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Bladder Cancer Breakthroughs: New NMIBC Therapies and EV + Pembrolizumab Updates From ASCO GU 2026

Released: March 23, 2026

Sam S. Chang
Sam S. Chang, MD, MBA
Matthew D. Galsky
Matthew D. Galsky, MD
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In this episode, Sam S. Chang, MD, MBA, and Matthew D. Galsky, MD, discuss the rapidly evolving treatment landscape in bladder cancer, highlighting new therapeutic options, emerging clinical trial data, including the latest results presented at ASCO GU 2026, and the growing role of biomarkers and multidisciplinary care, including:

  • New treatment options for BCG-unresponsive non–muscle-invasive bladder cancer
  • Intravesical therapies such as nadofaragene and N-803
  • The role of ctDNA in measurable residual disease detection

Dr. Chang: Hi. My name is Sam Chang. I'm from Vanderbilt University Medical Center.

Dr. Galsky: I'm Matt Galsky, and I'm from the Icahn School of Medicine at Mount Sinai.

Dr. Chang: We have the privilege of actually spending a few minutes going over how much the landscape in bladder cancer has changed, not only in the past 10 years, but I'd say over the past four to five years, the acceleration has been tremendous. We've had a series of talks looking at different treatment options. And we're going to have a discussion today about it.

Dr. Galsky: There's so much to talk about in bladder cancer these days. And maybe we'll start by talking about non-muscle invasive bladder cancer, in particular, all of the new treatments available. You know, as a medical oncologist, I try and keep up with the approvals in non-muscle invasive bladder cancer and the mechanisms, and it's getting harder and harder.

And so what should we be telling our patients with BCG-unresponsive disease in terms of treatment?

Dr. Chang: Yeah, it's that embarrassment of riches we never had before, Matt. And, you know, you think about from a medical oncologist, yes, I can understand how you struggle, just as we do with advanced medications or advanced disease and medication options. But for the practicing urologists, it has changed dramatically from nothing approved for decades to all of a sudden, we've gone from systemic immunotherapies to all these intravesical options. And now combination of actually systemic IOs plus BCG for people up front.

When we look at BCG unresponsive options, you have FDA approved now choices. And that would include systemic therapy with pembrolizumab and then intravesical options. One of those intravesical options is nadofaragene, which looks at a form of therapy that actually codes for alpha interferon that's given quarterly every three months.

And so that is an attractive option for many of our patients who've had multiple weekly sessions with BCG. And having that ability to be given once every three months has actually been quite attractive to patients who travel many times far away.

A second intravesical option, which shows significant—it appears long-term durability response is nogapendekin in AI or N-803, which is a form of therapy that uses a engineered IL-15 super-agonist that has a combination of promoting killer T cells, natural killer cells and at the same time suppressing or not allowing the Tregs to actually increase that would cause suppression of our immune response.

So we've got a lot of treatment options, you know, from our standpoint of what we give, how we give, it depends upon where the patient lives, depends upon kind of their treatment choices, what's covered by their particular carrier, is one better than the other? We haven't had any head-to-head comparisons.

And I'd love to ask you, now there's some data for those patients who are BCG-naive that actually combining systemic therapies, IOs with BCG is better than BCG with maintenance. So I'd love, you know, you’re kind of input in looking at those combinations.

Dr. Galsky: Yes. So, of course, we know that immune checkpoint blockade can have activity in non-muscle invasive bladder cancer. There's an approval for pembrolizumab for BCG unresponsive carcinoma in situ. And so that that really did beg the question should we move these treatments up earlier?

And so three randomized studies each designed a little bit differently testing this concept. Patients with high-risk non-muscle invasive bladder cancer who are BCG naive, should we combine BCG with immune checkpoint blockade versus give BCG alone? Two of those three studies were “positive”. They met their primary endpoints. One study didn't.

The study that didn't was a smaller study, and in probably the outlier in terms of design. The two studies that met their primary endpoint differed in a number of ways. One used subcutaneous immune checkpoint blockade, the other used IV. One gave one year of treatment, the other gave two years of treatment. So some differences.

But remarkably, the hazard ratio for event-free survival was - the identical number between these two large randomized studies. So lots of consistency there, which is impressive in terms of reassurance that this is a real signal.

Where things get a little bit more muddy is that the subgroup of patients between the two studies that seemed to derive all that benefit differed a little bit from one study to another. And one, it seemed to be patients with carcinoma in situ that wasn't reproduced in the other study. And I'll circle back to that because I think there might be some biology that explains that.

