Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, urologic oncologist in Houston, Texas, and it's a pleasure to welcome to the forum once again a dear friend, an expert in bladder cancer, and someone who's been pioneering, leading the field in an unmet area, which is low-grade, intermediate-risk non-muscle-invasive bladder cancer, and that's Professor Mark Schoenberg. Mark, welcome.

Mark Schoenberg: Ashish, thank you very much for the opportunity to talk to you this morning. It's a pleasure to be here.

Ashish Kamat: Oh, it's a pleasure to have you. We are at a pivotal moment right now when it comes to the management of non-muscle-invasive bladder cancer, specifically intermediate-risk disease, because this is a group of patients that clearly needs something, the low-grade, intermediate-risk patients. And with the FDA's approval of UGN-102, I'd love to hear your insights in general on the approval, obviously, but what it means to patients, where we are moving forward. And just to start us off, could you just summarize for the audience what this approval was, what UGN-102 is, and why this is such a huge milestone for us?

Mark Schoenberg: Sure. And thank you again for the opportunity. So UGN-102, which now carries a trade name called Zusduri, is a reverse thermal gel containing mitomycin. So it's a very familiar drug to urologists that has historically been recommended to be used in certain settings as an adjuvant following TURBT to forestall recurrence in patients with non-muscle-invasive bladder cancer. The importance of the approval is based upon data we may talk about shortly, but provides both physicians and patients with a nonsurgical primary alternative to repetitive TURBT, which has historically been the way we have treated patients with recurrent, low-grade non-muscle-invasive bladder cancer.

This is a very familiar patient population to urologists in the United States. These are older patients typically who have predictable comorbidities related to the cardiovascular system or the pulmonary system. Many are on anticoagulation for a variety of reasons. So they are tough to take care of and not optimal candidates for repetitive surgery. So the approval of Zusduri, which is delivered in an office setting as an intravesical instillation as a primary therapy for the treatment of recurrent disease, offers patients an alternative to repetitive surgery and gives physicians another tool to manage this patient population.

Ashish Kamat: And that's great, because we need options for patients. We need to be able to discuss different options that they have. Not every patient wants to have a resection, and this is clearly another alternative for those patients. And, of course, we will talk about the data and the safety profile, and you'll pull up the slides in a little bit. But just to, again, help our audience that are listening, where do you think this would fall into the workflow from a practical standpoint? Do you think people will be giving it in the office, in ASCs, more centralized? Logistically, how would you couch that?

Mark Schoenberg: Well, this drug was approved on June 12th, and the launch has just started. So right now, the drug is just entering the marketplace and obviously just entering practice. So it will be given probably initially in hospitals, maybe in ASCs, but ultimately, I would imagine it will be given predominantly in the physician office for a variety of reasons. This is actually nothing more than an intravesical instillation, and urology offices are well-prepared to give patients drugs intravesically, which we've all been giving patients for our entire careers.

These are drugs, and this is a drug, that can be given actually by an extender or by a nurse. So it does not require a tremendous amount of physician involvement. It does not require anesthesia. It's simply a matter of placing a urethral catheter into the bladder, instilling the medication as a chilled solution, because as a reverse thermal gel, it is a liquid at a cool temperature, and then as it warms to body temperature, it forms a soft gel depot that remains in the bladder for five or six hours, slowly disintegrating and delivering mitomycin to the target lesions. So patients come in, get the medicine, get dressed, and go home as opposed to the typical workflow today, which is, patient comes in, is found to have a recurrent tumor, then is prepped for the operating room.

A schedule is made. Preoperative clearance is undertaken, and all of the things we're all familiar with that are both time-consuming and resource-intensive for the management of a chronic disease that, for the most part, is not life-threatening, but very troubling to patients and very time-consuming for physicians to manage.

Ashish Kamat: Yeah. No. No. I agree with all those points. Obviously, the big elephant in the room, which you, again, are a champion of using our resources appropriately, is going to be the cost-benefit issue, but that's a separate issue. Right? That's a separate discussion. The data is obviously very important, and the ENVISION trial clearly formed the backbone of this approval. So if you can pull up some slides and we'll go through them.

