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Biomarker Analysis from the SunRISe-1 Trial in BCG-Unresponsive CIS - Félix Guerrero-Ramos

November 20, 2025

Sam Chang speaks with Felix Guerrero-Ramos about a biomarker analysis from the SunRISe-1 trial evaluating TAR-200 for BCG-unresponsive carcinoma in situ. Dr. Guerrero-Ramos presents findings showing that TAR-200, an intravesical gemcitabine delivery system, achieved an 82.4% complete response rate. The biomarker analysis revealed that genomic alterations including TP53 and TERT mutations, tumor mutational burden, PD-L1 status, and urinary tumor DNA did not predict response rates or duration of response. Dr. Guerrero-Ramos suggests that TAR-200's sustained gemcitabine release mechanism may provide broad efficacy across molecular subgroups regardless of specific alterations. The discussion explores whether the therapy genuinely works universally or if larger studies like SunRISe-3 might identify predictive biomarkers.

Biographies:

Félix Guerrero-Ramos, MD, PhD, FEBU, Urologist, Oncologic Urology Unit Coordinator, Hospital Universitario 12 de Octubre, Madrid, Spain

Sam S. Chang, MD, MBA, Urologist, Patricia and Rodes Hart Professor of Urologic Surgery, Vanderbilt University Medical Center, Chief Surgical Officer, Vanderbilt-Ingram Cancer Center, Nashville, TN

Related Content:

ESMO 2025: Association of Molecular Markers with Clinical Response to TAR-200 in the Phase 2b SunRISe-1 Trial in Patients with BCG-unresponsive Non-muscle Invasive Bladder Cancer (NMIBC) with Carcinoma in Situ (CIS), with or without Papillary Disease

SES AUA 2025: TAR-200 in Patients with BCG-Unresponsive High-Risk NMIBC: Results from the SunRISe-1 Study

SCS AUA 2025: TAR-200 Monotherapy in Patients with BCG-Unresponsive High-Risk NMIBC CIS: 1-Year Durability and Patient Reported Outcomes from SunRISe-1

EAU 2025: State-of-the-Art Lecture: TAR, a Novel Intravesical Drug Delivery System
Read the Full Video Transcript

Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee at Vanderbilt University Medical Center, and we have an internationally known incredible expert here in bladder cancer, Professor Félix Guerrero-Ramos from Madrid. He leads the uro-oncology unit at the ROC there, and has given presentations recently in 2025, most recently at ESMO, looking at the results of the TAR-200 kind of efficacy in SunRISe-1. Specifically looking at a cohort of patients and the impact of the TAR-200 device in BCG-unresponsive disease. So we're quite fortunate to have him today and we look forward to the presentation.

Félix Guerrero-Ramos: Thank you, Sam. Thank you, UroToday, for the invitation. I'm very glad to be here from Madrid. So what we just presented at ESMO for ESMO 2025 was a poster of the association of molecular markers with the clinical response to TAR-200 in the SunRISe-1 trial for those patients who harbor BCG-unresponsive CIS. These are my conflicts of interest. And up to now, we know that there were three agents approved by the FDA for those patients with BCG-unresponsive CIS. It is important to remind our audience that there is not still any approval for papillary only disease, which is BCG-unresponsive. These approvals were in 2020, pembrolizumab intravenously, with a complete response rate of 41%. Then two years after that, nadofaragene firadenovec was approved. And two years after that, ANKTIVA, which is BCG with superagonism of interleukin-15, which is N-803, was approved of both of them intravesically for these tumors.

But recently in September 2025, the FDA gave a green light to the approval of INLEXZO, which is TAR-200 intravesical delivery system of gemcitabine for BCG-unresponsive CIS patients. This approval was based on the data coming from the SunRISe-1 trial. You can see here the design. These are patients with BCG-unresponsive CIS who are not fit or do not want to undergo a radical cystectomy, and cohort 2 administered TAR-200 intravesically alone for these patients. It was every three weeks for the first six months, and then a three-week cycle every three months up to two years of therapy. These were the results published recently at the Journal of Clinical Oncology, where the complete response rate reached at 82.4%. This is the highest of the current approvals by the FDA. And the duration of the response, we can see that was over 56% at 12 months. Here you can see those patients with a complete response and the median time of response was not reached yet.

So in ESMO, we presented an update of this trial looking at the biomarkers of these patients who harbored these BCG-unresponsive CIS and were treated with TAR-200. We found that genomic alterations were present in over 85% of the patients. The most frequent ones were TP53 and TERT. And there were no microsatellite instability in any of these patients or any of these tumors. If we look at the tumor mutation burden, we saw that around one out of five patients presented high TMB, but none of these alterations was associated either with the complete response rate or with the duration of the response.

