Zachary Klaassen: Hi, my name is Zach Klaassen, Urologic Oncologist at the Georgia Cancer Center in Augusta, Georgia, and I'm delighted to have back on UroToday, Dr. Sandip Prasad, who is a Urologic Oncologist at Atlantic Health in Morristown, New Jersey. Today we'll be discussing the ENVISION trial in UGN-102, and some exciting updates that actually came out over the last couple of weeks with regards to duration of response. So Sandip, thanks for joining us back on UroToday.

Sandip Prasad: Zach, thanks again for having me. Always excited to provide updates about this important study.

Zachary Klaassen: Yeah, it is important, and you've been generous with your time in the past, and we're excited to have you on to discuss these longer-term outcomes. But before we get into that, maybe just level set for our listeners why it's important to have options for low-grade intermediate risk nonmuscle-invasive bladder cancer?

Sandip Prasad: So first, it's actually a pretty significant proportion of all bladder cancer. Anywhere from 30 to 40% of bladder cancer patients are going to have this phenotype. It's really characterized by low-grade disease. So very few of these patients, maybe in the upper single digits, are going to actually progress to invasive disease or high-grade disease. So it's really primarily a disease of recurrence, but unfortunately it is a disease of recurrence. So this brings patients back to the operating room. It's typically defined by really one of three characteristics. Tumors are either large, greater than three centimeters, they're multifocal, or they recur within a year. So again, all of these characteristics make them not so amenable to just easy office fulguration and really require patients to go back typically for TURBT and then intravesical therapy if desired.

But really by definition, this is recurrent low-grade disease, which again, most of us don't find in our practice is a life-saving disease that we have to encounter. But it actually fills up a lot of our operative schedule. It's a lot of our patient visits, potentially complications, bleeding events, ER visits. And so we've really only had TURBT historically to help manage this. And so it's really been needed that we have for this not terribly aggressive disease, some not terribly aggressive treatments, and I think that's really where UGN-102 potentially provides an option for patients.

Zachary Klaassen: Well summarized, as always. And I think we've talked about the fact that multiple anesthesias, these anesthetics add up on these patients, especially if they're elderly, so absolutely, absolutely true. The ENVISION trial, you were heavily involved in that. Maybe just give our listeners an update on just the trial design for ENVISION.

Sandip Prasad: Yeah, so this study agent UGN-102, I think we've talked about it before, but just as a reminder, it's a reverse thermal gel. It's really the opposite of water. So when you cool this gel on ice, it becomes a liquid. Then we instill into the patient's bladder through a traditional urethral catheter, just a 16 French catheter, and then it warms in the body, and when this fluid warms, it becomes a gel. So really the opposite of water. On ice, a liquid, and when it warms, it becomes solid. But really this allows you to basically coat or spray paint the entirety of the bladder lining, and really importantly, this treatment which uses mitomycin as its active agent. So it's something we're all really familiar with and have used for many decades. It's really this contact time that the gel affords.

So unlike a typical aqueous mitomycin where we leave it in the bladder for let's say an hour after a TURBT, once a patient voids it out or you drain with a catheter, that medication is gone, it's not going to provide any additional benefit to the patient. These topical gels essentially allow contact time, typically for around six hours or so, but really up to almost 24 hours. And this prolonged contact time actually allows for a really novel approach, something called primary chemo ablation. Chemo ablation, the idea here is that you don't do a TURBT. Essentially, the medication itself melts away the tumor. And so we find that really these tumors don't require TURBT, and so we wanted to study if this gel was something that we could utilize as a primary treatment for bladder cancer, specifically looking at these recurrent intermediate low-grade disease tumors.

So ENVISION, single-arm study, 240 patients, all patients received study treatment. So patients received a gel once a week for six weeks, and then we went ahead and investigated these patients with cystoscopy, cytology, and for-cause biopsy. So again, all patients received treatment in the office, traditional urethral catheter, the same way that we always manage patients, and we inspected the bladder. The primary outcome was a complete response rate, and what we found was that 80% of patients who had no TURBT but had a pre-existing low-grade tumor defined as recurrent and intermediate risk, had no bladder cancer left in the bladder after a series of six treatments. So again, a really novel and sort of innovative treatment type that we don't really have anywhere else in neurologic oncology except actually in the upper tract for low-grade disease, a treatment called JELMYTO, which is really a similar agent using mitomycin.

