Ask the Experts 2025

May 29, 2025

On May 28, 2025, BCAN’s Co-founder, Diane Zipursky Quale, led a powerful and insightful conversation about where bladder cancer care is today—and where it’s headed. The evening featured two leading experts: Dr. Laura Bukavina, Assistant Professor of Urologic Oncology at the Cleveland Clinic’s Glickman Urologic Institute, and Dr. Matthew Milowsky, a medical oncologist and pioneering clinical researcher at the University of North Carolina.

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Meet the Experts

Transcript:

Stephanie Chisolm:

Hello, and welcome. Thank you for joining us. I want to just give a few housekeeping announcements as everybody moves into their Zoom seats for today’s program. You are in listen-only mode, if you have any questions that are not answered by the physician’s presentation, please drop them in the chat and I will try to respond to you tomorrow with information. If I don’t have the answers, I will consult with the doctors. My name is Stephanie Chisholm, and I’m delighted to have so many of you join us for tonight’s Ask the Experts. Give it just one more minute and then I will turn control over to BCAN’s co-founder in our 20th anniversary year. We’re really delighted to have Ms. Diane Zipursky Quale leading today’s program. Diane, if you want to go ahead and get started.

Diane Zipusky Quale:

Great, thank you, Stephanie. Welcome to BCAN’s 2025 Ask the Experts live event. As Stephanie just said, I’m Diane Zipursky Quale, and I’m honored to be with you today.

When my late husband John and I founded BCAN in 2005, we were stunned by how little information was available to patients and families facing a bladder cancer diagnosis. Even more shocking was how little had changed in how bladder cancer was being treated. We created BCAN to change that, to give patients a voice and support, to provide trustworthy, accessible information, and to push for the research funding and attention that bladder cancer needs and deserves. Now in BCAN’s 20th anniversary year, it’s remarkable to look back and see how far we’ve come. While there’s still much work to be done, treatments have evolved. Research has advanced in ways we could only imagine back then, and a new generation of scientists and clinicians has stepped forward to lead the charge. Today’s program is a perfect example of that progress.

We have a bit more in store than hearing from our two bladder cancer experts. At the end of the program, we’ll announce the recipient of the 2025 BCAN of Hope Award, along with the newest recipients of BCAN’s Young Investigator Awards. These awards represent our continued investment in the future of bladder cancer research, and tonight’s experts are shining examples of the incredible talent BCAN has been privileged to support.

I’m thrilled to introduce our experts. First, Dr. Laura Bukavina. Dr. Bukavina is an Assistant Professor of Urologic Oncology at the Cleveland Clinic Glickman Urologic Institute and serves as the Translational Science Lead in Genitourinary Oncology at the Cleveland Clinic Lerner College of Medicine. She’s a passionate clinician and scientist, whose research focuses on personalizing bladder cancer treatment for better patient outcomes. Dr. Bukavina was also a recipient of BCAN’s Young Investigator Award in 2022.

Joining her is Dr. Matthew Milowsky, a medical oncologist and clinical and translational researcher at the University of North Carolina. Dr. Milowsky is the Section Chief of the Genitourinary Oncology Service and Co-Director of the Urologic Oncology program at UNC. His leadership in both patient care and research has made a lasting impact on the bladder cancer community. As a member of BCAN’s Scientific Advisory Board, Dr. Milowsky has been instrumental in the development of our research grant program, and is the leader of BCAN’s Bladder Cancer Genomics Consortium. Welcome to both of you, we’re so grateful to have you with us today.

Before we begin, a quick reminder, you don’t need to take notes. Tonight’s program is being recorded and will be available in a few days on the BCAN website at BCAN.org. Let’s get started.

I’m going to start with a question that’s going to be for both of you, but Matt, I’ll direct it at you first. Over the past 10 to 20 years, what would you say has been the most transformative advancement in bladder cancer care, either in diagnosis or treatment, that has changed the trajectory for patients today?

Dr. Matthew Milowsky:

Well, first, Diane, thanks so much for having me. It’s a pleasure to be here and always a tremendous pleasure to participate in any of BCAN’s activities, and exciting to see the impact that BCAN’s had over the past 20 years.

I think if we look back, what we used to write in all of our research papers, that there had been 30 years of very little progress in the treatment of patients with bladder cancer, and that has clearly changed. The past 10 to 15 years, or 10 to 20 years has been extraordinary, and particularly in the past 10 years. And I think as a medical oncologist, we had platinum-based chemotherapy and that was more or less all for patients with advanced disease. And it was really about 10 years ago that the development in bladder cancer of the use of immunotherapy with new drugs referred to as immune checkpoint inhibitors were tested in clinical trials, initially in patients who had progressed on chemotherapy. And this demonstrated that these drugs were very active as compared to sort of historical chemotherapy drugs that had little in the way of activity and have been truly transformative. With the development of regimens now that have led to really substantial improvements in survival for patients with advanced disease and in all likelihood, cures of patients with both advanced disease as well as in patients with muscle-invasive bladder cancer.

