Sam Chang: Hi, my name is Sam Chang, a urologic surgeon at Vanderbilt University Medical Center, and I am truly in the presence of greatness. I have three real experts in the world of urothelial carcinoma. And we've got Drs. Parminder Singh, Dr. Mark Tyson, Dr. Leslie Ballas, who will actually focus on the current discussion around bladder preservation therapy options.

We're going to actually focus on muscle invasive bladder cancer. We may have some time to talk about nonmuscle-invasive disease as well. But Dr. Singh, I'm going to start with you giving us an overview of the thought process. And then we'll have others chime in. And I'll, of course, have a few questions. So Dr. Singh, I'll turn it over to you.

Parminder Singh: Thank you. Thank you, Dr. Chang, for inviting us today to talk about bladder preservation. I think this is a very important topic which has come up through the advocacy for bladder cancer patients. And the whole field is moving in this direction, not only in nonmuscle-invasive space, but also in muscle-invasive space, which I think previously we would think about bladder preservation only in the muscle-invasive bladder cancer.

But now with newer medications coming in, nonmuscle-invasive, this concept is now kind of broadening up. But I think the driving factor for this is that why patients want their bladder preserved is clearly it entails less morbidity and mortality. We have data from SEER that across centers not just in high volume centers.

But if you look at across centers and patients who are 80 years or older, the morbidity could be as high as 50%. And mortality could be as high as 10% to 14% post radical cystectomy. Having bladder preserved allows them to maintain their continence function, they can maintain sexual function.

Also, there was a think tank which came together through the Bladder Cancer Advocacy Network, and they did a survey for over 845 patients and caregivers and asked about their priorities for their disease and treatment. And consistently, bladder preservation and durable response came up as their choice.

And so now, with advent of these newer drugs, I think we need to explore this space more so that we can figure out the right patient with the right combination of treatment to allow these patients to keep their bladder and maintain the normal continence function. So I think bladder preservation is an upcoming area of both research and clinical practice which we will be seeing a rapid evolution.

Sam Chang: Dr. Singh, I think all of us have a better appreciation of the role of bladder preservation and its attractiveness to patients. You have now a slide up talking about TMT, Trimodal Therapy, multi trimodality therapy, et cetera for patients with muscle invasive bladder cancer.

I'm going to actually ask Dr. Ballas here. Leslie, when you see a patient, tell me how the patient today looks different from perhaps 10 or 15 years ago. I mean, patients are now starting to ask for this. Tell me, as you see patients, what are you discussing with them? What types of patients are you seeing? And tell me how you're integrating the thought process of TMT for patients with muscle-invasive bladder cancer.

Leslie Ballas: Yeah. Thank you. So I would say that there's been a real sea change in the type of patients that we're seeing now in radiation oncology. Before, trimodal therapy seemed to be reserved for patients who were either elderly and felt to be too frail for surgery, or who were not surgical candidates for other reasons. However, over the past, I would say, five or so years, that's changed a great deal.

NCCN guidelines have made trimodal therapy, which is the combination of TURBT or scraping of the bladder with chemoradiation, a level I recommendation, along with surgery in the properly selected patient for stage II and III bladder cancer. And so now we're seeing patients who are more robust, who aren't just too sick for surgery, but who are really looking for that option to save their bladder.

Sam Chang: Leslie, Parminder has now put up a very busy slide regarding ideal candidates for TMT. In reality, Mark, when you see patients for cystectomy with the thinking about giving the best possible therapy to your patients, instead of telling us about patients that are ideal candidates, who do you not send to radiation therapy, or at least are somewhat too reluctant to give that as an option to patients?

Mark Tyson: Yeah. So I am glad I'm on Zoom and not within arm's length of Leslie for this comment. But in general, I think if somebody has gone through neoadjuvant chemotherapy and they still have large volume, particularly extra-vesical disease, let's say locally advanced stage T3 or T4, then that's somebody I'm much more inclined to lean towards cystectomy than I would be on radiation, assuming they're obviously clinically localized.

