Sima Porten: Well, thanks so much for having me. I'm going to take this moment to share this e-poster. SunRISe-5 is a phase III randomized, open-label study of TAR-200 in comparison with intravesical chemotherapy after BCG recurrent high-risk non-muscle-invasive bladder cancer.
So, as many people know, bladder cancer is recurrent despite our gold standard-of-care therapy with BCG, especially in these recent years when we've had a pretty tremendous BCG shortage. And I'll talk a little bit about that when we get to the inclusion criteria for this study.
But TAR-200 is a novel intravesical delivery system of slow-release gemcitabine. And some of the diagram of how it works is described up here. The device is in the shape of a pretzel, and you'll often hear people refer to it like that. And as you can see, it sustains the delivery of gemcitabine in low concentrations over a much longer period of time. And therefore, the hypothesis is that this is what provides superior efficacy in treating patients with non-muscle-invasive bladder cancer.
So this is indeed a randomized controlled trial of papillary-only patients. And that's one of the key eligibility criteria. And this is something that's a little different than the more recent studies that have had some great results and made a splash at a lot of our meetings and in the media. But this is for patients with papillary-only disease—no carcinoma in situ.
And that's one of the reasons behind designing a randomized controlled trial in this disease space. Because our surgical procedure, the TURBT, has oncologic efficacy. So the endpoints of looking at papillary disease are much different than that of carcinoma in situ, where you can look at presence and absence.
And so for this reason, this is where a randomized trial also helps really figure out if your treatment is indeed superior to that of standard of care. And so for SunRISe-5, patients are randomized between TAR-200 and intravesical single-agent chemotherapy—either gemcitabine or mitomycin, and that's per physician choice—with the primary endpoint of disease-free survival.
So when you look at our definitions of BCG responsiveness or exposure, there's the traditional FDA definition of BCG unresponsive disease. And that's one of the inclusion criteria. And so that's having adequate induction—so five of six doses—and maintenance, either two or three doses, or at least two rounds of six or a second induction. And that's the more standard FDA definition.
But as we all know, the BCG shortage has created patients who experience recurrence who may not meet that definition. And so this trial actually does include randomization of patients with BCG-experienced disease. This is a somewhat artificial definition, but it really allows anybody who's had an adequate induction and then developed recurrence as eligible for this study.
So in looking at the primary endpoint—again, this is disease-free survival—we have a variety of secondary endpoints, including patient-reported outcomes and health-related quality of life. And currently, SunRISe-5 is open and enrolling patients. This is a global trial at about 120 sites across 14 countries.
As of the last update, globally, there have been 285 patients screened and 160 patients randomized. So it is enrolling quite quickly, and hopefully, we'll have prelim results fairly soon if enrollment continues. And as always, thank you again for having me here to discuss this trial. And definitely, we appreciate the participation of all the patients, families, and all our healthcare team providers, physicians who make this possible. And hopefully, this will provide another much-needed option for patients who have this disease.
Zachary Klaassen: So, Sima, thanks so much. Great overview. I know that the SunRISe platform has been so fun to follow over the last couple of years. There's just so much good data coming out at all of our meetings. I think you mentioned that we have so many good therapies in the CIS space in the BCG-failure patients, and there really is an unmet need for this papillary-only cohort. And just expand on this differentiation between a component of CIS and just truly papillary-only and where this trial really fits in.
Sima Porten: Yeah. So I think, if you think back to the time where we didn't have a lot of treatment options available, aside from radical cystectomy and then perhaps valrubicin—that was FDA-approved a long time ago—we entered this era where there was an ability to do phase II single-arm trials.
And when you're looking at how you run those trials and trial design, how the trials were designed and accrued was across two cohorts. There was a cohort with carcinoma in situ, with or without papillary disease, and then papillary-only. And this is because, for carcinoma in situ, you can do biopsies and document presence. Then you can give intravesical therapy or systemic therapy and then document complete clearance through biopsy, cytology, cystoscopy—all of the above, some of those, et cetera.
And for patients with papillary disease, this was always a secondary cohort. And it just took a lot longer because, really, you have to look at recurrence-free survival or event-free survival because your tumor does have some oncologic impact. I would say the big difference for this study, in my mind, is looking toward the future in being able to run randomized trials now that we have a lot of agents that have developed efficacy.
And I think for papillary-only disease, this tends to be something that's done later or after. And indeed, it remains true even for indications for TAR-200. But this is the first big shot at really looking in the best way that we have possible through randomization if this really can provide benefit over our standard of care in this space.
Zachary Klaassen: Yeah, absolutely. And I think we see these patients all the time. I mean, the CIS component is certainly present. But we see these true papillary-only recurrences. And that's a huge unmet need. And I think this trial really hits on that. Not to put you too much on the spot, but I know when we look at the control arm, mitomycin or gemcitabine, physician choice, a lot of us in the academic or community are using gem doses in this space. What was the rationale between one of the two single agents?
