Sam Chang: Hi, I'm Sam Chang. I'm one of the urologic oncologists at Vanderbilt University in Nashville, Tennessee, and we are quite fortunate to have an international guest today who has helped actually lead some trials in bladder cancer. So Dr. Felix Guerrero-Ramos from Madrid leads actually the UroOncology division there at one of the largest hospitals actually in Spain. And thank you so much for spending some time with us.

Felix Guerrero-Ramos: Thanks for your kind invitation. It's a pleasure for me to be here.

Sam Chang: Yeah. So at this year's AUA 2025, there are certain actual presentations designated as practice-changing, paradigm-shifting, more-- I don't want to say important trials-- but prominent trials looking at different disease states. So you were actually the lead author and presenter of a SunRISe-1 cohort, cohort 4, in SunRISe-1 looking at actually TAR-200 monotherapy for treatment of BCG unresponsive papillary disease. So that's the introduction. Clearly, obviously, something that is important as we consider treatment options, tell us a little bit about the study, who was enrolled, the outcomes, et cetera, from this important trial.

Felix Guerrero-Ramos: Well, thank you, Sam. As you said, these presentations have been invited for the plenary session at AUA here in Vegas. SunRISe-1 trial is a trial for BCG-unresponsive patients. In particular, cohort 4 implies 52 patients with papillary-only disease without CIS. These patients are treated with TAR-200 every three weeks for the first six months, and then every three months up to two years. The primary endpoint here is disease-free survival, and the key secondary endpoints are safety and tolerability.

Sam Chang: Sure.

Felix Guerrero-Ramos: So this is an exploratory cohort for those papillary-only BCG-unresponsive patients as compared with the CIS patients. We know that TAR-200 has strong evidence behind in CIS unresponsive, also as a neoadjuvant with cetrelimab. And now these are the first results presented for papillary-only BCG-unresponsive disease.

Sam Chang: So intravesical therapy alone with what we've commonly referred to as the pretzel therapy.

Felix Guerrero-Ramos: That's it.

Sam Chang: A unique delivery system that is implanted with a catheter-like device that infuses over a period of time gemcitabine. And so when looking at-- placing it every few weeks and then removal and placement again, we're looking at a therapy that stays within the bladder. We know for sure because it's placed inside the bladder. And then hopefully, the benefit then of prolonged exposure gives us results. So tell us a little bit about the efficacy and the outcomes.

Felix Guerrero-Ramos: Well, the good thing about TAR-200 is that it ensures a permanent exposition of the bladder lining to the drug we are administering. We reported here the disease-free survival results at six and nine months with astonishing data. We see that 85% of the patients are disease-free at six months, and 81% of the patients remain disease-free at nine months of follow-up. Only one patient-- only three patients, sorry-- had to undergo radical cystectomy. And if we split the population in those high-grade TA and T1 patients, which is harder-to-treat population--

Sam Chang: Sure.

Felix Guerrero-Ramos: --40% of the included patients are T1, and the response rates are similar between high-grade TA and T1 patients. This is like a clinical translation of the PENELOPE study, which was presented at AUA in Madrid this year, where we demonstrated that administering gemcitabine with TAR-200 significantly increases the penetration of the drug across the bladder wall.

Sam Chang: Yeah, I think that's important because you take a higher-risk population like the T1-- clearly, those individuals that we worry. We do everything we can to try to avoid understaging, to try to avoid missing invasive disease. But the ability for this medication exposed over time to get deeper into the tissue, you would understand being able to successfully treat the mucosa, but to get deeper, and then, hopefully, then eradicate disease. And that T1 substratification really is an exciting development.

And the fact that the physiologic data corresponds now with outcomes data, the fact that there's really no big difference between TA and T1, I think, is encouraging. And also it gives us an idea that this is a medication that clearly has improved exposure compared to just the intravesical instillation. Tell me about the side effect profile. What do we see when we look at urinary symptoms, systemic symptoms? Were there any signals?

Felix Guerrero-Ramos: The side effects of TAR-200 are well-known from previous studies, especially with cohort 2 with patients with CIS or without papillary disease. For this specific cohort, cohort 4, we found that most of the side effects are grade 1 or 2, mainly related to lower urinary tract symptoms, and there were a very, very small number of patients experiencing severe treatment-related adverse events. Also, the rates of discontinuation of the therapy due to adverse events were really, really low, and there were no treatment-related deaths in this population. Regarding the success rates of the insertion, as we said, it's very easy to do a common instillation.

Sam Chang: Sure.

Felix Guerrero-Ramos: For TAR-200, we have stated that, in this population, 99.5% of the insertions were successful. So it's also an easy-to-administer therapy.

Sam Chang: So the fact that it can be placed easily, repeatedly and the fact that the majority of patients, by far, were able to actually complete treatment gives us some hope and rationale that our compliance is going to be very high with these patients. And the success rate associated with that is also very, very promising. So where do we go next?

That's the question that I would have because we have a unique delivery system with a chemotherapy agent that we know is beneficial. We have data that shows there's increased uptake in penetration. Do we use this medication or think about it, perhaps in an earlier state or perhaps even in a more advanced state. Put your thinking hat, prediction cap on. We're in Vegas, so we can gamble a little bit. So tell me what you think we would do next in terms of studies, what patients, et cetera.

Felix Guerrero-Ramos: Well, currently for these BCG-unresponsive patients with papillary-only disease, the only alternative is radical cystectomy. There are no approved therapies for papillary-only. And the data we present look better than other agents who have presented preliminary data. The first step to move forward in this particular population is already moving, and is the SunRISe-5 trial, which is a randomized phase III trial for this BCG-unresponsive or experienced patients, randomizing patients to either TAR-200 monotherapy versus intravesical chemotherapy.

Of course, the efficacy signals we have are very strong, and this has already moved to earlier stages. We are awaiting results, for example, from the SunRISe-3 trial against BCG induction plus maintenance in BCG-naive patients. So as we gather more data on all the different stages, I think we will be able to move, if we have good efficacy, this therapy to earlier stages of the disease.

Sam Chang: Yeah, it's obviously incredibly impressive trial, a thought process. We've got early, exciting data. Let's go here. Let's look at this cohort. But already enrolling patients that are being compared to intravesical chemotherapy-- because that's the first question people are going to say, oh, well if you're careful with gemcitabine, the results are going to be just as good.

We don't know that for sure. And hence, now you have a trial that basically will be able to compare. I think really all the investigators should be applauded. But then the thought process behind that I think is really important. And then whether or not it stacks up vis-a-vis BCG, a very high bar, will be also very important data. Felix, thanks so much for spending some time with us on UroToday, and we really look forward to future trials that you'll help lead as we determine the next best treatment options for our bladder cancer patients.

Felix Guerrero-Ramos: Thanks so much, a pleasure to be here, and exciting times for our bladder cancer patients that are coming.

Sam Chang: Very true.

Felix Guerrero-Ramos: Thank you, Sam.