Importantly, on the first study, we also followed patients with cystoscopy every three months, and then at 12 months, we inspected patients' bladders again, and this was now after four consecutive cystoscopies. And for those 80% of patients that were complete responders, 82% of those patients maintained that complete response at 12 months. Remember, these were all patients that had recurrent low-grade disease. And so again, this is something that suggests that maybe we're actually changing the natural history of this disease type, and I think this makes sense for bladder cancer. We think of bladder cancer as a field treatment. I'm sure you tell your residents this, I tell my residents this all the time, but we've historically managed this field disease with localized treatment, TURBT. So field disease, getting field treatment is sort of more intuitive that it may be effective and maybe even treating those microscopic or small tumors that are occult that can't be visualized.

Zachary Klaassen: Yeah, great background on the study. And now we fast-forward to August of 2025 and now we have longer term duration of response, walk through those new updates for us and how maybe we interpret this, how we explain that to our patients.

Sandip Prasad: So again, it's really important to realize this study has no maintenance. So patients received once a week treatments for six weeks. Again, they had a cystoscopy at three months, they were clear. That was 80% of patients. Then we actually did cystoscopy every three months for the first two years. So again, this is a pretty tight surveillance schedule, more than we probably would even do in practice. So now patients are getting cystoscopies every three months with no maintenance treatment in the meanwhile. So I told you about the one-year 12 month data that's 82% of patients maintain their complete response. When we followed those patients for another year. Now, again, this is two years out from their initial treatment, actually more than two years, it's two years out from their cystoscopy at three months. We saw that 72% of patients who had a complete response over two years prior maintain that complete response and again, with no maintenance therapy.

And I think this is really sort of where the most exciting parts of, in my opinion, UGN-102 study proceeds is that we're treating tumors now that probably would have popped up in this, again, this phenotype of recurrent disease. We would've probably seen these tumors at three months, six months, nine months, or 12 months. We just didn't know to treat them the first time. The study agents, again, this instillation procedure, it coats the entire bladder. So I think we're treating them all down to the microscopic level or even the molecular level in a way we've never done before. Probably not so much a fair statement, maybe we did do that with BCG, but we don't do that when we do just a TURBT or a fulguration.

And so it's actually creating a field effect, treating this field disease. And as a result, we're seeing much more durable responses. And I think these are remarkable responses in a cohort of patients that we all have, and we all know typically recur, and recur, and recur. And so I'm actually honestly excited to see what further long-term data shows. The final data I can tell you is that actually, at this point, the data are very mature. So we've had now, patients have been followed for almost four years from initial treatment. And so we have not just the 12 month data, we have two-year data. We have three-year data, and it continues to be stable out at 70 to 72%. And so I do think we're talking about data that reflects true field treatment and the effectiveness of it.

Zachary Klaassen: Yeah, it's super exciting. And just for context, because I think the listeners will appreciate this, these data with regards to the two-year data were just presented at the Bladder Cancer Advocacy Network think tank just a couple of weeks ago. Is that correct?

Sandip Prasad: Correct. Yeah, so it was presented at the think tank meeting and it actually will be or has been presented now at the AUA meeting as part of an oral session.

Zachary Klaassen: Great. Perfect. So now we shift a little bit. We've got the data. Obviously, probably most of our viewers have practices where they think low-grade intermediate-risk disease fits into their practice. How have you actually practically incorporated UGN-102 into your practice? And how should other people do the same thing?

