Sam Chang: Hi. My name is Sam Chang. I'm a urologic surgeon at Vanderbilt University Medical Center. And we really have great fortune to be joined by Doctor Patrick Hensley and Doctor Janet Kukreja from University of Kentucky and University of Colorado, respectively.

And they were asked by the AUA in 2025 to actually give the key takeaways associated with the bladder cancer presentations for the 2025 meeting. So, Patrick and Janet, thank you so much for spending some time with us. And we look forward to you guys telling us the key highlights and key takeaways from this year's meeting.

Patrick Hensley: Thanks so much, Sam and UroToday for having us this morning. We'll get right into it. So first we're going to start with some kind of landmark trial readouts in the non-muscle invasive bladder cancer disease space.

We did see some readouts for intermediate-risk non-muscle invasive disease. An ablative trial in the ENVISION trial did readout. We also saw initial data from the CREST trial after a positive press release several months ago in the treatment-naive high-risk non-muscle invasive disease space.

But I think let's focus our attention and discussion on the BCG-unresponsive disease space. And we saw III trials-- QUILT-3.032, BOND-003 and SunRISe-1 all report out cohorts for their BCG-unresponsive CIS group, as well as their papillary-only disease group.

So QUILT-3.032 is a prospective registrational trial that looked at the combination of BCG with Anktiva, which is an IL-15 superagonist and BCG-unresponsive disease. Anktiva, as we know, is FDA approved in this disease space. And we got to see some extended durability results that were presented none other than by Doctor Sam Chang.

And you can see the combination of BCG with Anktiva resulted in a 71% CR at any time, with a promising duration of CR extending beyond 50 months, which is likely mechanistically explained by memory T cell activation, resulting in a durable response.

Next, we saw BOND-003 cohort C report out in. And this was reported by Doctor Mark Tyson. This is a single-arm registrational trial of cretostimogene grenadenovec and BCG-unresponsive non-muscle invasive disease.

Cretostimogene grenadenovec is an adenoviral vector containing the GM-CSF transgene, and it selectively replicates in RB-deficient bladder cancer cells. This drug is dosed very similar to BCG, with a six-week induction followed by maintenance.

These are the results for the CIS cohort. And you can see that cretostimogene grenadenovec resulted in a 76% overall CR, with a 12-month CR rate of 46%. While we are primarily focusing our discussion on efficacy, I think it's important to highlight that cretostimogene grenadenovec is a very well tolerated drug with no severe treatment-related adverse events, no treatment discontinuations.

And lastly, we saw Doctor Jacob present data from the SunRISe-1 trial of the TAR-200 gemcitabine-eluting intravesical pretzel device for BCG-unresponsive CIS in cohort 2. And the trial showed a best-in-class 82% overall CR with a 12-month CR of 46%.

And notably, as we mentioned before, each of these three aforementioned trials included cohorts with papillary-only BCG-unresponsive disease and reported some early data. And I put these up here not for cross-trial comparison, but to show that there's promising data for all three novel agents and the papillary-only disease cohorts. And we'll wait for further maturation of the BOND-003 and the SunRISe-1 data.

Janet Kukreja: So I am very proud to have participated in this trial. This is the CISTO trial. So what it was is it was comparison of bladder-sparing therapy to radical cystectomy. And the hypothesis of the trial was actually that patients that underwent radical cystectomy would globally have worse outcomes than patients that did bladder-sparing treatment.

And they looked at general quality of life, emotional well-being and financial well-being. And this is just a quick breakdown here. The EQ-5D was better for radical cystectomy, emotional functioning, less depression, less anxiety on all the forms that patients filled out for patients that had radical cystectomy, as well as decreased financial toxicity.

So overall, bladder-sparing therapy did favor sexual health and bowel health. There was no difference in physical functioning, especially when accounted by overall and by age. The role of functioning, social functioning, urinary health was no different.

But the number of things that favored radical cystectomy, I think, were a surprise to a lot of people. Physical functioning was better, especially in patients with this CIS, cognitive, and then the mental and financial health.

Patrick Hensley: To wrap up our discussion and set the stage for further input from the team, there's a lot of emerging intravesical therapies for BCG-unresponsive CIS. We know that Anktiva is FDA approved, but we saw some durable response rates reported out at the AUA this year. And then we await FDA approval for the registrational trials for cretostimogene grenadenovec and TAR-200.

All three trials reported efficacy in the papillary-only disease patients. There's some implications there with the FDA label. Do these papillary-only patients truly need to be studied in a prospective randomized fashion or can a single-arm study inform an FDA label in this disease space?

But as Janet mentioned, and kind of the very important results that have tremendous ramifications from the CISTO trial, there's still a very clear role for radical cystectomy in this high-risk, non-muscle invasive disease setting for both oncologic control, cost control and patient-reported quality of life.

Sam Chang: Thanks to you both. Let's start with that CISTO trial for comparison of intravesical therapy versus radical cystectomy. Janet, how are you going to use this data now as you counsel your patients with recurrent non-muscle invasive bladder cancer?

Janet Kukreja: Yeah. I think it just provides data to what I've said for a long time. A lot of patients, they don't like coming in for the cystos. They don't like the repeated access to their urinary tract. And so it's a way to be done with it and move on.

