Sam Chang: Hi, I'm Sam Chang. I'm a urologist in Nashville, Tennessee, and we are with Dr. Alice Yu, Assistant Professor at Moffitt Cancer Center in Tampa, Florida. Dr. Yu is one of the true rising stars in urologic oncology. She was asked by the SUO to actually give highlights of urothelial carcinoma—important papers that she has reviewed over the past year or so—and this was presented at the AUA meeting in 2025.

So we were able to capture Dr. Yu for a few minutes to go over some of those key findings that you had. I think there were three different disease states that you presented, some key important papers. So, Dr. Yu, Alice, first of all, thank you so much for being here. And let's hear a little bit about the first area that you focused on.

Alice Yu: Yeah, sure. And thank you, Dr. Chang, for having me here.

Sam Chang: Sam. Actually, call me Sam, please.

Alice Yu: It's just such a pleasure and such an honor to be here. So I was asked to present three papers in the past year that influenced my practice, and I really struggled with this—there's been so much work done in the urothelial space over the last year. It was just so hard to narrow it down to three papers. So I cheated a little bit, and I presented three disease spaces that I thought were—there's been a lot of development, and there's been some influence in my practice where I know my practice has changed a little bit, and I'll highlight the papers that have influenced that.

So the first disease space I want to talk about is perioperative systemic therapy around the time—sorry—perioperative systemic therapy around the time of cystectomy. So the first paper I spoke about was the NIAGARA trial. This is a study that randomized patients to a neoadjuvant combination of durvalumab with gemcitabine and cisplatin, followed by cystectomy and then followed by adjuvant durvalumab. And this was compared to the standard-of-care arm, which was gemcitabine and cisplatin alone, given only in the neoadjuvant setting.

So what they were looking at were dual primary endpoints: pathologic CR and event-free survival, which they defined as progression. And the secondary endpoint was overall survival, and of course there were safety criteria as well that were assessed. So in terms of pathologic complete response, what they found was that in the durvalumab arm, there was an improvement compared to GemCis alone. And then the second co-primary endpoint, event-free survival, also showed a significant favoring of the durvalumab arm. And we saw a benefit in terms of overall survival as well.

Sam Chang: So this combination of adding an immunotherapy—an I/O—with chemotherapy, treating then with local consolidated therapy, bladder removal, then an adjuvant or a follow-up I/O with durvalumab showed not only a better pathologic CR but also a better event-free survival, and then ultimately, to have an improved overall survival. Clearly, a big type of practice-changing intervention to add the I/O, especially since we found in the metastatic state early on there didn't seem to necessarily be a benefit of combination therapies.

And now to have this set up, it's clear—or perhaps it's not clear—of OK, what's really helping? Is it the adjuvant? It's the neoadjuvant component. Is it both? It's unclear. But really, I think, I agree with you, a practice-changing shift of—and we'll have more studies on the way as they read out.

Alice Yu: Yeah, absolutely. Exactly as you said. So there's controversy with this study. It is just, is that benefit, that overall survival, event-free survival benefit derived from the neoadjuvant addition of the I/O? Or is it that prolonged adjuvant treatment, which was not standard of care at the time that this study was designed? It does still raise some questions, but I've definitely seen our medical oncology colleagues incorporating durvalumab more and more into practice, and I'm seeing that in my patients.

And then speaking about the adjuvant space, I do just want to briefly mention that the AMBASSADOR trial was also published last year. So now we have a second I/O option in the adjuvant setting with pembrolizumab in addition to nivolumab.

Sam Chang: Fantastic! What about the second disease state that you looked at?

Alice Yu: Yeah. So the second disease state—when it comes to urothelial, I think you can't not talk about non-muscle-invasive bladder cancer. It's just a field that's completely exploded in the last few years. In the last five years alone, we have several new agents that have become FDA-approved and available on the market for BCG-unresponsive disease, such as pembrolizumab, nadofaragene, and N-803.

A couple of papers I want to talk about that came out last year: One is the CG0070 CORE1 trial, which looked at a combination of an oncolytic immunotherapy agent—cretostimogene grenadenorepvec; it's an impossible word to pronounce, so we'll just call it creto—combined with pembrolizumab in patients who were BCG-unresponsive. And this was a phase II trial, a small trial, but it showed a pretty impressive CR rate at three months of 82% and a sustained CR rate at 12 months of over 50%—57% to be exact.

