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Sam Chang: Hi. My name is Sam Chang. I'm a urologist at Vanderbilt University Medical Center, and we have one of the true experts in bladder cancer. And we've asked Dr. Sandip Prasad, Dr. Prasad is actually the vice chair of urology at Morristown Medical Center and serves as their director of GU Oncology Surgery.

And so we've asked Dr. Prasad actually a little bit about the ongoings of a new agent that has recently been FDA approved for the treatment of patients with low grade recurrent intermediate risk bladder cancer. So, Sandip, thanks so much for spending some time with us.

And I was just going to start off with a little bit of background regarding your role as basically the lead author for the ENVISION trial, that basically I think was probably the basis for FDA approval. Let's start off with your role on the ENVISION trial.

Sandip Prasad: Sure. Thanks, Sam, and thanks to UroToday for being able to speak a bit about what I think is a really exciting, potentially paradigm shifting change in the way in which we manage bladder cancer. And we'll talk a bit more about that as we get into the study agent UGN-102 now approved, called ZUSDURI and available for use as of July 1, I believe. So really a timely topic for this conversation. But again, just FDA approved a couple of weeks ago.

So the ENVISION trial really piggybacked on two other trials using this study agent UGN-102. The first was a phase 2 study called OPTIMA II, and the second was a randomized controlled trial between the study agent and TURBT called ATLAS. But the ENVISION study, I think, was the pivotal study that was really what led to approval of ZUSDURI for this disease space, intermediate risk, low grade nonmuscle invasive bladder cancer.

And I think, Sam, you know we're seeing a lot more interest in this particular space over the past year to a year and a half with a lot of new trials looking in the adjuvant setting for this disease space. But UGN-102 is a bit different. It's primary treatment. So this is the idea of primary chemo ablation using a nonsurgical catheter installed agent. It's a reverse thermal gel.

So when you cool it becomes a liquid. It goes into the bladder via catheter. This can be done in the office. You treat patients once a week for six weeks, and you see if the gel itself will actually chemo-ablate or dissolve away a tumor in the bladder. And so these index studies where a tumor is left behind and then re-evaluated after treatment, I think is becoming more and more common.

We're seeing this, for example, with the J&J TAR product as another example of this approach. And in ENVISION, all patients had recurrent disease. So these were not de novo diagnoses, and that's important because that's on the label.

For the OPTIMA and ATLAS studies I alluded to earlier, you could actually enroll new patients, but for the study label and for ENVISION, all patients had recurrent disease. And I think that's important. I think doing a proper TURBT on any bladder tumor is important to discern between low grade and high grade disease. I'm not sure that visually we're perfect at doing that.

And so I think it's really important that patients are fully staged, they're graded. And then once you know that they're low grade disease, it's not that common that patients cross over into the high grade space. At that point I think the agent's appropriate, if you're a recurrent patient.

The intermediate risk space, as you know, but again, just to remind everybody because I think these are new definitions that we're going to be using really often now, these patients have to have multifocal disease, and that was the majority of patients on the ENVISION study. 83% of patients had multifocal disease. And so these are the patients that have small tumors throughout the bladder.

And ENVISION, when you aggregated tumor volume, the investigators estimated about 2.5 centimeters of disease. So I think it's a real amount. It's not the amount that we can just get away with office fulguration with a very small 1 millimeter papillary lesion or something. 2.5 of multifocal disease, I think is real disease that probably most of us would tackle with the TURBT.

And so ENVISION looked at patients that were either multifocal, they were recurrent within 12 months, or they were above 3 centimeters. And again, you're looking at, I think, what is real disease that most of us do not manage with office full duration, which again, I think is a nice approach for that solitary, tiny papillary tumor or even active surveillance of these small tumors.