Mark Schoenberg: So let me just, for the purposes of disclosure, make sure everybody understands that while I'm a professor of urology and the chair at Albert Einstein College of Medicine in New York, I'm also the chief medical officer for the company that brought Zusduri to the market called UroGen Pharma. The problem that we've touched upon already is that there are a fair number of patients in the United States who experience both the development of and then the recurrence of low-grade, intermediate-risk non-muscle-invasive bladder cancer.

And if we look at SEER data, 68% of patients have two or more recurrences, and 23% have five or more recurrences. So there are a lot of patients, as we all know from our own clinical experience, who are having lots and lots of recurrences that we are currently dealing with, predominantly in the United States, by repetitive surgical resection of these lesions in the operating room. If you look at the ENVISION trial, which is the pivotal trial that led to the approval of Zusduri, this is a medicine, again, that was given in the office once a week for six weeks as a primary therapy for the treatment of recurrent, low-grade, intermediate-risk non-muscle-invasive bladder cancer. The complete response rate six weeks after the last dose of the induction course was given was about 80%. So 80% of these patients, who would otherwise have had a surgical procedure to remove the lesions detected for inclusion in this trial, were free of disease at three months when the first cystoscopy would have been done following, for example, a TUR, given the standard of care. High-quality trial, low rates of progression, which is what you'd expect from this population.

Residual disease was present in a small number of patients, but the missing data rate was very low in this study. It's a high-quality study, I think, we can rely on. And again, this has been published in the Journal of Urology. As important or perhaps maybe more importantly, follow-up, and the durability of that complete response is very meaningful for patients and physicians, because why give a therapy that doesn't produce a lasting effect for the patient? At 12 months, following that initial complete response evaluation, more than 80% of patients who had achieved a complete response were still disease-free, and we have released information recently showing that this durability is maintained for an extended period of time. This study will run for a total of five years. So we'll be able to get to a median duration of response, but that has not been achieved yet, because so few patients are recurring who have been treated and achieved a complete response initially. There's no free lunch in urology. Everybody knows the therapy carries some risks. For the most part, the patients in this trial experienced relatively modest adverse events.

There were only two treatment-related serious adverse events. One was an episode of urethral stricture. That resolved, as well as a resolved episode of urinary retention. But again, very well-tolerated, very typical side effects of irritative voiding symptoms, some hematuria and infections, but again, very well-tolerated. The deaths that were reported in the trial were unrelated to the treatment. And again, we are talking about an elderly population. So the types of things that led to death in this population are rather expected and typical, namely cardiac events, pneumonia, and the like.

One thing that is important to emphasize is that research has been done on patients undergoing this therapy, and these are patients who have experience with TURBT. Angela Stover at the University of North Carolina has kind of independently taken a look at the population of patients treated with Zusduri in the clinical development program, and the themes that have emerged from her interviews and the questionnaires that she has used to study this question show that patients find that treatment with this nonsurgical therapy is associated with a minimal impact on activities of daily living and, particularly compared in their memory to what they experienced with TURBT, less adverse impact on work, recreation, sexual activity, and the like. Less bleeding, fewer catheter issues associated with this treatment, and that patients would recommend this to other patients considering therapy for recurrent disease.

So I think one of the things we're all very sensitive to is thinking about patient-centric care and deintensifying therapy for a disease that, again, is not associated with a high rate of mortality, but a very high rate of recurrence and patient inconvenience and discomfort. So, again, Zusduri does provide physicians and patients with what appears to be a very promising and effective and safe alternative to the standard of care currently, which is TURBT, and really will, I think, be very popular both for docs and for patients for a variety of reasons we've touched on, but it's going to be a very useful medicine for the appropriately selected patient.

