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Sam Chang: Hi. I'm Sam Chang. I'm a urologist at Vanderbilt University Medical Center in Nashville, Tennessee. And I toss around the word superstar—people say probably too often. But in this case, it's actually really pretty much on the mark. Dr. Fed Ghali, I first met when he was a resident at UCSD, when he was obviously a rising star.

He finished his residency there and a fellowship at the University of Washington, and now is an assistant professor at the Yale University Medical School and has an appointment, actually, at the Cancer Center at Yale as well. And he gave a really, really thought-provoking discussion at the SUO 2024, focusing on actually the management of the bladder, which we are familiar with as urologists, but actually in a unique situation in patients actually with metastatic disease or thought to be metastatic disease that have undergone systemic therapy and then have had a response. And the question is, what's next?

And so he gave an excellent discussion. We've asked him here to give an update or a Reader's Digest version of that for UroToday. So Dr. Ghali, Fed, thank you so much for joining us. And we look forward to your presentation.

Fed Ghali: Well, thank you so much. It's really great to get to speak with you. And it's an honor to get to share some thoughts and that you're taking an interest. So thanks for having me here. Well, Dr. Chang, just like you said, I gave a talk around this topic at the SUO. And I shortened it for this presentation here. And so hopefully, it will cover some of the same material.

So the question here is, is there a role for consolidative local therapy in the setting of patients with metastatic bladder cancer that are getting systemic therapy and are having a robust response? So that's what we're going to talk about here. And, by way of background, metastatic urothelial cancer, as many of us will know, has really poor outcomes. And these patients unfortunately experience really high rates of mortality. But we're seeing lots of progress in this space.

And so by way of demonstrating, this is a study from 2023, which tracks patients that received different regimens of first-line chemotherapy and shows their overall survival across different treatment types. And what you can see is that this is a Kaplan-Meier that we'd want to improve. If you see, overall survival rates at the five-year mark are really quite low, between 5% and 20% or so.

But in March of 2024, we saw one of two trials that showed an improvement over cisplatin-based chemotherapy in metastatic bladder cancer. This is EV 302, which showed that enfortumab vedotin in combination with pembrolizumab had really significantly improved outcomes, both in progression-free survival and overall survival for these patients.

And one of the things that many of us are seeing now in our practices is, many patients who are on this regimen and are experiencing either stable disease or responsive disease, where the tumors actually shrink away, and are just living that way, have a durable response or durable progression-free survival. So I highlight this line here. And I say, what do we do about these patients? These are patients that are becoming increasingly more frequent in our practices.

And the question is, is there a role for trying to improve outcomes even more for these patients using some of the treatment modalities that we can offer as urologists and radiation oncologists? And as many great questions go, I'm not the first to think of them. And we're not thinking of them for the first time today. And so this question has been explored in the past. It actually started with some really astute clinical observations back in the '80s and '90s.

One study that I like to reference is this study here from M.D. Anderson. This is a study reported in the early '90s. And what they saw is that patients receiving cisplatin, patients with metastatic cancer receiving cisplatin, that have some site of metastasis—so here I put a schematic of a liver or bone or so on—that gets some response, where the tumor shrinks away.

When these patients ultimately recur, almost 3/4, actually a little over 3/4, of the time, the recurrence starts in the same spot that had responded initially. And it spurred early on a sense that maybe these sites that were responsive were still harboring some resistance, some were the source of recurrence down the road.

Multiple studies have looked at this early on in the '80s and '90s. This is just one of multiple studies. This is from the Memorial Sloan-Kettering group, which looked at over 200 patients that had had metastatic disease and had some response. And these are patients who were consolidated with surgery, or at least attempted consolidation with surgery.

And what you can see is that these top two lines are patients that either had a complete response just with chemotherapy alone or with chemotherapy and surgery. So if you went in and surgically resected any leftover sites of disease, those two lines are really close to each other. That bottom line that shows clearly a worse outcome—these are patients who did not have a complete response with surgery. They refused surgery or were deemed surgically unresectable.

And this is one of several studies, like I say, we have studies from Stanford and from M.D. Anderson as well, that show that patients with, generally speaking as a trend, durable responders that get consolidation generally do better than those where the residual disease is just left behind. And this makes intuitive sense.

We're now in an era where we have really fantastic translational science that sheds light on some cancer biology to help guide us here. And what we see is that there's really significant intratumoral heterogeneity within bladder cancer. So urothelial cancers contain a really significant level of heterogeneity, even within a single tumor.

And we and others have shown that there's a significant amount of intratumoral heterogeneity even within one patient. So as the disease goes from one site to multiple sites, it's evolving and changing and responding to different environments as well. So it's really not the same single disease, maybe like the way we thought about it 100 years ago.

And finally, the treatments that we are administering are also causing the tumor to interact and change and evolve. So a really great study from Peter Black and Jonathan Wright and colleagues showed that if you compare, for example, TURBT samples in patients who got neoadjuvant chemotherapy and then look at their cystectomy samples, you can see molecular consensus class switching almost 70% of the time in some cases.

So the tumor is really changing and shifting in response to things like chemotherapy even. And what this further highlights is this idea of a sanctuary site on the translational level, a sanctuary site where tumors, even if they respond initially, can still harbor, basically, tumor resistance.

And so going back to these studies from the '80s and '90s, I think the time is now to reconsider and re-explore some of these questions that we've looked at back in the cisplatin era, in today's era. And that's because, as I mentioned, we have new systemic therapies that are more effective than cisplatin. We have new tools for patient selection, not just because our imaging and staging is getting much better and more refined, but we also have tools like ctDNA and molecular consensus testing and so on.

