Zachary Klaassen: Hi. My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. Welcome to UroToday at the AUA 2025, in Las Vegas. I'm delighted to be joined by Dr. Reuben Ben-David, who is a SUO urologic oncology fellow at the Icahn School of Medicine at Mount Sinai. Reuben, thanks for joining us on UroToday.

Reuben Ben-David: Thank you very much. It's really a privilege for highlighting our study.

Zachary Klaassen: It's great to have you. And you guys presented some great data at AUA looking at what the impact of pre-cystectomy ctDNA on oncological outcomes. So we're going to get into that study. But maybe just highlight the landscape of ctDNA in bladder cancer.

Reuben Ben-David: So ctDNA is really fascinating in the world of bladder cancer. And at the moment, most of the studies are using a specific assay, a Signatera assay. And it's a tumor-informed assay that takes the tumor from the patient, makes his own tumor signature, which is unique to the tumor of that patient. And then we go and check in the blood if we can detect any circulating tumor cell-free tumor molecules in the blood.

And then according to that, if it's detectable or undetectable, inform about the prognosis of that patient and the pathological outcomes in cystectomy. And really, the first study which brought it into the bladder world was the IMvigor010. That used it in the MRD. So in the post-cystectomy minimal residual disease window.

And they looked in a retrospective manner. It was a prospective trial, but they did an ad hoc analysis. And really showed that patients who received adjuvant atezolizumab and had a detectable ctDNA did better than those who did not get atezolizumab and had a detectable ctDNA. Interestingly, those that had undetectable ctDNA, the arms did the same. Eventually, the study ended up being a negative study.

But when you go and dive into detectable versus undetectable, adjuvant treatment did make a difference. And really then we wanted to take that one step ahead. Can we use ctDNA before radical cystectomy to inform our decisions at that stage?

Zachary Klaassen: Great background. I think that's really a transformative paper for ctDNA. And it's the beauty of taking the translational data from a negative study and really putting together the landscape of what we're talking about today. So, on that background, maybe just tell us about your study design that you presented at AUA.

Reuben Ben-David: So what we did, we were collecting ctDNA before radical cystectomy, informing it from the TURBT specimen. So we get the tumor signature from the specimen. And then before the surgery, we would check in the blood of the patient. Can we detect or not detect ctDNA. So we had that pre-cystectomy signal. And then in our study, we also looked after radical cystectomy. We would continuously collect ctDNA after.

But we really wanted to concentrate on the pre-cystectomy ctDNA. And we have published about it previously about how it is prognostic of pathological outcomes in cystectomy and also how it can prognosticate recurrence-free survival. But what we wanted to see here is that the ctDNA was till now looked in a very qualitative manner. Positive, negative, detectable, undetectable.

So we really wanted to see if the mean tumor molecules per milliliter reported by the company can define distinct groups within the detectable group. So we already know that the detectable cystectomy group does worse than the undetectable group in metastatic recurrence after the surgery. We also know that the detectable group has worse pathological outcomes in cystectomy than the undetectable group. But we really wanted to dive into the detectable group and really see if we can define distinct groups within the detectable group that behave differently.

Zachary Klaassen: Sure.

Reuben Ben-David: And then we call it the ctDNA burden. So looking at our cohort of about 120 patients, we were able to define three subgroups, undetectable, detectable low burden, and detectable high burden. We used different cutoffs. And we kind of chose a cutoff that provided relatively good specificity, and group distribution, and with acceptable sensitivity. And again, this is based on our cohort.

As we get larger cohorts, this cutoff might need to be changed. But we were really able to define two distinct groups there. And what we found that the patients with low burden ctDNA had worse outcomes than undetectable. This is again, we know that.

Zachary Klaassen: Sure.

Reuben Ben-David: But their median time to progression was almost 12 months.

Zachary Klaassen: Wow.

Reuben Ben-David: And about 50% of them were cured at one year. But when we looked at the high burden ctDNA, their median recurrence time was half of that. It's like five months.

Zachary Klaassen: Wow.

Reuben Ben-David: So we can define a group that progresses rapidly after cystectomy. And also looking just at the three-month period, more than 40% had metastatic recurrence.

Zachary Klaassen: Wow.

Reuben Ben-David: So this is the time we give these patients adjuvant therapy while they are developing metastatic disease. So, really, by looking at the burden, we might be able to define groups that behave differently and need different protocols. And it's not using a hammer and just looking at the pathological outcomes of the patients and then giving them this or that. We can really personalize the medicine to that specific patient.

And this is again in the cystectomy. So there comes a question. Do these patients need more intensive treatment than neoadjuvant? Do they have to get neoadjuvant? Do they need something else? And what about the undetectable group? Can they just benefit from upfront cystectomy?

So this really raises questions. And this hopefully will be able to explore in the future in clinical trials.

Zachary Klaassen: It's a great explanation. And you almost answered my next question was this is going to inform what should we do. Neoadjuvant, yes or no. Do we do adjuvant even before they become metastatic? Or do we just not even do cystectomy? Do we just give them EV pembro for what's going to be metastatic disease? So you've nailed it. And that there's a lot of different directions this goes. And I think your last statement was really good about this is informing clinical trial design going forward. Correct?

Reuben Ben-David: Yes. So part of the group, Dr. Sfakianos is really leading this exploration. And our next goal will be really to design a clinical trial. We call it the DECIDE trial. And hopefully, we will be able to maybe inform should the patient get neoadjuvant or not or something else. And then proceed to cystectomy. And really using ctDNA to inform us on our clinical decisions.

Now, we know that in the adjuvant setting, the MODERN trial and the IMvigor011 are already trying to answer that question in the post-cystectomy, who should get or not adjuvant treatment. But we wanted to really bring it to the cystectomy and try to maybe answer who should get neoadjuvant or more intensive treatment in the cystectomy setting.

Zachary Klaassen: Thanks so much for awesome discussion. Maybe just a couple of concluding statements for our listeners today.

Reuben Ben-David: So ctDNA is really fascinating in the world of bladder cancer. And I think from all the other GU cancers that we have, bladder cancer is really the highlight of ctDNA at the moment. We are finding really good signal for ctDNA in the cystectomy setting. And we are able already to define subgroups of patients who behave differently.

And hopefully, with future clinical trials, we will be able to also inform on how do we treat them before the radical cystectomy and really taking it one step forward for the patient. Because I can imagine for the patient getting cystectomy, losing his bladder, and then discovering he's metastatic after three months.

Zachary Klaassen: Devastating.

Reuben Ben-David: It's not good news. So really also setting up the expectations with the patients is extremely crucial. And really giving our patients better information and giving them better treatment with these novel biomarkers.

Zachary Klaassen: Absolutely. Well said. Congratulations on great data. We'll look forward to the DECIDE trial. It's going to be a really important trial. And thanks for joining us on UroToday.

Reuben Ben-David: Thank you so much for your time.