In the past five years, the development of another class of drugs called antibody drug conjugates has been extraordinary. There has been one agent in particular that targets a particular protein that’s expressed on bladder cancer cells, is called Nectin-4, and the agent is called enfortumab vedotin. And this drug not only has demonstrated activity alone in patients with advanced disease, but it’s really the combination of these immune checkpoint inhibitors, specifically a drug called pembrolizumab and enfortumab vedotin, that together in the first line setting of patients with advanced or metastatic bladder cancer has completely upended the way that we think about the management of patients. With an almost doubling of survival outcomes for patients with metastatic disease, many of whom in the past would certainly not have a potential curative strategy. Whereas as we look toward the future, I think there’s real promise to think about the potential for cure in patients with advanced disease.

And so, I think that these advances, particularly in medical oncology, have been transformative to the field of bladder cancer research, and most importantly, to the care of patients living with bladder cancer.

Diane Zipusky Quale:

Yeah, it’s really been amazing and exciting to see and to watch that over the past 10 years. Laura, how about you?

Dr. Laura Bukavina:

I have to agree with Milowsky regarding the therapies now available. I mean, even 10 years ago within many of our training lifetimes, we really had very little to offer to our metastatic or advanced bladder cancer patients, and now we’re seeing more and more patients cured and potentially moving from… We’re almost flipping the paradigm. We used to do surgery first, chemo or immunotherapy second, and now we’re seeing more and more patients where we’re flipping it, in terms of getting upfront EV pembro and [inaudible 00:08:49] at the antibody drug conjugate. And then they have such a great response in their metastatic sites to now doing a lot more consolidated surgery so that patients can stop systemic therapy and render them in remission at that point. So I definitely think that’s a huge paradigm shift over the last couple of years.

What I think within the non-muscle invasive space, if I can make a comment, I think our diagnostic tools are much better. So over the last 10 years, we’ve had increased use of MRI to really making sure that we stage patients appropriately and not under-stage them. Those patients who are non-muscle invasive are really muscle invasive, and I have seen many, many of these patients. The second is a use of blue light cystoscopy and understanding that CIS is a completely different disease at some point.

And also, we’re sort of at this renaissance, not only of diagnosis but treatment of non-muscle invasive space. It used to be we had BCG and pretty much a big huge void of after thing afterwards, but now we’ve had more and more. We have seven, eight different medications currently either approved or on the market or waiting to be approved, as options for patients. So we’re shifting not only the diagnosis, the sensitivity of our tools, but also how we’re treating many of our non-muscle invasive patients that previously the only option was a cystectomy, and are now able to keep their bladder.

Diane Zipusky Quale:

So this is really the amazing changes that we’ve undergone in all stages of bladder cancer for options for people with non-muscle invasive bladder cancer, as well as multiple treatment options for those with advanced disease, which is so exciting to see.

So Lauren, you mentioned the changes in the diagnostic tools and those getting better. How close are we to achieving a reliable, non-invasive early detection or surveillance test, such as a urine or blood based biomarker? So maybe one day, people don’t have to undergo the regular cystoscopies.

Dr. Laura Bukavina:

We’re getting very close, and I mean I suspect within five years there will be a change to guidelines in de-escalation of potential surveillance. So Diane, I don’t think it will ever go away where we will not do cystoscopy, but I think what we’re going to see is we’re going to see de-escalation of escalation, whichever way it’s going, of cystoscopy in patients based on their urine markers and based on their molecular signature of the tumor and what the prediction is for recurrence and progression.

So, not everyone’s tumor is the same. I always tell my patients, “The patients are different, your tumors are different.” You can’t treat Sue and John the same way. And I think we’re going to a space where we’re going to be able to really say, “Your tumor is less likely to recur. We have these great urine tests that are 80 to 90% accurate. I don’t think it’ll ever get to 100. We can potentially, instead of doing every three months cystoscopy, we can do every six months, because we know your tumor is less likely to progress quickly.” And vice versa in patients who are more likely to progress. So I think that’s coming, but it’s going to take a village to really make sure that’s safe. And I mean everyone from basic scientists to clinicians, to even industry sponsors to make sure we’re doing the right thing for our patients.

Diane Zipusky Quale:

To make sure we’re not missing anything.

Dr. Laura Bukavina:

Exactly, yeah.

Diane Zipusky Quale:

Okay. And while we’re on diagnostics and technology, Matt, we hear a lot about AI in the news these days. What role does AI or machine learning play in improving diagnostic accuracy or surveillance in bladder cancer?

Dr. Matthew Milowsky:

So we hear a ton about AI in all areas of our lives these days, and I think certainly medicine is a particularly ripe area to have AI as part of how we do research and how we care for patients. From the standpoint of improving diagnostic accuracy, in some ways it’s obvious. I mean, AI essentially is being used to help our pathologists potentially, in terms of rendering diagnoses. And also to be able to, as an example, look at a pathology sample and understand what the molecular makeup of a cancer is or the genetic makeup of a cancer potentially, simply by looking at the pathology. And these are things that are happening.