Sima Porten: I think part of it was to make it real world. This is a global study.
Zachary Klaassen: Yeah.
Sima Porten: And I think sometimes, depending upon where we practice, we forget that we are a bit spoiled in being able to have access to these things. And doublet chemotherapy is not actually very accessible in most parts of the world. And I think that went into the thought process critically on what should be the adequate thing to randomize to.
And so primarily, when you look across the last 30, 40 years, really there's pretty good data for both gemcitabine alone and mitomycin alone in this disease space, in particular over multiple eras of how we defined BCG refractoriness or unresponsiveness or however you want to state it. A couple of big trials from Di Lorenzo, Addeo, Ella Skinner, they have looked at the utility of these agents, and I remember thinking the same thing.
So I went back and looked at all these trials and read all of them. And the expected one-year disease-free survival, how this trial is powered, is about 40% for the standard-of-care arm and an expectation that TAR-200 will do better. And that's actually—now as we're seeing some of the one-year and two-year data in a different spot, in the unresponsive CIS spot—that's actually pretty good for single-agent chemo. And so that was the rationale, and I think appropriately so for choosing those as the comparators.
Zachary Klaassen: Yeah. Great explanation. You mentioned it's ramping up quickly. I think at the time of the SUO presentation, there was maybe 25 or so out of 250 randomized. And now we're up to over 150. So the $64,000 question is, when are we going to finish accrual? It sounds like that may be soon. Possibly when may we see some early data?
Sima Porten: I hope soon. Of course, accrual is one thing. But having that recurrence-disease-free survival and recurrence-free survival outcomes are different. And so I think it's still going to be some time, but I don't think it's going to be as long as we thought it was going to be before we see data just because of the ramp-up in accruals. So it's pretty exciting.
Zachary Klaassen: Very exciting. And I think you're right. The event rate will mature and will go off of that, for sure. So let's fast forward—I mean, this is the beauty of these discussions. Let's assume this is a positive trial. We've seen the great results in CIS, BCG unresponsive from SunRISe-1. Let's say in two to five years or so, where could you see TAR-200 just fitting into this burgeoning armamentarium that we're seeing in non-muscle-invasive bladder cancer?
Sima Porten: Yeah, I think that's going to be the million-dollar question. It's likely more than $1 million when you look at the cost of bladder cancer care, but also accessibility for patients.
Zachary Klaassen: Yeah.
Sima Porten: At SUO 2024, if folks go back to watch the different presentations, you could see there's a lot of excitement. But there is—it's going to be very difficult to choose, and it's going to be maybe even more difficult to afford as you look at the different agents. I do think in the end, choice will be driven by who has durable outcomes. Because I think we see really amazing three-month, six-month, 12-month outcomes, but when you start getting to something like five years, we're starting to see that much of the efficacy of these different treatments start to wane, at least in the CIS setting.
So I think, number one, of course, you have to go by efficacy. Number two, it will be durability. And then number three will be probably a toss-up between access—and that's what we're going to have to be very careful for in terms of insurance access for patients—and then also looking at quality of life outcomes. That's why I think these PROs, as part of the trial design, can be really helpful.
If it's found to be that one of these medications is not great in terms of specific urinary symptom profile, then that might push you, as a clinician, toward a different treatment in terms of one or another. If you're looking at really practical things like, OK, if this is something that can be placed and removed in a urologist office at a specific tempo once every three weeks, depending on where you are in the treatment, and then for maintenance as well, is this going to be less travel and doctor's appointments than maybe a different drug with a different dosing?
And I think those, in the end, will probably make small but meaningful impacts on how urologists will use this. But I do think it’s that durability. We’re all really excited about initial CRs, but I think now everybody is looking a lot more critically at durability.
Zachary Klaassen: Yeah, absolutely. Great discussion as always, Sima. Maybe just a couple take-home messages for our listeners today.
Sima Porten: I think I always like to remind everyone that, in BCG unresponsive disease, whether you're talking about CIS or papillary, there are a lot of options available for patients for bladder preservation. I think it's important to still always discuss with patients one that we definitely have, which is radical cystectomy, as how you structure that conversation. And then you work in these different medications and risk benefits of that whole package.
I think another pearl that I've learned, and I've definitely noticed over the last few years, is that you do indeed have time to usually try one more thing. If you have large volume or invasive disease like high-grade T1, you've got to really be careful that you're staging the patient appropriately and you haven't missed your window. I think that's one important thing. And then the other is that you really have to be careful of your sanctuary sites. So you got to be diligent of monitoring the upper tracts, prostatic urethra in men, and being very vigilant with each additional line you try of keeping patients safe.
Zachary Klaassen: Yeah, absolutely. Well said. Sima, thanks again. Great discussion on the SunRISe-5 trial. We're looking forward to data, hopefully very soon. Thank you again.
Sima Porten: Thank you again. Take care.