The other issue, of course, is that while the effect size is definitely there and was similar for event-free survival between the two studies, there is some discussion about the clinical relevance of the findings in an all-comer population. So in patients who ultimately do fairly well with BCG alone is the added risk of systemic toxicity worth the benefit. And I think in my personal opinion, that's going to depend on individual risk factors and individual considerations.

Dr. Chang: Now, I think that's a really important point. And as we look at combining systemic with intravesical therapies, we've got to balance those risks and the clinical effectiveness. If we look at the FDA approved medications, we seem to get an early signal for the medications, but over time, there seems to be a diminution.

The question is what happens then long-term? And ultimately, we do also have a combination of gemcitabine and docetaxel. And I'd be remiss regarding not mentioning that because although not FDA approved, if you ask a lot of academic urologists in terms of perhaps cost effectiveness, that combination of therapy, although not as rigorously studied based upon actually retrospective and multi-institutional trials with which are fraught with lots of issues. But that combination of chemotherapy intravesical gemcitabine followed by docetaxel, there clearly is a signal. How do we decide which of those is going to be important and what will actually be used for personalized care? That's up to question.

And it has us looking for certain things to help try to determine what's effective and what's not. And at least from the medical oncology field and perhaps with more advanced and metastatic disease, ctDNA is something that I hear about as much from a surgical standpoint.

You know, tell me, you know, briefly, Matt, kind of how you're incorporating now ctDNA? That—I mean, it could be an hour long discussion I know, but it's something that we should, as urologic surgeons and as clinicians, have some idea of how we're starting to incorporate it.

Dr. Galsky: So ctDNA in bladder cancer has really become adopted pretty rapidly and widely. And the ctDNA that we're talking about specifically is tumor-informed ctDNA testing as a measure of minimal residual disease. And this has a number of potential applications. The lowest hanging fruit application has been after cystectomy for muscle invasive bladder cancer. Can ctDNA help us determine who still has microscopic evidence of cancer and who might benefit from adjuvant immune checkpoint blockade?

And the data there are becoming fairly compelling in patients who have detectable ctDNA after surgery. They're clearly at markedly higher risk. It's a pretty decent measure of microscopic residual disease, microscopic metastatic disease that should warrant initiation of adjuvant therapy. So we're using it quite a bit in that situation. And patients with undetectable after surgery, there's some compelling data as well that those patients perhaps could be candidates for surveillance, although we need more information to ensure that that's the right thing to do for patients.

And then ctDNA is being tested as a way to inform other decisions across the spectrum of bladder cancer in muscle invasive disease, but moving into non-muscle invasive disease as well, and certainly into metastatic disease also.

Dr. Chang: Well, along those lines of perioperative multimodal care, I think, Matt, we're lucky to have you presenting probably the most anticipated and clearly the most attention garnering presentation, which was looking at a combination of EV plus pembrolizumab in the platinum-eligible population and then looking at its impact in perioperative care with cystectomy outcomes. And if you could tell us about the applause-arousing presentation that you gave at GU ASCO in this year, in 2026. If you could give us kind of an update on what you presented?

Dr. Galsky: So this study, also known as KEYNOTE-B15, sometimes referred to as EV-304 randomized patients who were cisplatin-eligible to four cycles of neoadjuvant enfortumab vedotin plus pembrolizumab followed by cystectomy followed by 13 cycles of adjuvant pembrolizumab, the first five of which were administered with enfortumab vedotin versus neoadjuvant GemCis for four cycles, followed by cystectomy. So sort of the older standard that we've - we've been pursuing for decades now versus this new perioperative approach with this newer regimen.

The study enrolled 808 patients randomized one-to-one between the two arms. The primary endpoint was event-free survival, and the key secondary endpoints were overall survival and pathCR rate. And the study hit on all of its endpoints. Event-free survival significantly improved, hazard ratio 0.53. Overall survival significantly improved, hazard ratio of 0.65. And then the pathCR rate increased from 32.5% with GemCis to 55.8% with enfortumab vedotin plus pembrolizumab.

So, you know, similar to what we saw in a sister study, KEYNOTE-905, which tested the regimen in cisplatin-ineligible patients. The pathCR rates are very high with this regimen. There's ultimately a survival benefit. And now that we have two studies in the cisplatin-eligible and ineligible population, it's a regimen that one could consider a standard for patients with muscle invasive bladder cancer, regardless of cisplatin eligibility.

Dr. Chang: I mean, that was obviously a game changer. And I'll be the first to say I was sitting next to other surgeons and our response was, wow. I mean, it really will represent, I think, the start of many other studies looking at what we do next, how we can de-escalate care and there'll be things that we talk about.