But when we asked study investigators in ENVISION how they would approach the tumor burden they were seeing, over 95% of patients said it required a TURBT, could not be managed with full duration. So I think this is real recurrent low grade disease that's multifocal. 240 patients who are in ENVISION, all the patients got the study treatment, over 95% of patients were able to complete all six treatments. So I think that's important.
You're not really seeing a discontinuation rate or an intolerance rate that's significant. When we look at study related adverse events of patients, only two out of 240 patients had an adverse event that was deemed grade 3 or above. One was urethral stenosis and the other was urinary retention.

Both of these resolved spontaneously in patients with catheterization and just a little bit of time. So again, that's only two out of 240 patients. So I would argue again, a well-tolerated treatment.

ENVISION importantly showed a really completely robust complete response rate at three months. So remember these are patients with disease, again, the majority multifocal on average about 2.5 centimeters that were not treated surgically. And then once the treatments were administered in the office with the catheter, these patients are then evaluated at three months. And 78% of these patients had a complete response visually. They also had negative cytology, which is expected in low grade disease and if needed, a for cause biopsy.

So I would just start off with that's a pretty impressive number in my opinion. Over three out of four patients had a complete response to a topical agent without going to the operating room. And I think very importantly, when we look at these patients and say, OK, well, how did they do going forward? These are recurrent patients, this disease comes back.

I think this is really where these topical nonsurgical options, I think are really innovative in that I think the durability is actually potentially better than what we see with TURBT. And you and I both know that TURBT is limited by what we can see. And we know that what we see with white light, which is how most TURBT are done, is not perfect.

We know that narrow band imaging helps, we know that Cysview and blue light help. And the reality is that TURBT is subject to what we can see and what we remove. These types of field treatments are different. They are coating the entire lining of the urinary system with the agent.

So whether you see it or not or it's tiny or not, it's getting treated. And that's where I think you begin to see some of the separation in terms of prior studies that show that these recurrent patients are generally going to recur within a year. When we look at complete responders, 79% of patients that completely responded at three months, when followed out a year later with cysto every three months, 79% maintained their complete response.

So again, I think that many of our recurrent patients, we just didn't know that they had a tiny tumor at the time of the first TURBT, and it took three months or six months or nine months for us to see the recurrence and then treat it. This is agnostic to where the tumors are, everything's getting treated. And I think that's the really, I think, special thing about topical chemo-ablation, whether it's with ZUSDURI or maybe some of the agents that are coming forward.

Sam Chang: Well, Sandip, that was a really, I think, excellent focused overview on a multitude of patient prioritization in terms of what therapies are, really patients that are most applicable to get this treatment. Secondly, the long term durability and the significant complete response rate, this is a paradigm shifting, just as you said, treatment option for patients in that we previously had surveillance or office for duration for those smaller tumors.

But then for those tumors that were larger, the vast majority would need to go to the operating room. And so, a concern that people would say, well, if you go to the operating room, you can give them adjuvant chemotherapy, they're not likely. In today's practice in the US, the use of adjuvant intravesical chemotherapy as you know continues to be somewhat limited.

And I think that's the key distinction is, it's adjuvant treatment. It's after a TURBT, after the general anesthetic. So I think all those points you raised, I think were really, really important.

I know you actually presented at the ODAC committee regarding your patient population, your role as a principal investigator, your findings. What do you think really had the ODAC come with a split decision of five to four, not to support moving ahead with this drug? What do you think really held them up?

Sandip Prasad: So it's a great question, and I thought it was a really interesting process to dialogue with. And I know you and I have talked about this as well prior to this conversation. So again, four to five against support from the ODAC. It was a very interesting conversation.

I think that it was clearly acknowledged that there was a clinical need for something else for urologists to use in their armamentarium. Both urologists that served on the ODAC voted for approval of the agent. I think that's really important.

As you know the ODAC is comprised of other folks that may or may not treat urothelial cancers, that does occur. There's radiation oncologists, there's medical oncologists. These are not folks that generally treat nonmuscle invasive disease and certainly not low grade nonmuscle invasive disease.

And I think what the biggest critique was, and I think it probably extended down to this study was that, there was a desire to see more randomized controlled trials in this space. Now, you and I both know that in the BCG unresponsive carcinoma in situ and high grade space, single arm studies were allowed for this space fairly routinely. And many of the agents that we now use and that have been approved came through with single arm studies.