We also looked at the PD-L1 status, which has led to several approvals in Europe to several drugs, depending on the PD-L1 status. And here we saw that two-thirds of our patients had PD-L1 negative tumors, and PD-L1 was not associated with the rates of response or the duration of the response. And the same happened with urine tumor DNA. We saw around one year ago, a previous report from the trial with nadofaragene firadenovec that the utDNA clearance was associated with the recurrence-free survival in this patient when this virus was administered. In this case, we couldn't demonstrate that utDNA was associated again either with the response rate or with the duration of the response.

So to conclude, we know that TAR-200 has demonstrated high clinical efficacy, and this has led to the FDA approval, but this is independent of any of the alterations that we have looked at, like genomic alterations, PD-L1 or utDNA. We see that these alterations do not impact the response rates or the duration of the response. The treatment has high efficacy across any molecular subgroup, and probably with larger trials, for example, SunRISe-3, where there are over 6 or 700 patients treated with TAR-200 with or without cetrelimab. We will have a larger sample and be able to demonstrate if there is any correlation between any of the alterations and the clinical outcomes of these patients. That has been all. I want to thank the audience for watching and for your attention. Again, thank you for the invitation to UroToday to Dr. Chang, and we can have some debate.

Sam Chang: Wonderful presentation. And as you ended with your conclusion, it just led to the questions that I obviously had. So this could be good news, this could be bad news. And what I mean by that is, it could be that this chemotherapeutic intervention with the gemcitabine impregnated in that pretzel is actually effective for all comers. And that the vast majority, as you showed in your complete response rate, quite high and that many may get benefit. Or it may be that, as you said, that the studies at this point are underpowered to show a specific genetic mutation, or the urinary tumor DNA wasn't enough to tell us who would benefit and who wouldn't. So what do you think is the case? I'm going to put you on the spot. We would hope that we could find something that's predictive with bigger numbers. Tell me your hypothesis and what do you think's going to play out?

Félix Guerrero-Ramos: Well, of course, a big limitation of this is the small sample size. There were 85 patients treated, but we didn't have samples from all of them. So it was around 60 something patients, the number of patients of which we could analyze all these alterations. I firmly think that TAR-200 is a very good therapy. It provides sustained release of gemcitabine, so we are subjecting the bladder mucosa to the chemotherapeutic agent for a long time in a continuous way. So probably this therapy, being a chemotherapeutic agent and not a targeted agent, probably this chemotherapy is killing cells for patients no matter what alteration they have. I believe that there might be some alteration that make our patients more sensitive to this therapy. This could be seen, as I said, in the SunRISe-3 trial with a larger sample, but I am not very optimistic that we will find a concrete driver to select patients and to do some kind of a personalized approach.

Sam Chang: No, I think that's a really good point. We've already pre-selected a group of patients clearly that is already a difficult-to-treat subset, they're unresponsive to BCG. And so it would be interesting upfront to see that that big denominator of initial BCG-naive, are there going to be signals? Are there going to be changes? And hopefully SunRISe-3, which is looking in the BCG-naive cohort, would help answer some of those questions as well. As you look at the different types of genetic changes that you studied, as well as the urinary tumor DNA, do you think there's a biomarker missing? Do you think that perhaps there is something else that we'll be able to uncover that will help predict response to the chemotherapy?

Félix Guerrero-Ramos: Well, I'm not sure. The analysis we have performed have been quite comprehensive. We've done a very complete panel, not only with genomic alterations as you saw, but also with PD-1, PD-L1 and utDNA. Maybe in some of these patients, the ctDNA status can predict those with a higher risk of progression because of this being an alert of a micrometastatic systemic disease. Especially in these early, but difficult to treat stage which is unresponsive to BCG. And we know these patients are at a high risk of progression if we don't do anything. So probably if we look at ctDNA, of course we will have a very small sample of these patients. I don't believe that more than 1% of them will be ctDNA positive, so we would need a very large sample. Maybe this can predict that patient will be at a higher risk of progression or even to failure to the therapy. And maybe for these patients, an approach could be both intravesical plus systemic therapy in order to try to look at that ctDNA clearance.

Sam Chang: No, I think that's a really good point. And as you look and as you've presented at this point with this cohort of patients, I think importantly, the CIS group with TA, with T1, there didn't seem to be necessarily a smaller response. All comers in different stages along with the CIS did have a high response rate. So we look forward as the data continues to accumulate. As we unpack more information from these series, there's going to be a wealth of information gained for all patients actually for BCG-unresponsive diseases. We learned the mechanisms of actions and the therapeutic benefits of the different options that are out there. So Félix, we look forward to more presentations. We know how prolific you are. We know how you and your team have really helped lead a lot of these initiatives, so we look forward to talking to you again soon.

Félix Guerrero-Ramos: Thank you very much. Thank you, Sam. It's been a pleasure and looking forward to seeing you again soon.