For example, we know that there are particular bladder cancers that harbor specific genetic alterations that potentially lend to treatment options. And in fact, there have been studies to simply look at the pathology using machine learning algorithms to be able to predict the presence of a genetic mutation within the pathology, simply by using machine learning to look at the slide. And in fact, through BCAN, Diane, as you know, we actually did some of this within the UC-GENOME project that was essentially run through BCAN at eight academic institutions. We created some elastic net regression modeling, which is a form of machine learning, to be able to include both clinical features of patients, as well as the biology of the tumors or the molecular makeup of the tumors. And essentially, develop a machine learning algorithm to be able to predict the outcome to treatment with things like immune therapy or chemotherapy. And so this really does represent, I think, the future of the way in which we’ll do research and ultimately the way in which we’re going to be able to care for patients.

And I don’t think it’s going to do away with radiologists or pathologists, but it’s certainly going… Or other medical specialties. I think it’s really going to complement our ability to provide care to patients for so many reasons, and pathology is just one example.

Diane Zipusky Quale:

So Matt, you mentioned the use of AI for the BCGC, the Bladder Cancer Genomics Consortium, that BCAN supported and you led. Can you also tell us, what did we learn from the study, and what its impact has been, but in addition to the algorithm you just described?

Dr. Matthew Milowsky:

Yeah, sure. So the UC-GENOME experience was conceived many years ago to study-

Diane Zipusky Quale:

We were a lot younger then.

Dr. Matthew Milowsky:

We were a lot younger, but it was a really truly collaborative experience among eight academic institutions that had specific expertise in bladder cancer and really led by the Bladder Cancer Advocacy Network, and there were two goals of this study. The one was to provide free, no cost to patient, next generation sequencing or genomic analysis of their tumors for potential treatment options in clinical trials. And this was at a time when doing genomic analysis was not reimbursed by insurance. And the other arm was to develop a very rich bio-repository or bio-bank of blood and pathology specimens to be able to do collaborative research. And that’s in fact exactly what we did. So that study, which we actually started accruing, I don’t know if you remember, in 2016.

Diane Zipusky Quale:

Yes, [inaudible 00:17:15].

Dr. Matthew Milowsky:

Over 200 patients, all of the patients had metastatic bladder cancer. And what we learned is we were able to molecularly characterize or understand the genetics or genomics of those tumors. We were able to understand the, what we refer to as the tumor micro environment, which has to do with the environment actually surrounding the tumor, including, for example, the immune system. And we were able to use that information along with clinical information we had on patients, to be able to develop models to predict response in the way that I suggested. And we published that in the Nature Communications Journal in 2022, after a lot of years of working really closely together with a fantastic group of researchers and clinicians and I think, and most importantly, patients. I mean, we couldn’t have done this without having over 200 patients participate in this study.

And so, this is just one example, and BCAN has made all of that information publicly available. So, all of the clinical and genomic information is publicly available for researchers, and therefore additional work can be done. There are additional efforts to use blood and tumor samples that remain to do additional research. And so this is something that will live forever in many ways, and it’s already being used in other studies because that data is publicly available. And I recently sent you a paper where the UC-GENOME was included as one of the datasets within that paper. So, it’s been really exciting to see.

Diane Zipusky Quale:

Yes, and thank you again for all your work on that. Laura, it’s still on the genomics side of things. Are you seeing genomic insights beginning to influence surgical decisions or surveillance strategies in the earlier stages of the disease?

Dr. Laura Bukavina:

Before I go into the genomics, can I just make a comment about the AI?

Diane Zipusky Quale:

Yeah.

Dr. Laura Bukavina:

Okay. So I think we often talk about AI as this research. So somewhere down the line, it’s going to be available, it’s going to happen. And the truth of the matter is, we use AI now. I mean, we use, I’m not sure if I’m allowed to say company names on here.

Diane Zipusky Quale:

Sure, go ahead.

Dr. Laura Bukavina:

Okay.

Diane Zipusky Quale:

Go ahead.

Dr. Laura Bukavina:

So we use Valer and we use Artera, and these are AI pathology-driven prediction tools. So patients come in with bladder cancer, we review their slides through our central pathology, and then these companies, which are actually the insurance covers this because it’s been FDA approved, they actually look and predict, giving a patient a score based on their pathology using their AI model, what the chances that the patient will respond to BCG. What’s the chance of their progression, and what’s the chance that they might be better off using chemo first versus BCG first? And that’s not theoretical anymore, that is already happening in our clinic. This is something that’s available for our patients. And think how quickly AI became a clinically relevant tool that we have, right? And we made many clinical decisions based on this, including if they did not respond to BCG, what’s our next steps and having those discussions early. So, that’s sort of my comment.

And I think we’re pretty very early adopters of AI pathology in non-muscle invasive bladder cancer, but I know and we are working with companies, and I know many, many institutions are working to move this along into the space of muscle invasive as well as metastatic, where we’re going to be able to predict there with some, not 100%, and not anything in medicine is ever 100%, but we’re going to be able to at least give you a best hypothetical sort of guess of what your next treatment should be or could be if you fail this treatment. So that’s sort of my spiel on AI.