Somebody has hydronephrosis and they're going to be stent-dependent, that's somebody else that I would tend to say is probably not a great candidate. Obviously, people who've had radiation before, that I usually defer to our radiation oncologists about if they're comfortable giving more or not, somebody who has active Crohn's disease and we're worried that it might worsen their colitis or worsen their ileitis. Those are generally the big ones.

But I will say that in the expert hands of folks like Dr. Ballas, I mean, many of these risks can be mitigated. So it is a conversation that I have regularly with the radiation oncologist. So I'll just say one more. If somebody has poor baseline urinary function, they're already incontinent or they're already dealing with bad urinary frequency, urgency, that'd be somebody else I would lean more towards cystectomy for.

Leslie Ballas: Mark, I would have been OK with that.

Sam Chang: I was going to say, do you agree, Leslie.

Leslie Ballas: I think you did good. The only thing I would say different is I think that unilateral hydronephrosis was allowed on the SWOG/NRG 1806 trial, and I think we've become more comfortable with that. Hydronephrosis is a poor prognostic indicator for both radiation and surgery. It's just evidence of potentially more disease there.

The other patients that I personally have a harder time saying yes to for TMT are certain variant histologies. We know that pure squamous cell carcinoma, pure adeno may do worse with TMT. Plasmacytoid, we have lack of information really on that particular variant. And patients who have extensive CIS are patients that we just don't have good modern data on to do TMT without some caveats.

Parminder Singh: Yeah. I kind of concur with that patients in what we have seen is that if they have extensive CIS in the bladder or had prior BCG refractory disease and that is evolving into muscle invasive disease, I've seen those patients having residual noninvasive disease requiring further management and then may end up getting a radical cystectomy for that. And so diffuse disease could also be a potential exclusion for these patients.

Sam Chang: Let me add one more to consider. And I would love to hear all of your standpoint about that. A key point of the trimodal therapy as outlined by all of you is the systemic therapy, obviously, the systemic or the radiation therapy.
And then the maximal TUR. If we cannot-- if the bulk of the disease-- this is to Mark's point-- if their disease is so bulky, et cetera, not extra-vesical but actually within and we think it's organ-confined, those patients probably aren't going to do as well with bladder-preservation therapy. Does everybody agree with that?

Leslie Ballas: I would typically say that has classically been the teaching. Just this past year, there was a Canadian multi-institutional study that was published in our radiation oncology Red Journal with over 750 patients that asked this maximal TURBT question.

And what they found was that there was no difference in five-year overall survival, cancer-specific survival, or metastasis-free survival in those who had complete TURBT and those that did not. Additionally, the patients on BC 2001, the trial that randomized patients to either radiation alone or radiation with chemotherapy, not all of those patients had complete TURBT. And so I think that that's still kind of an open question. If you can't do truly a complete TURBT.

Parminder Singh: And I think I can add something to this, is these patients who, as Mark pointed out, because Canadians are very open to giving neoadjuvant chemotherapy and BC 2001 also allowed neoadjuvant chemotherapy, I think somehow there was this selection that patients who didn't have or they had a lot of disease in their bladder, they end up getting neoadjuvant chemotherapy.

And so that's where the selection comes in, where if we see in our practices there is a higher volume disease or even N1 disease, I would convince the patient to go through neoadjuvant chemotherapy and then reassess. Maybe the neoadjuvant chemotherapy can debulk the disease itself if the TURBT is not able to do that. And then we can consider that patient for TMT as we line up those patients for your trial, Leslie, S2427. I think by giving better treatments upfront, would make more patients eligible for that?

Sam Chang: This is a good time now, Dr. Singh. I think we have a slide regarding the trial that Dr. Ballas is helping to lead with Dr. Tyson. Let's talk about this. Leslie or Mark or both of you, kind of give us an idea of what is going to be starting hopefully in the summer of 2025.

Leslie Ballas: Yeah So we're hoping to activate this trial in July or early August 2025. So this trial was initially started-- the idea for this trial was initially started because we had a number of patients that would get neoadjuvant chemotherapy as part of their package to undergo cystectomy.

These are either patients who opted for cystectomy upfront or who never met with a radiation oncologist. And they have a good response to neoadjuvant chemotherapy, and they then decide that they want to save their bladder. And there's no real paradigm for those patients because neoadjuvant chemo is certainly not required for bladder preservation with radiation.

