don’t like talking to their cardiologist, they don’t like the bleeds—I mean, we all know this list of things—let alone strictures, urethral discomfort, etc. And so for patients who are recurrent, you’re going to see adoption, and really a lot of it may be driven by patients. For the de novo patient with a large tumor, so a patient who has a large low grade tumor, these patients are—they may pick and see which direction they go in, and all of us have had patients that don’t recur. They have a large initial tumor. For those patients, I still want to grade and stage; I’m going to do a complete TURBT. And I probably would just follow them traditionally. I don’t think that topical chemo ablation is for everybody.

But certainly when you’re talking about a CR rate near 80% and a very low progression rate, you’re not really losing a lot by offering this to everybody and then saying, “Listen, I’m going to salvage anyone who does not—that minority of patients that does end up not having a CR at three months. You’re very likely to do significant harm by doing that, and you may take four of those five patients out of the OR.” And so again, for me, it’s an easy no-brainer to say, “Listen, you can see me in the office once a week for six weeks, and I’ll just check your bladder anyway,” so the urologist is not going to lose the cystoscopy—we still need to go back in and look—but we may be able to take away all the other issues that are inherent in the morbidity of TURBT.

Zachary Klaassen: Yeah, absolutely. You kind of dovetail into my last question that’s focusing on—let’s fast forward to approval. Where do you see UGN-102, let’s say in two years, in our armamentarium? How do you think it’s going to be used for the urologist out there—community, academic? What’s your thought on the uptake and where we really can use it?

Sandip Prasad: Yeah, so again, there’s been some experience already with topical chemo ablation in the upper tract. Jelmyto was the same—essentially the same agent, using topical mitomycin in a gel form. And so this has been out on the market and FDA-approved. I think many of us have had really positive experiences with Jelmyto actually preserving renal units, avoiding nephrectomy in low grade tumors. So there’s certainly a patient population and a urologist population that is going to be familiar with topical chemo ablation, and maybe, like me, interested in offering this to as many patients as possible—especially my older patients, especially those with strictures, especially those that have to stop their blood thinners, especially those with cardiopulmonary disease where I don’t want to do general anesthesia.

Some of us are going to still manage patients with fulguration in the office. I think that’s a very reasonable strategy for small tumors that are multifocal, but I don’t think it’s as durable as this is. My patients that I do fulguration on, I’m often going back and re-fulgurating probably the same tumor again. And again, this is more comfortable for patients, and I think clearly the CR and durability are superior to what we would see with office-based fulguration. So you’re going to see multiple waves of urologists that are either going to be rapid adopters who are familiar with chemo ablation and are interested in sparing patients from the morbidity of TURBT, or you’re going to have patients who are seen by urologists who still feel that TURBT remains the standard of care.

And while I don’t fault that approach—it’s reasonable to begin to start using topical chemo ablation in those highest-risk patients. For your patients on blood thinners, your elderly patients, your patients with cardiopulmonary disease where general anesthesia does have some risk—start with those patients. That’s an easy place to start. You’re likely to have a CR rate in the vast majority of those patients, and you can salvage the others safely.

And again, you’re not going to reduce or remove the type of work that we do. We’re still going to be doing cystoscopies on the same intervals to ensure that the chemotherapy works, right? So I don’t think that this is going to eliminate what urologists do; it’s just a very new and powerful toolkit to keep some patients out of the operating room. To me, it’s hard to argue not doing this first if it’s going to be such a robust CR rate for most patients. Again, pricing and cost are going to be an important factor for any new therapy that we adopt, but when you talk about clinical data, this is very strong. And I’ve encountered very few urologists who look at these types of CR and durability response rates—especially for those patients that by definition have recurred within a year—and seeing that the vast majority of these patients are not recurring, and understanding the mechanism of why that may be the case.

When I have that conversation with people at meetings—and we’ll be presenting this again at GU ASCO next month—most urologists look at this and say, “That makes a lot of sense.” So it’s going to be like every other thing that we adopt, except for the fact that there’s no competitive alternative. It’s not like BCG-unresponsive disease where we’ve got to cycle through four or five new treatments, and how do we use them? Should we sequence? Are there biomarkers? It’s really this or TURBT/office fulguration. And so it’s a very clear alternative to what we typically do.

And in a couple of years, you’re going to see people who’ve just started with their highest-risk patients begin to see the efficacy of these types of treatments, the safety profile for patients, and begin to allow that opportunity to bleed into more patients in their practice.

Zachary Klaassen: Yeah, awesome summary. This is such an educational video for our listeners, because we’re going to start seeing this rolling out in 2025, and this is going to be a great resource for people, particularly when we’re starting to select these patients, work it into our clinical workflow. So thanks so much for the time. Wonderful discussion, and appreciate your expertise on UroToday.

Sandip Prasad: Zach, thanks so much. Appreciate it. Have a great night and thank you again.

Zachary Klaassen: Thanks.