Diane Zipusky Quale:

Yes. Actually, if the treatment fails you, excuse me.

Dr. Laura Bukavina:

Yes, the treatment fails you. Yes, you don’t fail the treatment, the treatment fails you. It’s just not a good treatment.

Diane Zipusky Quale:

Yes, yes.

Dr. Laura Bukavina:

In terms of incorporating molecular and genetic markers, I think that’s all… So we are also very early adopters of things such as ctDNA, which is circulating tumor DNA markers. We’re also early adopters of what’s called whole exome sequencing of your tumors. So when I speak to patients, if I see them even with T1 disease, because it’s approved, even with T1 disease, all of our tumors get sequenced. And based on this information, we’re able to not only build up our bio-repository of information to be able to predict better, but also we’re able to look at the mutations. And we know if someone has FGFR mutation or if someone has DNA repair enzyme mutation and they ever need any other therapy, there’s some evidence to sort of guide them one way or another.

And also with ctDNA, which is that circulating tumor marker, patients even with a non-muscle invasive space, are still found to be about 20% actually, to be positive for circulating tumor DNA. And that is something new and something that I think only happened over the last 12 months that we discovered that. So, these are very important and clinically relevant pieces of information that we continue to learn from, and it’s an exciting time. I mean, I think we’ve been building up to this point like 10 years and now we have all the tools and easy tools to use to be able to actually make sense of the data.

Diane Zipusky Quale:

That’s wonderful. That’s wonderful. One of the things that I’ve noticed that has changed so much in the last 20 years is the conversation around bladder preservation or trimodal therapy, because when I was first engaged in the bladder cancer sphere, it wasn’t anything that was talked about. It was seen more, done only at a few institutions. How has that conversation evolved and changed in recent years? And what’s the current role of radiation and systemic therapy for helping more patients keep their biological bladders?

Dr. Matthew Milowsky:

And I’m happy to respond first, and then would love to hear what Laura has to say. Having been in the field of bladder cancer for a while, and I think again, Diane, you’ve seen this as well, there was much less in the way of sort of a mutual understanding about the potential benefit of both radical cystectomy and the use of trimodal therapy, among radiation oncologists and urologists and frankly, medical oncologists as well. And I think that’s changed tremendously and I think it’s changed as a function of excellence at certain institutions, as you suggested, that have really shown us how effective in appropriately selected patients, trimodality therapy could be. I think BCAN’s done a wonderful job at sort of educating the community and bringing the community of physicians together to really have important dialogues about this.

And again, we’ve seen something that is transformative in the field in that both urologists that are intimately involved in the care of trimodal therapy, because urologists importantly do a as complete resection of the tumor as is safely possible before the chemotherapy and radiation therapy, have really come together to ensure that patients are selected appropriately for trimodality therapy. And I think that there is now this equipoise that exists in those patients, and it is something that should be presented to patients, and patients should be made aware if they are a potential candidate, if they are potential candidates or they’re not potential candidates and the reasons why. And this whole concept of bladder preservation is obviously very, I mean, patients want to live, but they really want to live with their bladder intact, right?

Diane Zipusky Quale:

Yes.

Dr. Matthew Milowsky:

And so I just want patients to know that there is a tremendous amount of research going on right now to do just that. And I think Laura alluded to this earlier, which is even looking at approaches where we can characterize molecularly the tumor, incorporate novel agents like enfortumab vedotin, like immunotherapy, potentially without radiation therapy to be able to preserve the bladder in patients. The pause is that we need to do a really excellent job in understanding that patients are responding in the way that they need to respond. And so the research community, I would say is on it working very hard collaboratively toward that goal. And again, I’d love to hear what Laura has to say.

Diane Zipusky Quale:

Yeah.

Dr. Laura Bukavina:

I think it’s certainly, so trimodal therapy or TMT, it’s more accepted, and I think because we talk about it more. And we make sure that we look at the studies that show that its efficacy, and like you said Matt, in a very selected population of patients, is essentially equivalent to what we consider to be standard of care, which is chemotherapy followed by cystectomy.

The reason why I think there has been a lot more resistance to acceptance of TMT is the lack of prospective actually one-on-one clinical trials. So a lot of the therapy that we have in many, many cancers is based on some sort of prospective clinical trial, comparing one to the other. For example, there’s a trial looking at robotic to open cystectomy, evaluating outcomes. Right? We accepted that there’s no difference, and everyone kind of went happily along their way saying there’s no difference. The problem with TMT is there’s no such trials have ever been done. They have been attempted, it’s not that we haven’t attempted to do it, and we have attempted multiple times. It’s just very difficult to randomize people when you’re sub selecting a very specific cohort of patients. So I think that we’re talking about it more, BCAN has been great in having those conversations, but we also have to be careful and understand that there’s only select cohort of patients that benefit from TMT.