The only randomized trial that's ever looked at that question showed that there was really no difference in overall survival between those that got neoadjuvant chemo and those that didn't. And so we find that there is an unmet need in our patient population for what happens to those patients who have had a really good response to neoadjuvant chemo? Can they then save their bladder? And so that is what this trial is aiming to address.

Basically, it takes any patient who has muscle-invasive bladder cancer, node-negative, who've received at least three cycles of neoadjuvant therapy. They then have good response by CT scan and cystoscopy. They need to have clinical T0 or T1 disease. They undergo TURBT to make sure that they don't have muscle-invasive disease. And then they can register onto trial.

Every patient gets the same treatment. They get radiation to the bladder with immunotherapy, pembrolizumab. And they would then continue to be evaluated with every three-month cystoscopies, cytology, and imaging. Obviously, reserving salvage cystectomy for those who had muscle-invasive failure.

But this trial is built not only on that clinical need that I expressed that we hear from patients somewhat regularly, but also there have been a couple of phase II trials that have looked at patients who've had complete response to neoadjuvant chemotherapy or neoadjuvant chemoimmunotherapy and have done really quite well with just systemic therapy.

We've added radiation to that systemic therapy in patients with good response because we know the importance of local therapy. SWOG trial in the past has shown that those who look like they have clinical T0 disease end up with pathologic T0 disease in about 40% of the time. And so the importance of local therapy, even in a really good response, we know exists. And so it's trying to address both of these sort of demands from patients and from expected outcomes.

Parminder Singh: Yeah. And I think this also highlights the de-escalation strategy. I don't know if you mentioned that we are taking off the chemotherapy. And that is going to be a kind of very novel strategy of checking just immunotherapy as a radiosensitizing for the radiation. So very excited to look towards this trial.

Sam Chang: I think this preneoadjuvant treatment in whatever form we take-- chemotherapy currently, obviously, I think the landscape will be changing as many predict with combination ADC and IO, et cetera. But then this kind of evaluation of this clinical T0 state and then subsequent therapy, radiation therapy, radiation plus IO, cystectomy, surveillance, just systemic.

To me, my struggle is this clinical T0 determination. And so, I would love to hear what Dr. Tyson thinks about, what's the best and fairest way that we can determine clinical T0? Obviously, the simple ways are cystoscopic evaluation, negative cytology. Doing the biopsies, I think, are really important. But are there other things? Should we be looking at circulating tumor DNA? Should we be using mandating MRI imaging, et cetera? Can you tell me your thoughts of this determination of clinical T0?

Mark Tyson: Yeah. I think Leslie did a really nice job designing that into this trial. And she alluded to it with SWOG 0219, where we know 60% of patients who we think have a complete response, in fact, have residual disease. And so, for me, when I do this, it's a little off the beaten path and certainly not guideline-concordant.

But when I do this in the real world for patients who either are just not candidates for cystectomy or otherwise really don't want it, that does consist of some type of cross-sectional imaging. I generally try to do a bladder MRI, but CT scan is very reasonable and a TURBT to assess. TURBT of the area that we previously resected and any other area that's fluorescent on blue light, and obviously a cytology as well.

I am not to the point where I'm using urinary biomarkers regularly, although I could see in the near future where something like convergent testing could be very helpful to quantify the number of mutations in the urine. And that's what I really like about this trial too, is with HCRN GU 16-257, we know for many of these patients that we can salvage them.

But if a patient has persistent disease, let's say T1 disease after neoadjuvant chemotherapy, I think it's probably better to do something definitive locally out of the gate than waiting for the need to salvage them. So that's why I'm really excited about S 2427. And will just take this opportunity while I have the microphone to congratulate my buddy Leslie on designing a really nice study.

Sam Chang: No, that was great. You broke up a little bit there, but I think the story came through regarding that importance in the valuation and then going from there. And I think a key component of this is really that adjuvant arm after the red box of localized control and systemic.

And how long do we do the systemic, all those types of things? I'm sure you all will be collecting data along the way at different time points that will help us ex post facto in terms of what we're doing. But up front, to me, I really appreciate the study design because we see these patients.