And finally, the options for consolidative therapies are improving. Surgery itself is becoming less morbid with time. And we have novel therapies like SBRT, which are really effectively able to deliver quite high doses of radiation with minimal damage locally. So as we think about how would we do this, I think I made the argument at SUO, and I would make it here today, that this should be done in the setting of a clinical trial to generate high-quality evidence, prospective evidence.

This clinical trial should focus on responders to systemic therapy. So I think that these are the ideal candidates to consider consolidating response rather than, say, trying to salvage patients who are progressing in the face of therapy. I think there's some good evidence I didn't share today, but there's some good evidence that maybe surgery is not that effective in that setting.

These have to be motivated, highly selected patient populations, of course. And a multidisciplinary team needs to be involved. This will involve medical oncologists and radiation oncologists. And finally, translational correlates really should be integrated in most clinical trials. At this point, I think we've seen the benefit of that. So that was the majority of what I presented. And I've got some backup slides in case we want to dive into any of these in more detail.

Sam Chang: Fed, that was a great presentation. Thank you so much for your historical perspective of systemic platinum-based therapy and then followed by consolidated localized therapy. As you think about these new systemic therapies, the ADC conjugates with your immunotherapy—the response rates of those that respond seem so good. Are we perhaps doing too much for those patients?

And perhaps with these newer systemic therapies, we should look at those that maybe have a good systemic response, but clearly haven't had much impact locally. I'm trying to figure out the best patient population, as you outlined. I agree with a lot of them. I'm just trying to figure out how do we determine this is going to be helpful or not?

Fed Ghali: It's a great question. The question of, well, if they've had a complete response, maybe we don't need to do anything for them. Maybe we can just leave them alone, and we would be overtreating them by doing anything further. I imagine I'm going to say this a lot with a lot of these questions: the real answer is we don't know. I mean, I think we need prospective data.

But I have some reason to think that maybe even for those patients that appear radiographically like they have responded, there's some benefit. One of those lines of thinking that I have is that in some of these prior studies—which I didn't dive into today, but some of these historical data—when they have done cystectomies, or sometimes what they've called surgical restaging on these complete responders, almost 40% and 45% of these patients will have residual disease on pathology, even when they were considered complete responders prior to that.

And we've seen this even in a different arena when we try to, for example, avoid cystectomy in the muscle-invasive setting for patients who we think had a complete response to neoadjuvant chemotherapy, for example. What we're learning is our ability to clinically stage probably underappreciates the level of residual disease when compared to pathology.

So if we're already looking at patients who had significantly aggressive disease and were metastatic, and these are already, as we say, highly selected and very motivated patients, and knowing or suspecting that many of them will have some residual disease if we were to take their bladder out, my thinking is, in this patient group, there's potentially a real benefit to proceeding, even if it's true, just like in muscle-invasive disease, we may be overtreating some. And we know this. But given the limitations of the tools we have, I think that it's a reasonable question.

I'm looking forward to prospective data one day, where we might, one, have correlates maybe that tell us exactly who falls into which camp. I think that that's going to be really welcome data. Or, like you say, maybe when we run the studies, we'll learn that maybe we were a little overeager. But I think some of the retrospective data suggests that we might be missing a significant group of patients by leaving a significant amount of—for example—leaving the bladder in in this case.

Sam Chang: And as you consider those individuals that respond, and hopefully respond, to systemic therapy, I always struggle—we are learning more and more about the role of cytoreductive nephrectomy. And we did too many, and then now we didn't do too enough. And now we're shifting back and forth and timing and the role.

For bladder cancer patients, as we start seeing some of these really significant responses, tell me what you think of, knowing the biology of urothelial carcinoma, what a reasonable time frame would be. In other words, we've gotten basically a complete response systemically in nodal sites or metastatic sites. Do we wait three months, six months, a year? We continue the systemic therapy? How do you see the time frame of this situation for patients?

Fed Ghali: Another great question that will ultimately be answered with more data. I think in my mind, the framing that I would have is that we have a window that will last an unknown amount of time in patients who are currently experiencing their systemic disease on their back foot. That's the model, the mental model, that I have.

And so it may be the case that some patients get a very long window where we maybe can keep them on systemic therapy for six months or nine months or a year until it either changes or they declare themselves as being fine on systemic therapy for the foreseeable future. Or other patients will have a very narrow window. So that's not a way to dodge the question.

In my practice, it's been somewhere around the six- to nine-month mark of really durable response, and I felt comfortable, with a lot of counseling, saying, I can't guarantee you that this is going to make you live longer, but I can tell you here's the evidence that we have. And I think it's reasonable to try it and that sort of thing. I think around the six- to nine-month mark has been the timeline for me.

But really, I suspect, and at least the model that I have in my mind, is it's more of a dynamic process rather than a strict time point. And I'm hoping that one day we'll have really significant prospective evidence to help guide that.

Sam Chang: Yeah, I think the use of the word "dynamic" is an important one, because it's going to be personalized and it's going to be dependent upon volume of disease, location of disease, all those types of things. But I think your discussion regarding making those decisions will really depend upon further study and will really depend upon our ability to continue to assess the true current status of a patient's disease process, be it ctDNA, be it urinary ctDNA, be it certain types of imaging.

Other things are going to be actually all coming into play to help us determine what is truly going on with that individual patient. Fed, I just want to say thank you so much for spending some time with us. Your presentation was very well received at the SUO and obviously quite thought-provoking.

And for all of us, as we attempt to try to maximize and utilize that window, as you described, I mean, I think the only beneficiary truly is our patients in the long run, as long as we do careful and thoughtful studies, just as you've outlined. So thanks again. And we look forward to your future work as well.

Fed Ghali: Well, it's a pleasure to be here. Thanks so much, and great talking with you.