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Leslie Ballas: Welcome to ASCO GU 2025. I'm Leslie Ballas, a radiation oncologist at Cedars-Sinai, and I am extremely lucky to be joined today by Dr. Matt Galsky from Mount Sinai Hospital in New York to discuss his abstract, "Additional Efficacy and Safety Endpoints," from the NIAGARA study. Thank you for joining me today, Dr. Galsky.

Matthew Galsky: Of course.

Leslie Ballas: Such a pleasure. Why don't you tell me a little bit about this analysis of the NIAGARA data?

Matthew Galsky: So the NIAGARA study, just quick recap—randomized phase III study. Patients were randomized with muscle-invasive, clinically localized bladder cancer to receive neoadjuvant gemcitabine-cisplatin plus durvalumab followed by cystectomy, followed by adjuvant durvalumab or standard neoadjuvant chemotherapy followed by cystectomy and then no planned adjuvant therapy for that group of patients.

So the primary endpoints were event-free survival and pathological complete response rate, and those primary endpoints have already been reported. Paper’s been published in the New England Journal of Medicine showing an improvement in event-free survival with perioperative durva, improvement in overall survival actually, too, which was a key secondary endpoint. And then the path CR rate’s about 10% higher in the durvalumab arm versus the comparator arm.

So this analysis is really based on additional secondary endpoints, metastasis-free survival and disease-specific survival, and then really taking a look at the impact on path response in time-to-event outcomes because there’s always been this debate, is path CR meaningful? How does it correlate with how patients do in the longer term?

Leslie Ballas: And what is the importance to patients of metastasis-free survival and this particular secondary analysis?

Matthew Galsky: So I think the two secondary endpoints that we present in this analysis are relevant to patients. Event-free survival is a composite endpoint. It’s an important endpoint, but it’s a composite endpoint, and so it’s hard to explain that to a patient.

But metastasis-free survival is pretty straightforward: time living without development of metastatic disease or dying of cancer. And disease-specific survival, we don’t think about this a whole lot for bladder cancer studies, probably not as much as we should because we haven’t done so many perioperative studies in the past 15 to 20 years, actually more so in the past five to 10 years. But prior to that, there was a long period of time when we didn’t have these huge randomized studies. And as you well know, this is an older patient population. Unfortunately, there are competing risks, and so particularly in the neoadjuvant and adjuvant setting, I do think we have to start thinking about disease-specific survival as well.

Leslie Ballas: In this study, you found that the path CR rate was about 40%, which is very much in line with other studies in the localized bladder cancer space. VESPER showed, with just a differentiation in which neoadjuvant and adjuvant chemotherapy was used, similar, about 40% path CR rate. PURE-01, where they looked at just neoadjuvant immunotherapy, found a path CR rate of about 40%. Here we have a combination of neoadjuvant chemo with durvalumab, path CR rate of about 40%. Why are we seemingly not able to get better path CR rate with different drugs, combination of drugs? What are your thoughts on that?

Matthew Galsky: So I think it’s a great question. I think it’s a question that requires a little bit of context. One of the benefits of having large registration studies in this space—and if you think about it, we haven’t had that. This is really the past five years; now we have a bunch, but we hadn’t had that before.

That really forces one to be quite rigorous in terms of how you define your endpoints and measure your endpoints. And so a lot of the data sets that you reference, if you look at those studies and the methodology, the path CR rate is defined in patients who underwent cystectomy. Well, that makes sense because you can’t measure path CR if a patient didn’t have a cystectomy. But that’s not a true intent-to-treat analysis, and you don’t know what happened to that denominator. If a patient progresses before cystectomy, clearly that patient should be included in the denominator, but that’s not been the case in the vast majority of studies that you reference.

So this was an intent-to-treat analysis, and I think the differential between the two arms because of that is probably more important than comparing to the other studies. And there’s a 10% higher path CR rate. So then you can ask, well, is that good? Is that as expected?

If you look at the response rates in metastatic disease to something like gem-cis plus nivo versus gem-cis from the CheckMate 901 study, it bumps up response rate by about 10%. And so I think all of that really lines up. So yes, different methodologies probably make cross-trial comparisons that are typically dangerous even more dangerous. Yes, we are seeing a bump. Could we do better? Ideally.

Leslie Ballas: And this data confirms what we know, which is once you achieve a path CR, you end up doing—the overall survival is better, and that holds true in this data whether the patients got path CR or did not. Still durvalumab makes a difference. Perioperative durvalumab makes a difference. I guess my question would be, when you have now metastasis-free survival as an endpoint, is path CR an important endpoint? Do we need to be focused on that?

Matthew Galsky: So I think there are two aspects of that. One is, what does it teach us about what the regimen is doing and what it’s not doing? Two, can we keep using path CR as an intermediate measure of activity of novel regimens in the phase II setting before we go to the phase III setting? And then three, is it a meaningful endpoint from the standpoint of regulatory approval? Does it impact how patients feel, function, or survive?

So taking the last one first, we’ll now have multiple randomized phase III studies to see if it is a true surrogate for overall survival. And if it is, then the regulatory implications of path CR as a definitive endpoint I think come into play.

Whether or not it helps us sort out what the regimen is doing and not doing, I think it’s quite valuable, actually, in this study for the reason that you point out, because patients who had a path CR and patients who didn’t have a path CR still benefited from the addition of durvalumab. And that teaches two important lessons. One, it teaches that you don’t have to have a path CR to benefit from perioperative chemotherapy or immunotherapy. And we’ve always known that. There are these patients that are, quote unquote, “downstaged” but still have primary tumor in place. And those patients probably have eradication of micrometastatic disease but not full eradication of the primary tumor. So it makes sense intuitively, but it’s been difficult to show that.

And then, as importantly, there’s a separation of the curves for event-free survival in patients who have a path CR with the addition of durva. And so I think that was not necessarily expected by many individuals, and I guess I was somewhat surprised. But I think that makes sense intuitively as well. In the metastatic setting, to borrow the gem-cis nivo study again, if you have a radiographic CR on that study—on CheckMate 901 with gem-cis nivo versus gem-cis—the quality of your radiographic CR is completely different. So how you get to the endpoint in terms of what drugs you receive does seem to matter, and I think that’s a contribution of the path CR analysis in this study.

Leslie Ballas: You mentioned downstaging in your discussion point, and I’m actually curious, did you do any sort of subset analysis within this patient population of those that did not have a path CR—whether their path T stage made a difference in terms of outcomes, or whether the fact of just being downstaged—maybe they started with T4a disease and then went to T2 disease, clearly not a path CR. But does that downstaging make a difference?

Matthew Galsky: So we haven’t done that yet. It’s a great analysis to do. We previously published a paper trying to see whether or not downstaging by one or more T stages has implications regarding time-to-event outcomes using observational data. Despite the difficulty with clinical staging of bladder cancer, it does seem to, and so I think that analysis makes sense to do. But it hasn’t been done yet.

Leslie Ballas: Congratulations on your abstract and to all NIAGARA investigators on an incredible randomized phase III trial. Thank you again for coming and discussing this with us today.

Matthew Galsky: Thanks.