And we’re sort of moving into a space where, like Matt said, well, maybe we don’t even need radiation. Maybe it’s a combination of specific drugs, systemic drugs and surveillance is all we need, really removing the radiation, which is where a lot of the side effects come from locally from that algorithm. So it’s going to be interesting to see where TMT, what role TMT has in the next five years.

Diane Zipusky Quale:

Now, this might seem like a strange segue as we’re talking about bladder preservation, but one item has been in the news that I know a lot of people have read about and very interested about. There was a reported bladder transplant done by doctors in LA, I think just last week it was reported. Laura, can you tell us a little bit more about that, your thoughts? What does this mean? Who would be a candidate for it? Is it as sort of wonderful and exciting as it sounds?

Dr. Laura Bukavina:

Thank you. So, I think it’s exciting from the surgical standpoint. It’s kind of like when the first face transplant happened, I don’t know if you remember that couple years ago. Everyone was really excited. It’s a huge surgical feat, it’s difficult surgery and was done robotically. But we have to sort of take a step back and kind of understand what actually happened.

So the patient that had the bladder transplant had what’s called the neurogenic bladder, which means the bladder was malfunctioning, it was not a good bladder. In addition to, the patient needed a kidney transplant. So the patient received a kidney transplant to be able to get off dialysis, which is a very life-limiting thing. And at the same time, when you have a bad bladder, it puts the new kidney at risk because it causes the kidney to malfunction because it built just too much pressure in that kidney. So this was a perfect patient in whom you can try combination of both kidney and bladder transplant.

We just have to be careful and understand that patients with cancer, by guidelines, are supposed to be two years minimum cancer-free before they undergo any kind of transplant because immunosuppression alone will increase the risk of terrible outcomes with bladder and bladder cancer. That includes metastasis, progression, and death. So if we think that we can potentially do a cystectomy for muscle-invasive bladder cancer and then put in a new bladder at the same time to essentially have a new bladder in all sense of the word, it doesn’t quite work like that, because we know that your outcomes from the cancer standpoint are going to be much, much, much worse.

Diane Zipusky Quale:

And that’s because, we just explained to people, that transplant itself requires the patient to be immunosuppressed.

Dr. Laura Bukavina:

Correct. [inaudible 00:31:57]-

Diane Zipusky Quale:

And the immunosuppression then causes the cancer perhaps to grow even faster.

Dr. Laura Bukavina:

Exactly. So if you are on immunosuppression, it’s going to decrease your response, your own body’s response to cancer cells. And that’s how a lot of our new drugs are working, right? A lot of the immunotherapies stimulate your immune system to detect and kill cancer cells. So by putting someone on immunosuppression, you’re essentially getting rid of your body’s defense, not only against infections but against cancer. So your body, it’s not going to be able to defeat spread of cancer.

The second thing, being on immunosuppression also makes you ineligible to receive many of the drug therapies currently available. So, Dr. Milowsky administers immunotherapy or even a combination of immunotherapy and antibody drug conjugates. By being a transplant patient, you are not typically allowed to take these medications because you risk organ rejection.

Diane Zipusky Quale:

Got it. So it’s a very exciting development in the field of medicine, but it’s applicability to bladder cancer is not quite there yet.

Dr. Laura Bukavina:

Yeah, and I think the population that might benefit from it if it pans out to be something that the bladder actually works in a couple years down the line and doesn’t contract and become sort of like an empty vessel that doesn’t squeeze anything out, I think the patients that would potentially benefit from it are those patients that have end stage bladder. So the patients whose bladder is so, for example, post radiation is so difficult. They have severe pain, they have frequency, they’re running to the bathroom all the time. They have what’s called small and contractile bladder, their bladder volume is very low. Those patients potentially might benefit. I think for the cancer patient, the applications are far more limited because of the immunosuppression.

Diane Zipusky Quale:

Okay, thank you.

Matt, I want to turn to you and talk a little bit more, and you mentioned in the beginning the great changes that we’ve seen in the last 20 years, in terms of the number of treatments now available for advanced disease. And with both the immunotherapy, as well as the ADC drugs. How do medical oncologists determine which treatment is best for each patient when you have options out there?

Dr. Matthew Milowsky:

Sure. So as I said, if we go back 10 years, 15 years ago, we were treating patients with platinum-based chemotherapy. And that was generally cisplatin-based if they were eligible, or we would say fit for cisplatin-based chemotherapy due to the fact that it has specific side effects, or otherwise treating them with its sister drug, carboplatin, that could evade some of the side effects that would otherwise be associated with cisplatin. And that’s essentially what went on again for decades.

And then with the development of immunotherapy and these antibody drug conjugates, things have really changed. We don’t think about that division, that cisplatin eligible or ineligible anymore, because it’s not relevant to this new treatment that combines enfortumab vedotin with pembrolizumab. Not to say that there aren’t side effects, but the benefit is again, one that is really transformative and it doesn’t require that same need to split patients in that cisplatin-eligible, ineligible way. So for patients in the first-line setting with metastatic disease, there are certain rare contraindications to using that combination, but in general, we should think about that combination for all patients. And obviously, we look at their coexisting medical problems, but it has really, again, made the first-line treatment of patients easy in that way. There’s a lot more work to do, and that work is ongoing, but from a first-line treatment strategy, that is the recommendation.