A lot of patients hate being reminded that they have cancer. And I think we saw initially with the patient survey network that patients wanted this idea of bladder preservation. But it's interesting, as more drugs have come out that prolong that, how patients have actually almost re-centered on that. Curing the cancer and just moving on with their life may be a priority for some people.

Sam Chang: Yeah. I think that's really an important point, Janet, that you brought up regarding the definitive nature of cystectomy and the decreased burden and surveillance, decreased burden in terms of treatment.

I think we all-- to be honest, just as you said, the hypothesis was people were going to prefer, in intravesical therapy, prefer a bladder sparing. And that's kind of been the sentiment that's been really kind of propagated.

But in reality, when-- and importantly, patients chose these therapies. These were not randomized, just as you said. They chose cystectomy or they chose-- so obviously, there's some bias. Oh, I prefer cystectomy, I prefer-- but when you look at that comparison in those patients-- and I was really surprised honestly, regarding the functional well-being, the physical well-being. It makes sense regarding costs and that type of thing.

But I think just as you said, looking at each patient's individualizing care and saying here, here's some data that would support, don't feel like you shouldn't have your bladder removed. Here's data that helps support that. Patrick, what are your thoughts on the CISTO trial?

Patrick Hensley: I was very surprised. I personally was not a participant in the CISTO trial. I think a lot of this comes down to the mutual discussion between provider and patient. And the surgeon leads that discussion. And I think a lot of times patients can really pick up the kind of tone that the surgeon is setting in this disease space.

The CISTO trial just leads more credence to the fact that this has to be shared decision making. There has to be continual reevaluation of a patient's disease state and risk of progression.

But ultimately, with the incoming novel treatments in the non-muscle invasive disease space, we all thought that bladder preservation was the way to go and we would just kind of march through these therapies and patients would, of course, want to move on to the next clinical trial or the next FDA approved drug. But perhaps definitive surgery should be more on the forefront of our patient counseling and setting those expectations early.

Sam Chang: Yeah. I think the move to remove radical cystectomy is the preferred option. Clearly, there was a sentiment behind that. Maybe that was a little bit premature. I think for your point, that I kind of want to key in on is the fact that this is a dynamic, non-static situation.

You can't make the assumption that this patient is always going to have their bladder preserved and that's the best way to go. Just as you said, as treatments go, conditions vary, patients conditions vary, patients bladder capacity issues all change. So I think being able to continually evaluate and personalize, just as both of you stated, I think is really important.

Everybody compares these new medicines for BCG-unresponsive disease. And just as you say, cross-trial comparisons are not fair. And in no way do I think anybody can say one is superior to the other. And I think that it allows options to our patients.

As you counsel your patients. Pat, when you look at all these different agents, ultimately what do you think is going to happen? Are they going to be studies on sequencing? Are there going to be kind of default where if patients are tolerating it, they'll switch to other treatments? Tell me what you think may happen as these drugs get approved and further studied.

Patrick Hensley: I think first of all, these drugs are all powered behind a primary endpoint of CR at any time. And as we know, without durability results, that's kind of a meaningless endpoint. So I'm really excited to see the maturation of the data we saw-- Anktiva report out on QUILT.

And we'll wait for maturation on the TAR-200 device and cretostimogene grenadenovec. I think from a sequencing standpoint, it's going to come down to, again, the provider and the patient discussing or prioritizing efficacy, tolerability, cost, access to the drug, favorable dosing schedule.

I think there's always going to be a role for intravesical nadofaragene from that standpoint. I work in a very rural environment where patients come from a long way away for intravesical instillations.

So each of these drugs has their strengths and their weaknesses. And I think we as bladder cancer experts and academic centers have the luxury of having access and knowledge of this data and getting a lot of these drugs in our formulary.

I think it'll be a major challenge for community practices to prioritize which drugs they want to have their patients have access to and prioritize for their formulary addition. So it's going to be a challenge for sure.

Sam Chang: Janet, any other points you'd like to make as this field evolves, especially in the BCG-unresponsive space, and as these medications are moved earlier in the disease process? Give me your key takeaway or points of emphasis.

Janet Kukreja: Yeah. I think I would emphasize what Pat said. I think it's going to be very patient-specific, and we might recommend certain drugs for certain patients. I also take care of a fair amount of rural patients, and I do have residents who have graduated who are in rural Colorado taking care of patients. And some of these medicines can be a real struggle for them to get in the office.

Not having access to a cancer center pharmacy, stuff like that can be a real struggle too. Sometimes they can't even give sequential chemotherapy, gemcitabine and docetaxel. So I think we're going to see how this evolves in the next couple of years. But I also think that really setting patient expectations up front.

None of these-- to go back to what we were talking about earlier with the CISTO trial, none of these have the same really cure rate that-- or endurable cure rate that cystectomy has. And so I believe cystectomy will remain part of guidelines.

And I also believe at some point, we're going to have to put a limit on the number of sequential treatments recommended. I don't think we can do the sequential intravesical therapy forever. I think there's going to be-- maybe we try two or three and then we're going to call it type situation.

Sam Chang: Well, thank you both. It's really great to have actually two leaders in the field look at obviously, the data that was presented at AUA, but also give us insight in terms of their own particular practices. And in the future, we'll look forward to future trials from both of you very much. And thank you for spending some time with us today.

Patrick Hensley: Thanks, Sam.

Janet Kukreja: Thank you.