Sandip Prasad: Yeah. So I think it's a really good and important question. And I think we talk about sort of the work flow, which I think can be easy. I think there is a learning curve as to who are the patients to use this for. And so maybe I'll talk about who are sort of the optimal candidates. I think we can certainly come back to the workflow aspect of it. So the first thing is, how do you bill for it? And I think this was sort of a big concern initially. Is this buy and bill? It technically is, but I would say that if you're in a community center and you're in a multispecialty group or you're in an academic center, the idea is is that at the end of the day, probably 99% of patients are going to be covered for this drug. So it's not like sometimes when we send things out and we have patients call us back and we're worried about that. This is again, a drug that is actually covered by almost everyone, part D, all the commercial plans, Medicaid, those that are part D eligible. And so again, there are always some private plans that maybe don't cover it or are some gatekeeper plans where there's some concerns. The idea is that UroGen has to actually provide the drug to your center.

And I think we found that UroGen has been very helpful to actually triage if there's, for example, preauthorization that is required. But again, I think financial toxicity is going to be very, very limited here. I would estimate it to probably be less than about 1% of patients. So again, I think if you're worried about that, for whatever reason, there are potential billing codes that you can consider if you're not comfortable with buy and bill, but they require a site of care designation. And so there's potentially codes you could use, say if you're an academic center that has a 40B type approach where maybe you can bill and collect certain monies and then eventually get the drug delivered, et cetera. So I think the opportunity to get the drug into your practice, and I think the coverage is going to be more straightforward than we probably have dealt with in our BCG unresponsive space for some of the earlier drugs. But again, that's because the drug's been out for a few years now, and obviously through the NDA and FDA, there is data to support sort of those requirements.

So I think from a workflow standpoint, getting it actually into your practice and actually administering it is pretty easy. I think there are some groups, and I think you guys may be considering this too, where the idea is our reps are actually going to travel and administer the drug. And so I actually have not done this in practice, but we had one patient who was in a wedding for his daughter, was traveling for several months. And so UroGen actually sent a representative in two different cities to deliver the drug and administer the drug on this patient for a few of his once-weekly treatments. So again, if you're really concerned about workflow and really just even getting started, there is actually I think a potential offering there for groups that may be a little more concerned about that aspect of it.

That being said, the way to integrate into your practice is very, very easy. We have our nurses that do our BCG and other intravesical treatments simply administer this treatment as well. I think UroGen, the company that makes the drug, now calls ZUSDURI after FDA approval, is really helpful to sort of bring in a team to help you understand what you have to do. It's again, pretty easy. The drug is delivered, it's very easily constituted. It's chilled, and then it's instilled via urethral catheter. Actually, it all comes in one kit, so everything's in one box type of treatment. We integrated it into our intravesical treatment program, so our nurses do it. We don't have a PA or NP or MD administer the drug.

So it's really easy to sort of drop in the mix of everything else you do. It's once a week for six weeks. So the scheduling is really easy for our offices to do. Again, similar to almost everything we do, and there's no maintenance. So patients really like that idea that, Hey, I can get this series of treatments and be done. And that's obviously different than what we do with, for example, adjuvant chemotherapy where we're often giving monthly treatments as well. So integration into the practice is really easy.

I think our job is to identify those patients that you think will most likely benefit from them. And then UroGen has a very easy enrollment form online, which basically allows you to contact them. They will help you with benefits review. They also provide a warranty against if they say that a drug is covered. And down the road, if you find that it's not, there's an ability to get a rebate for that drug that's delivered, which I think again, protects practices that are looking for, are concerned about financial risk for some of these agents. And so I think again, our job is really let UroGen help us with the benefits, and our job is to find those clinically important patients to treat. And I always sort of think about three primary patients. I don't think it sort of fits into every single patient that has low-grade intermediate risk disease, although you certainly can offer it. And I would tell you, the more patients you offer it to, the more patients they're going to want it.

Especially those that have had TURBTs, they're very happy to go and not come off their blood thinners. Very happy to not go to the surgery center, have a family member drive them home. We often underestimate, we talk about a couple days of burning, maybe a couple days of blood. When you actually query patients and actually get them to quantitate those, they're actually much, much longer. I think we actually underestimate what patients go through, even for a fairly small TURBT in a surgery center.