The problem, Diane, is now, what happens if a patient unfortunately goes on to progress after that first-line therapy? And there is where research needs to continue. We have things like platinum-based chemotherapy still. We have certain targeted therapies, so patients are selected by the presence of a mutation. And Laura mentioned this, like an FGFR3 mutation in a tumor. And there is a drug called erdafitinib, which targets that particular mutation. And there are many drugs in development. There is a new drug approval for targeting HER2, patients may be familiar with that from the treatment of breast cancer and gastric cancer, using a antibody drug conjugate again called trastuzumab deruxtecan. And there are more and more therapies that are both targeted and using things like antibody drug conjugates. There are newer combinations of immunotherapy that are being looked at.

So what cancer does, is cancer unfortunately builds a force field around it. And that force field does not allow the immune system to recognize the cancer as being foreign in the way that the immune system would recognize, for example, a bacteria or a virus. And these immune checkpoint inhibitor drugs, as well as others, are able to essentially break down that force field and thereby allow the immune system to react against the cancer cell.

And that observation, that research has led to the development of many drugs that are used in bladder cancer and other cancers, and led to a Nobel Prize that was awarded in 2018 based on that finding. And again, it’s these combinations of drugs that we’re using, and again, new drugs with different mechanisms of action that are rapidly coming down the pike, such that we can begin to think about these for patients based on the specifics of their tumor, incorporating things like artificial intelligence to understand more about the tumor, more about the patient, more about that microenvironment that I mentioned, which is essentially what’s surrounding the tumor, to be able to make decisions about the best treatment for an individual patient.

Diane Zipusky Quale:

And Laura, can you comment on that for non-muscle invasive or even muscle invasive disease, in terms of any challenges as a treating clinician, in terms of determining the best course of therapy for each patient?

Dr. Laura Bukavina:

Certainly. I think our problems are very similar across the spectrum. So we see a lot more available medication in the second line setting. So if patient has failed BCG, BCG [inaudible 00:39:35]-

Diane Zipusky Quale:

Oh, let’s go back. If BCG has failed the patient.

Dr. Laura Bukavina:

Sorry, if BCG has failed, so sorry. I’ll get it right. I’ll get it right by the end.

Diane Zipusky Quale:

You know it’s my pet peeve, I’ve been doing this for 20 years.

Dr. Laura Bukavina:

If the treatment has failed the patient, if BCG has failed the patient, now the next steps is we have three available options these days. And that’s just something that’s already approved and there’s a couple more options available after that, so whether it’s ADSTILADRIN, whether it’s ANKTIVA, whether it’s Gem/Doce. So a patient is showing up with BCG unresponsive disease to urologist office, we have no answers about what is the actual subsequent best therapy for that patient, because many of the trials have been single arm trials, which means they were not compared to anything. It was just one medication in a specific population, they were not compared to something else. And that is great because it got drugs approved quickly, but now we’re dealing with the consequences because we don’t know what actually performs better, which patient performs and which medication works better for what patient. There is very limited data about connecting treatment to the actual tumor signature.

So we can really just pick out of the hat. And a lot of that’s what happens. What is available at your institution out of the three treatments? Chemo is very cheap, but it requires patients to come in once a week for six weeks, similar to how BCG is. ADSTILADRIN is great, it’s once every three months but costs a lot of money. And same thing with ANKTIVA. ANKTIVA requires that you get BCG installation with it. So, I think that’s something that we’re struggling with in the non-muscle invasive space, and I really am looking forward to having not just the single arm trials, but having trials comparing it to standard of care if we decide what that actual standard of care is in the BCG unresponsive space. So, and there are trials.

The second thing is we see a lot, and I know Matt probably knows about this as well, is that we have been treating metastatic with EV pembro as the first line therapy, but now we know that EV pembro is moving on into the perioperative space, which is a neoadjuvant space.

Diane Zipusky Quale:

Which is before surgery to remove your bladder.

Dr. Laura Bukavina:

Correct, exactly. So before the surgery. So we’re taking a treatment that works really well in the metastatic setting, and we’re putting it in much, much, much sooner in many patients who potentially might be over treated, and the results of that trial will be out soon. However, we’re seeing very similar sort of shifts in the non-muscle invasive space.

So we are used to treating local disease with local therapy. So that means you have non-muscle invasive bladder cancer, we give you installations into the bladder. Local treatment, local disease. What we have seen now is there’s phase three and phase two trials, we are doing combination of systemic therapy for localized disease, in combination with intravesical therapy. So we have to decide what patient actually benefits from that, because I do believe that not everyone is going to benefit from the systemic therapy, potentially having the side effects of the systemic therapy, but really very limited actual benefit if they would respond to BCG alone. And that, we have no answer to at this point. We just have a lot of data showing that it’s slightly better or clinically statistically significant, but what patient actually benefits is still under investigation.