When we look at the population of patients that received UGN-102, you're looking at over 500 something patients. And the argument, I think, was that not that necessarily this should replace or compete with TURBT, but that this is potentially just a meaningful alternative in those patients for whom TURBT may or may not be the right approach, but it just gives the urologist a different approach.

So a little bit of this, I think, may have been that no matter what the clinical data were to be that the lack of it being a complete clinical trial and ENVISION being a single arm study, albeit 240 patients, which is much larger than we typically see for other agents, especially in the BCG unresponsive space, that it was an uphill climb no matter what. I think that's the dialogue that I got, and I'd be curious to hear what you thought because I know you were there as well.

Sam Chang: I agree with you. I think it was almost a sense of let's have the process trump the reality of the problem and the findings. In other words, we understand all of us that statistically, the validity of a randomized controlled trial really does carry significant weight trumps a lot.

But I don't think and this is what I think was lost by the ODAC, was that there is a benefit here. In fact, the presentation put forth basically said, look, 80% of the time, yeah, you're not having to do a resection, you are eliminating at least resection. Oh, but we're not so sure what's going to happen down the line.

Well, what the clinicians and the urologists specifically said on the panel as well is that, these are patients that are already recurrent. These are patients that have already shown a trend. These are patients that have shown that basically what we have done in the past has not been that useful.

So I think it's actually to the FDA's credit that they understood, took the advisement of the ODAC and looked at the data though as well, and basically came to the approval of this use in addition to continued postmarketing study, analysis, long term follow up. But I think it's really, I think, beneficial for patients.
And that's what I think the vast majority of us feel, is that this is going to be an option for patients, which then leads to my next question for you is, how do you visualize incorporating this into your practice? Obviously, we had clinical trials, we use a type of this formulation in the upper tracts with Jelmyto. So how do you see this being integrated into a busy practice like I know you have?

Sandip Prasad: And I think there's probably a couple of reasons why these agents will be in use. The first I think is actually quite a bit will be driven by patients. I can tell you I was the lead investigator on ENVISION and an ATLAS, the randomized controlled trial between this drug and TURBT.

And as you know from being a lead on many trials that it's hard to randomize patients to a medicine versus surgery. It's giving up a lot of autonomy for a patient to allow the coin flip to tell them if they're going to the operating room or getting a drug. And I can tell you we accrued so rapidly to those two trials in our site. Patients want the option, these are recurrent patients.

They know the TURBT, they know the experience. I probably saw five or six patients in clinic today, the rebleed at day 7, the bladder spasms, the pieces of debris that pass through. This is not a pleasant experience for these patients from the moment they sign up for it. It's a real operation.

And so patients who are recurrent, they know what they're getting into. And I can tell you patients are seeking out this option. And obviously because I've been very involved with the agent from a research perspective, I have patients who ask me every time they see me, where are we at with the drug? And it's nice that for the first time I can tell them, hey, we have something actually clinically available, but these are patients who are actually waiting for this, who are undergoing TURBTs knowing there's repetitive disease. So some of this is patient-driven.

I think we all have in our practices certain patients who are clearly the first ones you're going to want to use this on. The most obvious are those that are really frail and probably unfit for the operating room in general, and you're triaging them with fulguration and a little bit of surveillance there, have urethral strictures, they're on anticoagulation, they're not supposed to stop because they've got a valve. They've had complications after every TURBT.

And the reality is these patients all exist in busy bladder cancer practices. And you do your best to triage the situation because it's low grade disease, they're unlikely to die from the disease, but they can have morbidity from bleeding and other events. So that's clearly a very, very easy first spot where these patients are not really being offered the standard of care TURBT for clearance anyway. I think that's probably the first.

The second patient population that I think this is really valuable and I put on trials are those patients that I just can't completely resect. It's not a huge proportion of patients, but I probably have 5% of my patient population where anterior dome, 25 tumors, I just cannot do it. And again, it's low grade every time. And so I'm not scared about the metastasis.

