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Sam Chang: Hi, I'm Sam Chang, I'm a urologist at Vanderbilt University Medical Center. And we have the honor to have Dr. Sima Porten, associate professor at the University of California, San Francisco. But she really doesn't need an introduction because everybody knows who Dr. Porten is. She will be actually giving a review of the SunRISe-5 trial. It's a trial in progress that was presented in part at the AUA 2024 annual meeting. And this is an evaluation of a novel targeted release system, the TAR-200, and its evaluation in a disease process. So first of all, Dr. Porten, thank you so much. Number two, I really look forward to your insights on this trial and the landscape of non-muscle invasive bladder cancer. So I'll let you take it away.

Sima Porten: Thanks so much for having me here. My name is Sima Porten, as Sam or Dr. Chang so eloquently introduced me before, and kindly introduced me. I had the pleasure of presenting a trial in progress, so SunRISe-5. This is a phase three, randomized, open-label study of TAR-200 compared with intravesical chemotherapy after BCG in recurrent, high-risk, non-muscle invasive bladder cancer. These are my disclosures.

And so to kind of set the stage, many patients with high-risk, non-muscle invasive bladder cancer recur or progress after BCG. Over 75% of newly diagnosed bladder cancers are non-muscle-invasive. And of patients with high-risk NMIBC, 20 to 46% of patients experience recurrence after BCG treatment. There's a pretty wide range there depending on what data set you look at. Additional BCG is not effective in early recurrence within one year, and is not recommended by our guidelines. So right now, the standard of care in early BCG-unresponsive recurrences with papillary only high-risk disease is radical cystectomy. However, many patients either refuse or are ineligible for RC. The most recent approved bladder preservation options, which we also had the opportunity of listening to and hearing about at AUA this past April, are limited to patients really with just carcinoma in situ. And so there's a pretty high unmet need to look at different bladder-sparing options for patients who have papillary-only disease.

So a little bit about TAR-200. It's a novel targeting release system designed for sustained release of gemcitabine in the bladder. How this works is that the TAR-200 device maintains activity over a seven to 10-day period. It is inserted with a small catheter and kind of curls into this pretzel shape and sits in the bladder for a period of about three weeks. And over that seven to 10-day cycle, you can kind of see on the graph on the right-hand side, you see that it maintains activity and has a slow release and is able to increase the amount of gemcitabine that the bladder sees in a very prolonged fashion. And when you look at the interim data from SunRISe-1, that was presented at this past AUA as well, this supports further investigation of this device in patients with papillary-only disease, whereas SunRISe-1 really examined its use in patients with BCG-unresponsive carcinoma in situ, such as the other FDA-approved indications.

So when you look at our trial design, really this is a randomized controlled trial, meaning that patients are either randomized to group A with TAR-200 monotherapy or group B. And group B as a comparator was chosen to be intravesical gemcitabine or intravesical mitomycin as a single agent. And there is an option for crossover for patients to move into group A after TAR-200 develops hopefully a positive signal at any of the planned analyses. So patients will be randomized in a one-to-one fashion. 250 patients will comprise this study. ECOG performance status is pretty permissive. You have to be less than three and patients have to either have refused or are ineligible for radical cystectomy.

So as stated before, patients who are assigned to the TAR-200 arm will get the device inserted every three weeks. So again, this is done through a small catheter and at the three-week mark is removed with cystoscopy. Induction phase is what kind of leads in. And then afterwards there's a maintenance phase that's every 12 weeks. Patients in group B, again, one of the single-agent chemotherapies either with gemcitabine or mitomycin. This is given standard weekly for six weeks during induction and then monthly during a maintenance phase. Our primary endpoint is disease-free survival. And this is defined as the time from randomization to the development of high-risk disease, any cause of death, or progression, whichever comes first.

So I just wanted to go over the definitions of patients who are eligible for this study. So there is your true BCG-unresponsive definition, and that's what was defined by the FDA. And many of you have seen this in the context of other trials and are familiar with this. But to review, patients have to have at least adequate induction, so five of six doses, and either two of three doses of maintenance therapy or another second induction. And what you're really looking at is patients who develop high-grade T1 papillary disease at the first assessment after induction or high-grade TA or any T1 disease within six months. So again, this is the papillary-only cohort. And that's the definition of being truly BCG-unresponsive. This trial also includes patients who are BCG-experienced. This does not meet a BCG-unresponsive definition and is defined as receiving adequate induction, five of six doses, with or without maintenance therapy. And then includes these patients with early recurrences, again, high-grade TA or any T1 within 12 months.