Diane Zipusky Quale:

Laura, you just mentioned clinical trials and some that are going on. How has the design of clinical trials evolved over the last 15 years to be more adaptive and inclusive, if indeed it has?

Dr. Laura Bukavina:

I don’t know if inclusive really has changed, but I think there’s a lot more adaptive trials to, and Matt can talk a little bit more about this, where we have these sandwich approach trials in bladder cancer.

And the other thing that we have done, as I mentioned, is that we have done single arm trials due to need. We needed new medication and we didn’t have the capacity or the standard of care to compare it in the BCG unresponsive space, so the FDA has opened up the ability to do single arm trials for us in that space. So that has changed, at least in the non-muscle invasive space. And I’m wondering if Matt can kind of comment about the sandwich approach.

Diane Zipusky Quale:

Yeah. What is a sandwich trial?

Dr. Matthew Milowsky:

Yeah, the trials that we’ve been doing for years have been effective in terms of developing new therapies, but unfortunately, they’re not particularly pragmatic in general. And we need more pragmatic trials to be more inclusive, Diane, and that not only goes for bladder cancer research, but it goes for research in all cancer. And so there are major efforts that are going on through the NIH, through the NCI, as well as other research organizations to develop what are referred to as pragmatic trials. And these-

Diane Zipusky Quale:

Which means?

Dr. Matthew Milowsky:

Pragmatic trials essentially have less stringent eligibility criteria. They are designed to evaluate interventions in a real world type environment. And this means that they are not just occurring at academic medical centers, but they can actually occur within clinical practice settings. They focus on the effectiveness of the treatment under the real world conditions, rather than sort of these ideal conditions. So we may not be collecting all of the same data that we’ve historically collected in the setting of an academic medical center doing a clinical trial, but we are getting a potentially faster readout of a therapy and how effective it is, and being able to do that clinical trial out in the community.

So as an example, at UNC, we have many satellite centers. We take care of patients in the western part of the state, we take care of patients in the eastern part of the state. Oftentimes these are very rural type areas, and these patients would otherwise not necessarily been able to participate in a clinical trial. But the development that these type of pragmatic trials, not just in North Carolina but throughout the country, I think is going to really change the way in which we design our clinical trials to be able to get answers more quickly, to be more inclusive, so that we’re making sure that we’re capturing patients from essentially all backgrounds. And there are differences, in terms of outcomes for patients coming from different backgrounds, so it’s really important to understand that. And unfortunately, the accrual that we often have within our own medical centers that is academic medical centers in the typical way that clinical trials are designed, don’t allow us to get those answers in the same way that we hope to get those answers using these more pragmatic type approaches.

Diane Zipusky Quale:

And so, are those more pragmatic type approaches becoming more common? Are the new clinical trials that are coming online now more of the pragmatic?

Dr. Matthew Milowsky:

Yeah, so I wouldn’t say more of them, but there is an effort through, again, the NCI and elsewhere to develop these studies. And I think that we’re just going to begin to see more and more of them as not only in bladder cancer, but again, throughout our entire clinical trial infrastructure in caring for patients with cancer and frankly, outside of cancer as well. And I think that’s really going to help, in terms of being more adaptive and inclusive.

Diane Zipusky Quale:

Okay. I have lots of questions left for both of you but I’m aware of the time, so I have just a couple more before we have to end. For each of you, what is one topic or area that you think is a critical research priority for bladder cancer going forward? What do we need to know more about? Whoever wants to go first. There you go, Laura.

Dr. Laura Bukavina:

I can go, I can start. I think one most important question I would like answered over the next couple of years and a research priority is stratification of patients who are BCG unresponsive based on their AI, based on their signature, clinical factors, into the best next therapy based on what we have available.

Diane Zipusky Quale:

Okay, and Matt, how about you?

Dr. Matthew Milowsky:

Yeah, it’s a difficult question, in terms of looking ahead, what do I think. I think, and Laura brought this up when she talked about bringing our treatments earlier in these clinical disease states, so taking effective therapies in the metastatic setting and how can we bring those treatments earlier?

And I would say that yes, there are the issues of potential over-treatment, no question about it, as Laura suggested in the neoadjuvant setting that is prior to surgery or even in the non-muscle invasive bladder cancer setting. But I do think in taking those therapies earlier such as the combination of enfortumab vedotin and pembrolizumab, I think that the real important outcome will hopefully be that we are curing more patients at the end of the day. And we’ve seen this in other areas of oncology as well, it’s the way in which we’ve developed drugs in oncology.

And if you take examples in colon cancer, where the use of drugs called 5-FU and unlucavirin in metastatic disease led to an improvement in survival in metastatic disease. And then when you took it into the adjuvant setting, that is after a removal of the tumor, you saw a 30% relative reduction in the risk of death. And I hope that with the effective therapies that we’re seeing often investigated in later stages of disease, that as we move those earlier, we will actually be curing more patients with bladder cancer.