Also at ASCO GU was the SWOG 1602 trial, which was a comparison of actually three different arms looking for an alternative to TICE BCG that's currently available in the US. And this was looking at the Tokyo strain BCG.

Those were the two arms, but a third arm was actually a combination of a subcutaneous prime with the Tokyo strain and looking at basically a non-inferiority compared to TICE BCG.

What this trial showed was that, in fact, the TICE and Tokyo strain were not significantly different, that the Tokyo strain was not inferior. About 300-plus patients in each arm really showed no difference in the high-grade, recurrence-free survival rate. So important things were also noted.

Unfortunately, the subcutaneous prime, in fact, did not show any benefit. There's really no difference. In looking at the non-inferiority, there was a slight signal in favor of the Tokyo strain.

The trade-off to that was perhaps a slightly higher side effect profile. But you're talking about five-year, high-grade, recurrence-free survival rates of mid 60s in all three arms showing again the effectiveness, the long-term effectiveness of BCG and the strain itself, Tokyo versus TICE was not significantly different.

Now this hopefully in the future will give us an alternative to allow actually continued other options to hopefully decrease the pressure we have in terms of our BCG supply.

Dr. Chang: You know, I think the relationship between urology and medical oncology is continuing to become, if anything, more and more intertwined. And so, you know, I'd love to hear your perspective, Matt, regarding, you know, what that means, what the next steps are in terms of that relationship.

Dr. Galsky: So I think that's absolutely true. At the same time, I think that we - you know, as medical oncologists, we’re anticipating maybe a shift in the way that we approach patients with non-muscle invasive disease, you know, five to 10 years ago where we thought there would be this sort of onslaught of patients with non-muscle invasive disease in medical oncology clinics because of the pembrolizumab approval. And clearly, with so many new intravesical options and risk versus benefit, that didn't happen.

And so I think that that was an interesting shift in the field that we thought would make our multidisciplinary care occur even earlier and earlier. But clearly what we're seeing, I think, is maybe a shift in the opposite direction, which is that we need to be even more closely looped in together on the care of patients with muscle-invasive disease to ensure that patients with muscle-invasive disease are getting the latest in terms of systemic therapy.

And then in patients with advanced disease, I'm sure you're experiencing this as well, as patients are living longer and longer, more and more issues related to the bladder itself related to possibly new clones of tumors developing in the bladder that need to be managed locally.

And so I would say it's changing across the board, but probably in a direction that I wouldn't have guessed 10 years ago.

Dr. Chang: Yeah. I think that if we were asked to predict what would happen in bladder cancer 10 years ago, I'm very glad that none of those predictions, at least I've been able to find have been on record because I would have been way off. I would not have done well in Vegas, that's for sure.

So as we consider these things, Matt, tell me kind of what you think, you know, are the biggest challenges, the most exciting next steps? I mean, because you've helped lead the way. I would love to hear kind of your perspective.

Dr. Galsky: So in terms of the biggest challenges, I think that's trying to get patients, the minimum amount of treatment that they need to cure their cancers with the least morbidity. And that's always been the biggest challenge. And I think we're doing better and better at doing that. But that needs to be front and center in terms of how we design our studies and how we care for patients.

In terms of the development in the field, we're rapidly approaching the age of superintelligence, right? And I think what's going to be the case in six and 12 months? I can't predict. So I think whatever it is that’s excites me most in the field a year from now is something that I can't even envision right now probably.

Dr. Chang: Now I think that's incredibly insightful because the rapidity of what's being found. But then our ability to perhaps predict that or determine what the next steps are only getting actually better and better. And we've started utilizing that in medicine specifically in bladder cancer, looking at certain AI produced factors that help predict outcomes, predict response, give us prognosis as well.

I think determining what that development is just as you say, is fraught with risk, for sure. And I love that combination of what you say of giving the appropriate treatment. The very minimum in terms of producing the response we want, which is ultimately cure. And to me, I think a great kind of field that we could replicate is, you know, think about testes cancer. Think of that we've made huge inroads in terms of, “oh, it's sensitive to platinum based chemotherapy.” And then ever since then, it's been actually honing in, focusing on therapy to decrease the amount, decrease the morbidity.

And the amount of patients we've actually switched their surveillance in testes cancer, minimizing downsides of not only surgery, but as well as systemic therapy, I think is really a framework of what we need to do next. We've made huge inroads in terms of therapeutic interventions. But your point regarding personalizing that therapy for each individual, I think we're going to get there.

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