I think Parminder and I know Leslie and Mark would agree, these are patients now we're seeing more and more of. And we're going to only see more of these in the future. So I guess the only other question I have is, you have three cycles of neoadjuvant therapy, and you say it has to be at least three cycles of a platinum-based regimen.

Leslie Ballas: For those who receive neoadjuvant chemo, it must be a cisplatin-based regimen. However, we specifically left the neoadjuvant therapy vague because as we know, obviously, NIAGARA has changed neoadjuvant therapy with the addition of durvalumab. We don't know what BV 15 is going to show. And so if EV pembro becomes a standard in the neoadjuvant space, this allows for that.

Sam Chang: So that's what I was going to ask. The neoadjuvant, if it's chemotherapy, it has to be platinum-based. But other neoadjuvant therapies could be in that bucket. No. Fascinating All right. Parminder, what's your next slide?

Parminder Singh: So I wanted to summarize S1806, which will probably change how we look at bladder preservation as immunotherapy combinations have come up in advanced stage disease.

We just finished accruing on S1806, which was one of the largest bladder preservation trials looking at chemoradiation and immunotherapy in combination versus standard of care chemoradiation. And this trial will show us if adding immunotherapy for six months concurrent with the radiation help improve the needle or bladder intact event-free survival.

And this trial also has built in a lot of translational work, which you just alluded to and Leslie said the urine markers and the ctDNA for a clinical evaluation because these patients are not getting radical cystectomy. They are getting their blood test ctDNA done at baseline and then at 18 weeks and at one year. And similarly, the urine specimens are being collected.

So we'll be looking at a lot of translational studies and using different platforms to look at how ctDNA fraction moves along with clinical assessments, be it radiomics or how the pathologies or even looking at subtyping of these tumors to see if we can accurately predict response at the time of the evaluation. So this will be a game changer trial coming up both clinically and also translationally. And we are hoping we'll have positive results on this in early 2027.

Sam Chang: OK. Any comments there, Leslie or Mark?

Leslie Ballas: No. I think that, Parminder, the SWOG and the NRG teams deserve an incredible round of applause for accruing so quickly to this trial. It is the largest randomized trial in bladder preservation and has really changed, I think, the way that people are using bladder preservation, both urologists and medical oncologists and radiation oncologists. And so we're just excited to see what the results show.

Sam Chang: Yeah. Mark.

Mark Tyson: No, I agree. I don't have anything to add actually. I think Leslie and Parminder said it well.

Sam Chang: Yeah. No, we were fortunate enough to be one of the sites. And to me, obviously, the comparison will be important. To me, also importantly, is in a more contemporary cohort of patients. I will be very, very fascinated to see how the conventional or the control arm does with patients.

And I think that-- and then obviously the comparison with the IO component. I agree with you all. I think it's going to be eye opening for a lot of urologic surgeons. I do think that. And then secondly, I think it will be important long term to follow these patients over time.

And what I don't want, and I hope this is not the case is that individuals will harp on, well, the tests could have been shorter or should have been longer or this or that. I mean, this trial to accrue this quickly and to be able to have results hopefully in the next year and a half, everyone should be very much applauded.

So on that optimistic and positive note, I wanted to thank the panel for all their efforts. And I think the key is the fact that this is a panel. This is a multidisciplinary panel of individuals that are really experts in their field, but always are looking for ways to improve the outcomes for all our patients.

And obviously, we're starting to look at this for nonmuscle-invasive bladder cancer as we try to get treatments that avoid cystectomy. But it's really trial data that will help dictate things. And I just wanted to use this opportunity to mention the cysto data that came out in the AUA 2025, which the authors were the first to admit they were surprised by the findings regarding the role of cystectomy.

So I don't think cystectomy is going to go away yet. I think it'll be there. But I do really want to emphasize what you all have done, being able to give our patients a true multidisciplinary approach and idea of options that are out there for them. So thank you all for spending some time with us.

Leslie Ballas: Thank you for inviting us.

Mark Tyson: Thank you, Sam.

Parminder Singh:Thank you. Thank you for inviting us.