But I recognize that when I take them to the operating room, again, I'm in triage mode, but I'm really never completely clearing that patient. I talk about this quite frequently. I had a patient on trial, a Vietnam vet, I look in the bladder and I'd estimate 30 to 50 papillary tumors every time, measuring from 2 millimeters up to 2 centimeters, TURBT him for five to six years.

I put him on study and he went from the first response to three month response assessment, he went from 50 tumors to probably about four. And so he actually is a treatment failure. He's one of the 20% that it didn't work on. I then resected him completely. He's three years out, he's disease free.

I have taken care of him for five years, never getting probably below 25 tumors, looking every three to four months. So there's a role for that patient which I think is maybe the most important patient to put this on. And I think for me, those are patients I already have in the back of my mind that as of July 1, I'm going to re-approach this patient when their TURBT arises and allow them to potentially consider the treatment.

Then I think there's probably a softer group that comes second. Patients that are obviously highly recurrent, where we just feel TURBT isn't working, I think it's a really nice group to offer this field treatment again. And then the last are probably those patients that recur really rapidly or have a significant complication of TURBT, where you really are going to have a hard time convincing them to go back.

But I think honestly, it's in the conversation for every patient. It's an 80% complete response rate and arguably a durability rate that's maybe better in recurrent patients than what we do naturally. I think you have to talk about it. I'm not sure it has to be what you propose in every patient, but in my opinion, I'm not sure there's many patients for whom you shouldn't at least make them aware of the availability of it.

Sam Chang: I think really real world. Every scenario that you have brought up, everybody has examples of those in their practice. And to have another option is just I think and for the patients that understand the pros and cons of different treatments, you'll be hard pressed for someone to say, well, why don't we try this?
And I understand people's hesitance, people being both physicians and patients regarding the possible, what about the possible side effects of mitomycin and this and that. And I think a key point is the one that you've emphasized throughout is that this medication is given not after a TURBT.

This is the chemotherapy agent in the bladder basically non-TURBT naive so that in a sense that you won't get or you won't see that in the study in terms of the calcifications, the poor healing, the eschar, those types of things.

So understanding that and also getting some experience from the Jelmyto with careful administration, understanding the pros and cons, we're not seeing the stricture rate. We're understanding the impact and its efficacy. I think just having this option and I think patients are quite fortunate that it was FDA approved.

But I think more importantly, they're quite fortunate to have leaders like you, Sandip, who have done the research, who have really advocated for patients and for the inclusion of research and evaluation of new medications. And that's what helped bring this to actually FDA approval.

So many thanks to you and a credit to all your efforts and to your team's efforts. And we look forward to future research, and we look forward to your real world experience with ZUSDURI and how that is going over time. And I'm sure as we gain more data, we'll get even a better understanding of its efficacy and its best use profile.

Sandip Prasad: Yeah, it's an exciting time. Sam, thank you. And those are really kind words, obviously a huge research team and many sites and investigators really accruing patients rapidly to these studies to allow us to turn a study that opens and closes within a year and allows a drug, this was published in February and the drug is approved in July. So really, I think--

Sam Chang: That's amazing.

Sandip Prasad: --credit to both the research component of things, but also to the clinical importance of these types of agents, achieving and getting into the workplace for us. So it's really exciting. And I think that it's rare and fun to be part of something that really shifts urology a little bit. And so it's exciting to see what this may do in the future for us. But any tool like this that really gives you something else that can help a patient out is just tremendous.

Sam Chang: Well, thanks again for spending some time with us, and I think I'll end with that point. This is the first approved medication for bladder cancer in this disease population, never had one FDA approved before. We had others that have attempted in different trials and in different focus groups, but this is the first. And like I said, you deserve huge, huge credit.

So again, kudos to you. Thanks to you. And we look forward to future research and everything that you contribute. So thanks again Sandip. We appreciate it.

Sandip Prasad: Thank you again.