So this trial will hopefully mitigate sometimes access in the current landscape of BCG shortage and allow these BCG-experienced patients to have an option for bladder preservation. So the first global site opened on March 29, 2024. As of May 4, 30% of US sites have opened with three patients in screening. And SunRISe-5 is recruiting across multiple countries, about 15 with enrollment planned at 129 sites. So we would like to thank the patients who are participating in the studies, the family, the investigators, and clinical research staff from all the study sites. We're really excited to get this trial going and for the interim analysis and hope this offers another way for bladder preservation for our patients.

Sam Chang: Sima, thank you so much for that overview of that trial. Really, actually, I have some questions at this point because it's, I think, an incredibly important population of patients with papillary disease, which is, in fact, the majority of patients I think we see that have been either exposed to BCG or have had recurrence and have tumors that are not responsive to BCG. When you look at the study, are you going to or are they upfront going to stratify these patients within the BCG-exposed versus the BCG-unresponsive?

Sima Porten: Yeah. Meaning by definition of exactly how much BCG...

Sam Chang: Exactly, upfront. Yeah. Is that going to be a stratification criterion upfront? Because you are going to randomize, obviously, so that you'll help distribute. But I was wondering upfront if there's going to be basically kind of a strata understanding that BCG-experienced versus BCG-unresponsive may be a little bit of a different population cohort. So I was wondering if there was going to be a pre-specified risk stratification strata.

Sima Porten: Yeah. So the two stratification factors right now are T-stage and also prior BCG. And that kind of includes a little of what you're talking about in terms of these little bit different populations as you go through. And I think that accounting for this will be important because although it is randomized and that does control for some bias, I think there with the stratification that should hopefully account for even more, right? And really make this applicable to—

Sam Chang: The real world.

Sima Porten: ... population we see in the real world.

Sam Chang: Exactly. That's why I think it's so important because, as you know, as we treat these patients, there are so many that are having a non-standard course of BCG being interrupted for shortages, being interrupted for urinary tract infection or hematuria, different types of things and being able to get there, et cetera. I think the realization that there are a lot of different patients that really fit in this cohort I think is really important. As you look at the comparative arm of single-arm gemcitabine or mitomycin, as you all have looked at the trial, I think worldwide there is without question the alternative to BCG is single-agent chemotherapy. Is that what you all found in terms of setting up the trial?

Sima Porten: Correct. And also, when you look at past large studies, like the SWOG study with gemcitabine after a variety of BCG experiences, exposure, unresponsive, standard and un-standard definitions in that study too, as well as other larger studies from ADEO, primarily with mitomycin, and some other larger, more robust datasets, it did seem that the single-agent chemotherapy was the appropriate comparator arm, particularly when making estimations of what do we anticipate the DFS to be, right? And then how do we then power a study with what we would believe is a clinically relevant metric? And I think this is an interesting point, particularly because here in, definitely parts of the US, many people feel that maybe double-agent chemotherapy, right? There are many of us who are gem/doce lovers as our alternative agent, and that question has come up. But when you really look at the larger historical data, especially around the world, that's where the single-agent chemotherapy kind of pops out.

Sam Chang: No, I think you're exactly right. The academic ivory towers can claim that this is the doublet is the treatment of choice, and we're obviously going to gain information with that with upcoming trials. But in reality, in terms of practice if you actually look at the practice protocols, the majority of practices definitely worldwide and in the US still use single-agent therapy, be it mitomycin or gemcitabine. And so again, it goes back to, I think, the real-world nature of this trial evaluating, hey, we've got a new agent. We think it's effective. We're going to compare that to what's mainly being used throughout the world and the US and we'll see what the differences are when it comes to a disease-free survival rate. So I think that's really important. Do you know, I know this trial is somewhat early in enrollment, do we have any idea of the landmarks of when we're expecting accrual, or enrollment rather, to be completed? Are we looking at a year, a year and a half? Do you have any idea regarding that?

Sima Porten: Not right now with the early data. We could extrapolate from the other SunRISe studies, in particular SunRISe-1, which definitely accrued a lot faster than I think was anticipated. And I think we hope that for this study as well. I think having a variety of sites with a diversity of backgrounds and patient populations and practices is important. This is a randomized study versus just one of a single-arm study. And so I'm hoping that at next AUA there is data to share or present, but that might be being really optimistic and ambitious.

Sam Chang: No. But no, I think that's fantastic just to show an early signal regarding or close to accrual or no signals from, we wouldn't expect because we haven't seen it from others, but at least no signals from the independent data safety committee saying that, "Hey, there's no signals in terms of safety concerns." Anything like that I think would be beneficial and positive. And so I want to thank you for your leadership in these trials and how you've been such an important voice in terms of evaluation, risk stratification, and then moving towards the next treatment realms. Because I know what a skilled surgeon you are, but to be able to involve in these clinical trials I think is really important and really, hopefully, sets the stage for improved therapies for our patients. So thanks to you, Dr. Porten, Sima, if I may. And thank you for all your contributions and thanks for spending some time with us.

Sima Porten: Thanks so much for having me.