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Ashish Kamat: A warm welcome to all of you from the UroToday studios. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center. We're live at ASCO GU '25 here in San Francisco, and it's a pleasure to welcome to the studio, Professor Nimira Alimohamed from Calgary. Thank you for taking the time, Nimira.

Nimira Alimohamed: Thank you for having me.

Ashish Kamat: We're really excited to see what you have to say tomorrow, but of course here with us on ctDNA and its role in bladder cancer.

Nimira Alimohamed: Perfect. So tomorrow I'll be taking you through the evolution of ctDNA in muscle invasive bladder cancer. So really focusing on localized disease, where has the data come from, how has that evolved, and where are we going? And most importantly, how will it help us make treatment decisions in the future?

Ashish Kamat: So where do you think we are today, and where do you think we're heading, say, in Pthe next 6 to 12 months?

Nimira Alimohamed: So today, I think we have enough evidence to tell us that the detection of ctDNA at multiple time points is prognostic. I think that's clear. We know that patients who have detectable ctDNA before neoadjuvant therapy do poorly. Patients who have detectable ctDNA after neoadjuvant therapy do poorly. And again, patients who have detectable ctDNA after surgery do poorly.

So I think that's clear it’s prognostic. What's really exciting is now we're in this era—seeing a few trials read out with some early data about the impact of intervention when we do detect molecular residual disease or molecular recurrence with a positive ctDNA test. For example, we recently heard the TOMBOLA initial results, and that was an intervention study based on positive ctDNA only. So it's really asking the question, we don't think everybody needs adjuvant therapy. How do we prevent overtreatment and select the best patients who may benefit from treatment? And the early readout looking at atezolizumab at the time of ctDNA positivity has shown us that we see ctDNA clearance and no evidence of disease in about 55% of patients. So that's early data. It's encouraging.

We've learned a lot from IMvigor, from the IMvigor010 study, which was a negative study with adjuvant atezolizumab, but really ctDNA informing, which then has led to the IMvigor011 study. So those results are eagerly anticipated. The MODERN study, which is a very important study in this field, I think, asked two very important questions. Number one is, do patients who are ctDNA negative benefit at all from adjuvant nivolumab immunotherapy? So there'll be a randomization in those patients who are ctDNA negative. And in those patients who are ctDNA positive, the randomization is between nivolumab alone or nivolumab plus relatlimab. So we're escalating care in those patients who are ctDNA positive. I think those two studies are going to give us a lot of information as to how we treat patients in the future.

Ashish Kamat: Absolutely. And as you mentioned, a lot of the work that's being done—we've almost learned by looking at ctDNA in a failed trial, because that was the first time we actually saw that. With the trials ongoing, and clearly with intensifying and deintensifying based on MRD, I think that's the way we're going to be in the future. But today, when you see a patient in the clinic, how are you using ctDNA assays in your day-to-day clinical practice?

Nimira Alimohamed: So I'm from Canada, and unfortunately, this technology is not funded for use in regular clinical practice. We've had some patients who have sought it out and are paying for it, and it's currently not integrated into our clinical decision making. However, if someone comes to you post-neoadjuvant therapy, post-cystectomy with a negative ctDNA test, that, to me, is really interesting. I don't have any randomized data yet to say, I shouldn’t give you adjuvant immunotherapy, but also, it gives me pause to say, perhaps you're the patient I'm overtreating.

Ashish Kamat: You know, and I think that's an important point because clearly I see a lot of patients that will come in with the assay having already been read out. Or we will get it, but we’ll get it more for a research tool purpose. But today I'm using it more to counsel patients but not making clinical decisions. And I sense that that's what you're recommending our audience and leaders do until the trials read out.

Nimira Alimohamed: Until the trials read out, I think that we need that validated data. I think we’re also learning that a landmark test may not be enough. A landmark negative—so a one-time ctDNA negative test—may not give us enough assurance that we can stop our adjuvant therapy or not start it. I think that we’re going to need serial detection. And that sort of brings me to talk about the challenges: we need to make this technology accessible.

Right now, many different assays are being used. Dr. Wyatt is going to talk about this tomorrow. Many cancer centers, academic centers around the world, are trying to develop their own in-house assays, which is fantastic. If we can do this, we need to do it in a conjoint effort globally so that this isn’t a technology that becomes important for societies and patients who can afford it and irrelevant for those who can’t.