So that was quite interesting. And then another study in the BCG-naive space was the phase II trial looking at combination gemcitabine-docetaxel—again, a single-arm study in BCG-naive patients. A small study of 25 patients with high-risk non-muscle-invasive bladder cancer, but impressively, they found a CR rate of 100% at three months and a 12-month recurrence-free survival of 92%. And of course, that segues into the BRIDGE trial, which many people have known about, which is a phase III randomized study comparing BCG to upfront GemDoce.

Sam Chang: Yeah, no, absolutely. I think the BRIDGE trial will really give us information on a regimen that some academic institutions have really bought into—combination chemotherapy. In the community, quite difficult to do that combination sequential on one day—the difficulty in terms of administering, the difficulty with operational efficiency with that combination. But to have that randomized trial that's led by Dr. Kates will really be very, very important.

The combination of cretostimogene plus a systemic I/O—the results were very impressive. And, as you know, at this year's AUA, there was a combination of systemic sasanlimab—I said that really quickly because I don't know exactly how to say it—but that combination of subcutaneous I/O therapy in addition to BCG, better than BCG by itself. So we're starting to get some information and data that says the combination of I/O plus a treatment may be better than the single-arm or single monotherapy treatments we've had in the past.

So we look forward to, obviously, further data in this non-muscle-invasive space. Having the FDA-approved agents that you mentioned just really started this tidal wave of other studies looking at other disease states, and we look forward to those readouts. This year's AUA, a lot of different results obviously came out. And we're going to start more and more—I think have more and more options for our patients. How about the third disease state?

Alice Yu: Sure. So the third disease state has to do with risk stratification. I think we are really moving past that stage where we overly rely on clinical-pathologic stage and features to determine who needs treatment. So really, we need to start looking more at biomarkers and AI and all these kinds of adjuncts. So the paper I wanted to talk about was the updated IMvigor010 trial data.

So, as you know, the IMvigor010 phase III trial looking at adjuvant atezo versus observation after cystectomy was a negative study. However, there's been updated data that were published last year looking at the role of ctDNA in terms of determining response. So I thought that was really interesting. Even though the original trial did not meet its primary endpoint, what they've shown is that ctDNA positivity actually does influence the response.

So what they did in this study was that prospectively, they collected blood samples at cycle 1 and cycle 3 of treatment, and the goal was to explore biomarkers. And what they found was that, in their cohort, 37% of patients were ctDNA-positive after cystectomy. And in the observation arm—so patients who did not undergo any treatment—ctDNA positivity was associated with shorter overall survival, and the hazard ratio was quite impressive at 6.3.

And then among patients who were ctDNA-positive, those treated with atezolizumab did better in terms of overall survival. And what they also found was that, now if you compare their baseline ctDNA to their cycle 3 ctDNA, if there was a reduction—a response to atezo—that also showed a really significant survival benefit. And those who had 100% clearance—median survival in this study, the cutoff point was 60 months, but really the upper limit was not even met.

Sam Chang: So how—I mean, I think we are a little bit behind in the urothelial-cancer space with advanced disease using ctDNA. Talking to colleagues in GI, talking to colleagues in lung, and other malignancies in breast, understanding the role of ctDNA in terms of determining what's the best treatment—do you continue treatment? All those types of things I think will become increasingly important and pervasive.

I wanted to give a shout-out to you and your colleagues at Moffitt, Dr. Li and others, really looking at actually urinary findings in terms of tumor DNA and how that may influence findings with urothelial carcinoma. So the role of biomarkers, I think, will continue to be important not only for predictive capabilities but prognosis as well. And I agree with you totally.

This really set the stage of, boy, we really need to start evaluating this progressively. What are we doing? How are we actually then determining what patient treatments should be given, and then when to stop treatment? So there are a lot of investigators now looking at different stages, but I think I agree with you totally. This paper really set the framework of, OK, we need to look at this and look at this carefully. So Dr. Yu, thank you so much for spending some time with us. It was an incredibly well-received review of the key areas within urothelial carcinoma, and we look forward to hopefully spending some more time with you in the future at UroToday.

Alice Yu: Wonderful! Thank you so much.