Ashish Kamat: Great. Thanks so much, Mark. Again, this sort of falls within the realm and what we in the International Bladder Cancer Group and the community in general, including Beacon, has been trying to say, which is we need to offer patients deintensification of treatment when appropriate and, obviously, when it's appropriate, ramp up treatment too. Right? But patients that have these tumors don't often tolerate the anesthesia and other things that go with it. So having this option is really great. I'm going to have you put on your hat now as an expert bladder cancer physician. Right? Not the medical officer, and I'm glad you made that disclosure early on. Tell us a little bit about the ATLAS study, because the question often comes up saying, "Yup. ENVISION wasn't randomized. ATLAS was." And people get lost in the weeds a little bit. Tell us a little bit about the ATLAS study and the decision to move forward with the ENVISION as the pivotal trial.

Mark Schoenberg: Thanks for the question. The answer is, as you are alluding to, somewhat nuanced and has to do with complexities related to trial design, comparing a surgical treatment to a nonsurgical treatment. We spent hours working with the FDA initially to design the ATLAS trial, which was, as you point out, a randomized trial comparing primary treatment with UGN-102, now Zusduri, compared to primary treatment with a TURBT.

Due to issues that the FDA raised in the course of designing that trial, demanding, for reasons having to do with statistical considerations of the trial, that a superiority outcome be achieved. We felt at the time, because we had a lot less information about how UGN-102, Zusduri, worked in this population, we had very low confidence that we would be superior to TURBT, and we felt it was really an unfair comparison or a bar to require that this drug be better than surgery in the treatment of this population of patients, because as we understand clinically, even an equivalent outcome would have been clinically meaningful and useful to physicians in the treatment of this population.

So for a variety of reasons, even though the ATLAS trial actually demonstrated, and there are statistical nuances that are clearly delineated and discussed both in the body of the article that appeared in the Journal of Urology as well as editorials that appeared after the publication of that article, despite those nuances, the ATLAS trial did actually show that treatment with Zusduri produced a better outcome and a greater benefit in terms of durability of response than TURBT. A caveat of that study, which has been widely disclosed and pointed out by many experts, is that the control arm was TURBT only and did not include adjunctive therapy. And while we could debate the merits of that, the decision to make that control arm look the way it did, an interesting side point to keep in mind when looking at the ATLAS data, which are complicated, is that in the United States, to the extent that the peer-reviewed literature is reflective of contemporary practice, only about 20% of American patients get adjuvant therapy.

So the majority of patients are actually undergoing TURBT as monotherapy. So the ATLAS control arm, while academically controversial, and it's been discussed in the literature, is actually probably a very clear representation of how patients are currently treated in the United States and what results we could achieve with surgical monotherapy, which is, again, how most patients are managed.

Ashish Kamat: Yeah. And again, Mark, thank you always for being so candid and open. I mean, again, you and I have debated this, and I am one of those experts that said, "Hey, listen, why this control arm?" Right? We need to ramp it up, and I totally recognize what you're saying. The standard of care in the U.S. is monotherapy, and pretty much that's what you went against. So thank you for being candid there. As always, it's a pleasure chatting with you. And in closing, if you could just highlight for the listening audience, in your expert opinion, and obviously, I know you have to follow the label, so you will, but in your expert opinion, who is the ideal candidate for this therapy?

Mark Schoenberg: Thank you. The appropriate candidate is the candidate described in the label, namely that patient who meets... And I'm carrying coals to Newcastle here, because, of course, you've led the charge in identifying and defining the intermediate-risk population for us, starting back in 2014 with your seminal article on the subject, but it's the patient with recurrent, intermediate-risk disease, who has low-grade histology. Physicians will obviously make their own independent decisions about patient selection, but it's very clear that that is the FDA approval in the label, and the details of what an intermediate-risk patient is, I think, now, thankfully, pretty clear to the urology community, patients with multifocal disease. A solitary tumor greater than three centimeters, but low-grade histology.

Of importance, all of the clinical development program that UroGen undertook focused on patients with low-grade disease, and there is, as you've pointed out publicly, some controversy about the inclusion of small high-grade tumors in the intermediate risk population. So for the purposes of this conversation, it is important to point out that we don't have data in high-grade histology, and physicians should be aware of that.

Ashish Kamat: Great. Thank you so much, Mark. And as always, it's a pleasure to have you on.

Mark Schoenberg: Thank you so much for the opportunity. Have a great rest of the day.