Ashish Kamat: That's a very sobering thought, too, right? Because obviously our listeners are from all over the world, and there are parts of the world where EV pembro is not available, let alone technology such as this, which is very expensive. And you bring up an interesting point, because we don't want ctDNA to go the way of cytology, where it's so operator-dependent that you can't use it in a broad sense. Share with us a little bit your thoughts on tumor informed versus tumor non-informed assays.

Nimira Alimohamed: Yeah. So the tumor informed assays are the ones that have been used in some of these larger trials. The biggest example is a Signatera assay by Natera. The pros of that, I think, is we’re going to see a lot of data read out with that assay. It has been commercialized, so it’s probably easy for many of our patients in North America to access and send their samples for. I think the downside is that it takes time. So a tumor informed approach requires the tissue, requires a specific panel made based on that tissue, and that can take some time. So in certain disease sites and in certain questions, that treatment decision may not be able to wait for that time.

The tumor agnostic assays—I think we’re going to see the development and validation of more of these tumor agnostic assays, which don’t require that lead time. So, for example, in the VOLGA trial, in that safety run-in cohort, they’re using a more sensitive assay, which, again with more data, we may see being more applicable. Right now, it’s hard to tell which one we’ll use in the future. I think it’s going to come down to accessibility, cost, and validation.

Ashish Kamat: Yeah, and validation was the key point I was going to say, because we obviously need to make sure it’s accessible and available. But then the studies are not really—you can’t really co-translate from one aspect to the other, especially when we’re making life or death decisions and very expensive life or death decisions.

Nimira Alimohamed: Exactly. And I think that’s going to be our challenge. We will have one assay answering the question of, can we de-escalate therapy? But in the real world, in our cancer center, if we don’t have that assay, are we still going to be able to use a ctDNA test without that assay to answer that question? So I think we’re going to, as a community, have to decide what level of evidence we’re willing to accept in each of those clinical scenarios.

Ashish Kamat: And you brought up TOMBOLA, and Lars has done a lot of work there, and obviously Alex and everyone. But I'd like to probe you a little bit on this question about ctDNA assays very early on. So you see a patient with muscle invasive bladder cancer in the clinic, and assume you have it available. Let’s assume you're not from Canada, or you have it available and it’s something today that you could get at a low cost. At what time point would you recommend assaying ctDNA? Is it at the time you're deciding on neoadjuvant therapy, or after you've completed neoadjuvant therapy?

I know you talked about serial, so clearly you’d want some time points. What’s your sense as to the clearance of ctDNA and how it correlates with tumor burden? And is that relevant in today’s day and age, when we’re moving from cisplatinum to more targeted therapies?

Nimira Alimohamed: That’s an excellent question. So I think that that initial diagnosis ctDNA level is important, not in and of itself, but what's going to be important is the clearance. If you don't have the baseline, you won't know if it's cleared. So, for example, with our novel agents—I'm thinking of an example of a patient who's ineligible for cisplatinum. Many trials are ongoing in this space, and we're going to see a lot of exciting data, I think, in the near future.

If we have a patient who is ctDNA negative—or positive, sorry—at the time of diagnosis, and they clear with whatever neoadjuvant treatment we're giving them, I think that’s encouraging, and they should go for their consolidative therapy. But maybe then we use that ctDNA clearance to say, “You know what? This patient has had a really good response to systemic therapy, and now maybe they want to save their bladder.” So now with this clearance of ctDNA, can we move to bladder preservation instead of a cystectomy?

And conversely, patients who we treat with whatever systemic therapy and we don’t see that ctDNA clearance—if their ctDNA remains positive, maybe those are the patients who we need to think very hard about. Do we send them for a cystectomy, or do we need to escalate their care to something else? Do they need an MRI? Do they need a PET scan? Do we need to do everything we can at this time point to ensure that we see no clinical or radiographic evidence of disease recurrence before sending them for a life-altering surgery which may not have benefit?

Ashish Kamat: Right. And it applies even to TMT, right? I mean, anything you’re doing for local consolidation. And using that, like you said, is going to be very important, but again, a little caution. We need to make sure.

Nimira Alimohamed: Exactly. We need the data first. We need the data first. In an ideal world, we'll have the data to answer all of these questions.

Ashish Kamat: I really enjoyed our discussion. Any closing thoughts?

Nimira Alimohamed: I think it's a really exciting time looking at the impact of ctDNA in the spectrum of muscle invasive bladder cancer. But again, we’re at a cautious time point where we’re awaiting the data. The data is coming, and it’ll be exciting to see where that lands.

Ashish Kamat: Thank you so much for taking the time.

Nimira Alimohamed: Thank you.