Diane Zipusky Quale:

And so, kind of a compliment to where are the gaps, what is the big gap, before we end, I’d like to hear looking ahead over the next 10 years, what innovation or current area of research most excites you as being a potential defining advancement? Matt, you want to go first?

Dr. Matthew Milowsky:

Yeah, I mean, I’m happy to jump in. There’s so many things that excite me, and I think probably Laura, the same, that it’s really hard to just come up with one or a couple.

I mean, I think that as much as we’ve learned from efforts like the Cancer Genome Atlas, which was essentially this comprehensive molecular characterization of bladder cancer, this huge effort that started in the early 2000s through the NCI to understand the true biology of bladder cancer, we have so much more to learn. And I’m really excited with all of the new technologies, whether it is single-cell sequencing and other efforts, to really being able to understand even better what makes bladder cancer bladder cancer, to provide opportunities for how we best treat it.

I’m going to add on that I’m also really excited about these bladder preservation strategies, because as I said, patients want to live but they want to live with their bladder. And so I think those efforts to try to come up with treatments and with rigorous methodology to ensure that we do studies in the right way such that patients can live and retain their bladder, are I think an incredible area of research using genomics, using circulating tumor DNA, using new imaging type approaches, and some of the new therapies that we have available. And I’ll stop there.

Diane Zipusky Quale:

And I think, yeah, that’s a number one priority from the patient perspective too, is being able to keep your bladder. Laura?

Dr. Laura Bukavina:

Well, I think in my perfect world, if I had in 10 years, what I would like to see is a patient showing up to my clinic with the diagnosis of a bladder mass or bladder cancer, and having the ability to essentially get all the information, their ctDNA, their signature of their tumor, prediction of different treatment responses, all within one patient visit. So that way, I can tell this patient, “This is the best course of therapy to cure your cancer so you can leave your bladder intact.” And all of that to be, I think it’s possible. I mean, I know it’s a dream, but I think it’s possible if you think about how quickly our technology is improving. Maybe it won’t happen in a day or two, but I think if we have a week or two, we’re getting really close to getting that. And if the treatment is systemic, but that’s the medication that’s going to give them a cure, then that’s the medication they need to be on.

Diane Zipusky Quale:

Well, I hope for all of us that those wishes, dreams, desires, and hopes do come true in the next 10 years.

Before we end tonight, I’m going to turn to a couple other things. It’s my great pleasure to introduce the 2025 recipients of BCAN’s Young Investigator Awards. These awards support the development of research scientists and clinical investigators who’ve demonstrated a commitment to improving the understanding and treatment of bladder cancer. Please join me and congratulating Dr. Mohamed Osman, a Postdoctoral Associate in Medicine at Weill Medical College of Cornell University. Dr. Patrick McGillivray, a Medical Oncology Fellow at Memorial Sloan Kettering Cancer Center. And Dr. Meera Chappidi, a Urology Fellow at the University of Washington. We’re proud to support these rising stars as they pursue innovative research and continue the work of transforming care for people affected by bladder cancer. Congratulations to each of you.

Finally, it’s wonderful to be able to introduce you to the 2025 BCAN of Hope Awardee. This year, BCAN received more than 80 nominations for this award that recognizes a very special person in the life of a bladder cancer patient or caregiver. We received almost 3,200 votes, a record, for our three finalists. Doug Cappiello, Maryellen Towey, and Sandy Weicher.

It’s my great pleasure to introduce the recipient of the 2025 BCAN of Hope Award, Maryellen Towey. One of the people nominating Maryellen, said, “Maryellen is humble, kind, caring, and compassionate. A nurse by training, she is always there to help others. Last year, she cared for her husband who was battling pancreatic cancer while she was battling bladder cancer. When her husband lost his battle last year, she remained fully present to her grieving family while undergoing treatment for cancer herself. Every day, Maryellen chooses joy.” Congratulations, Maryellen, the BCAN staff will follow up with you soon with more details.

Let’s also congratulate the two other finalists, Doug Cappiello and Sandy Weicher. Both are survivors and have done so much for the bladder cancer community. Thank you both.

And as we come to the close of today’s program, I want to extend my heartfelt thanks to both of our experts, Doctors Bukavina and Milowsky. Thank you for sharing your time, your insight, and your compassion in answering all my questions. As someone who co-founded BCAN now 20 years ago, it’s deeply meaningful to see leaders like you carrying this work forward. Your dedication to advancing the science of bladder cancer and to improving the lives of the people behind the statistics means more than I can say. We are truly grateful to work alongside you.

Thank you also to all of you who took the time to join us today for the 2025 Ask the Experts event. As I mentioned earlier, a recording of this will be available on the BCAN website in the coming days at BCAN.org. Good evening, everyone.

Stephanie Chisolm:

And that concludes today’s program, thank you all for joining us. You should also be receiving an email from Zoom with the recording if you missed part of today’s program. And we look forward to letting you know that it’s available on our website in the next few days. Thanks so much, take care.

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