But for me, it's really three patients that I think most benefit. The first I think is fairly obvious, it's patients who have unresectable or very large volume low-grade disease. I think I've mentioned this to you, but on study, I had put a patient on this. I think I talked to you about this, 50 or 60 tumors in the bladder, never ever cleared him. I really was trying to get 60, 70% each time. Gave him the drug. He actually didn't completely clear. And so he's actually one of the 20% that failed, but had just lateral wall tumor. I resected him. He's now three years out disease-free, getting annual surveillance, and he's a study failure. So again, I think those patients that have very, very large tumor volume, that's very difficult to resect up at the dome, deep in the posterior wall, maybe bladders that are very tall and hard to reach with a resectoscope, a great initial agent to use. That's maybe 5% of patients.

I think patients that you clearly are not succeeding with the existing strategy, so I do have some patients where I think I'm doing a really good job. I take my time on the TURBT, I'm giving adjuvant chemotherapy for an hour afterwards. Sometimes I even give intravesical chemotherapy for adjuvant treatment, yet they recur every three to six months, and they're recurring in different spots. It's not that I'm just adjacent to a prior resection site, they genuinely have a field tumor. And again, I think those patients merit from a different approach than just TURBT over and over again when you know your gestalt is that this isn't a successful strategy for this patient. For me, that's again, about maybe 10 to 15% of patients.

And I think the final group of patients are those patients that have some sort of comorbidity. These are older patients, patients who are on blood thinners, patients who have anesthetic complications. My patients who are on oxygen in the pre-op area, the pulmonologist is clearing them before every one of these procedures. I think you really have to offer those patients an option for a non-surgical alternative. And I can tell you 100% of those patients are going to choose to do that rather than going back to that room, because they really, really get anxious about discontinuing blood thinners or they restarted it, but had to go to the ER with clot retention. Again, maybe 10, 15% of patients. But when you add those numbers up, you're talking about 25 to 30% of our patient group for this. And that's a lot of what we do.

I also tell urologists, you still have to do the cystoscopy. You're not giving up procedures, you're not giving up the care of the patient. You're still going to check their bladders to make sure the treatment works, but you're going to offer a treatment that works in the vast majority of patients and honestly, may be more durable than what we do right now. And so again, I think for those patients, it's sort of my first line offering. I actually mentioned it to all patients. I think if a patient has done really well but recurred two years later with a small tumor, I often actually do surveillance. So I don't think every single patient that recurs needs this treatment, nor do they even need a TURBT in every setting. But I think those patients where you have the general feeling that, "What I'm doing right now with TURBT just isn't working." And I think all urologists know who those patients are in their own practices. That's where you start.

And then I think as you begin to integrate this, realize how simple and straightforward is to instill in the office once a week for six weeks, your office gets more and more comfortable with just integrating the workflow, which is very straightforward. And I think we've had to do this with all the new agents that have been in the BCG unresponsive space, it's not just BCG anymore. And so when we look at our BCG clinic, it's actually not that much BCG in the BCG clinic anymore. A lot of other things that we give, so I think it's just another one of those agents and more are coming. The idea of chemo ablation is going to become, I think, a standard paradigm in intermediate risk low-grade disease. This is really the first and I think very effective option for patients, and I think more is coming down the way.

Zachary Klaassen: Awesome. That's a great update, Sandip. Always enjoyed high level discussion. Any take home messages? Anything we didn't hit on before we wrap it up?

Sandip Prasad: No. I think again, I think as urologists, we're sort of always obligated to talk to patients about the new treatments that are there. It's always up to our discretion whether or not we think they're the right treatments to recommend. But I think it's sort of time that we begin to integrate the idea of chemo ablation into the management of low-grade intermediate risk disease. And if you put it alongside TURBT for our patients, I think you're really giving them sort of two very distinct, but effective options. And I think it's important for patients to have the opportunity to choose.

Zachary Klaassen: Yeah, absolutely. Sandip, always generous with your time. We really appreciate it. Thanks for joining us on UroToday.

Sandip Prasad: Thanks, Zach.