Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and I am in the presence of greatness. We have Dr. Patrick Hensley. We've known Patrick for years. He finished his MD Anderson Fellowship after being a resident at University of Kentucky, and now he's an assistant professor there in urology as well as in pathology. We've asked Dr. Hensley to actually give us highlights of an upcoming, very important, exciting session at the SUO in 2025 in Phoenix. Dr. Hensley, they always choose really the leaders when they choose the moderators of such sessions, and you've actually been chosen to be the moderator for a very important session on bladder cancer. Thank you for giving us a preview and some upcoming highlights, and look forward to having a big crowd there at the SUO.

Patrick Hensley: Thanks so much for welcoming me this morning, Sam. Really excited to share some of the highlights of the Bladder Cancer 2 session. All right. As you mentioned, Sam, I'm going to present some of the highlights from the Bladder Cancer session that'll take place on Friday, December 5th, at the upcoming SUO meeting in Arizona. A lot of what I'm going to cover are late-breaking abstract of clinical trials for which the data is embargoed. I'll share the study schema and kind of contextualize where we're at from the trial standpoint.

The first trial that I'll present is SunRISe-1, and we've seen results published from this trial. This is a phase 2B trial investigating the intravesical gemcitabine delivering system TAR-200 in BCG unresponsive patients. We saw cohort 2 data. This is BCG unresponsive CIS with or without papillary disease treated with TAR-200 alone as monotherapy, initially presented back in 2023 at AUA by Dr. Daneshmand. This trial was recently published in JCO with a median follow up of 12 months. And at a median follow up of 12 months in the JCO publication, we saw a complete response rate at any time of 82%, and this has obviously led to FDA approval of TAR-200 in September of this year. But at SUO this year, we're going to see the one-year disease-free survival rates at a median follow-up in the cohort of 16 months, and I think this will give us some really vital context with respect to durability of response of TAR-200.

Next, we'll see top line results from BOND-003 cohort P. We're aware of the emerging FDA approval for BCG unresponsive patients with CIS, lots of emerging drugs in that disease space. We've seen some NCCN guidelines support as category 2B recommendations for several agents in the papillary-only disease setting. But we're in tremendous need clinically in our routine practices for effective bladder-sparing intravesical treatments for patients with BCG-unresponsive papillary-only disease. As you may know, cretostimogene is an oncolytic immunotherapy and BOND-003 Cohort P. It was a single-arm trial assessing the efficacy of intravesical creto and high-risk papillary-only patients in the BCG-unresponsive setting. We eagerly anticipate the reporting of these data from Mark Tyson. This readout will join the likes of other BCG-unresponsive trials that have reported out kind of exploratory papillary-only cohorts. KEYNOTE-057 included a Cohort B investigating pembrolizumab. We saw papillary-only patients for the nadofaragene trial. We've seen papillary-only cohorts reported for Anktiva. And then as I mentioned in the previous slides, SunRISe-1 at Cohort 4 that has presented some early papillary-only disease. So really exciting data for BOND-003 Cohort P.

The last intravesical trial in the late-breaking abstract session will be CORE-008 Cohort A. This will be presented by Trinity Bivalacqua. This is investigating cretostimogene in patients with BCG-naive, high-risk non-muscle invasive disease. We've seen a number of important trials read out recently for BCG-naive patients including three-combination BCG plus systemic IO trials that included POTOMAC and ALBAN, which reported out at ESMO this year last month. And then CREST, which reported out at AUA last year. I would categorize these as kind of underwhelming results in terms of efficacy in the face of added systemic toxicity from IO. The creto results from CORE-008 will kind of lead the way for intravesical therapy trials reporting in the treatment-naive space. I'm really excited about that. Likewise, we'll await some additional results from SunRISe-3, which is TAR-200 in the treatment-naive setting. And then QUILT is investigating Anktiva in the treatment-naive setting as well. So lots of exciting stuff as we move these intravesical treatments to the treatment-naive, high-risk non-muscle invasive disease setting.

Next, we will have an update on KEYNOTE-905 or EV-303. This was kind of a landmark trial investigating a combination of enfortumab vedotin and pembrolizumab in the neoadjuvant setting, specifically for cisplatin-ineligible patients. Again, this was reported out at ESMO in Berlin last month, looking at the EV plus pembro versus upfront surgery cohorts. From their ESMO presentation, the primary endpoint of event-free survival demonstrated a significant improvement in the combination EV and pembro group versus upfront surgery, and there was also an overall survival advantage in the combination group. I think what was most exciting or anticipated by us as surgeons and urologists was the pathologic response rates to this drug. You can see that the neoadjuvant EV plus pembro achieved kind of a best in class 57% path CR, and that really kind of sets a stake in the ground for pathologic response rates and these neoadjuvant trials. I'm really excited to hear some additional follow-up data and some exploratory cohort analysis that's going to be presented at SUO this year.

And then, lastly, we are going to look at trials in the adjuvant setting following radical cystectomy. IMvigor011 was also presented at ESMO this year and subsequently published in the New England Journal by Tom Powles. This was a phase 3 randomized trial using serial ctDNA measurements on high-risk patients with muscle-invasive disease post cystectomy. Patients with a positive ctDNA were randomized to either atezolizumab or placebo, while ctDNA negative patients were just surveilled. You can see that the ctDNA positive patients treated with atezo exhibited significantly improved survival outcomes. At SUO, we're going to see some really exciting exploratory analysis and subgroup analysis from IMvigor011. This is on the heels of some additional data from CheckMate 274. We know adjuvant nivo is approved after cystectomy for high-risk patients. Again at ESMO this year, we saw some nice data that looks at risk stratified use of adjuvant nivo in patients with positive ctDNA. So I think this is really laying the groundwork for ctDNA as an increasingly validated biomarker to select patients for adjuvant therapy after cystectomy.

Lastly, the bladder session 2 will conclude with an exciting session led by Armine Smith on defining clinical response in minimal residual disease in the metastatic urothelial carcinoma disease space. We'll discuss things like the role of metastasis-directed therapy and surgical consolidation in patients with metastatic disease. I think this session is really going to highlight the role of a multidisciplinary team and growing cohort of patients that we're seeing in daily practice who are achieving really meaningful responses to systemic therapy, particularly EV and pembro in the metastatic disease setting. When these patients achieve a clinical complete response, how do we manage them? How do we manage the primary tumor? How long do we continue maintenance treatments? I think a lot of exciting topics in this disease space to discuss as well.

Sam Chang: Patrick, what a session that's going to be because, in my lifetime, I have been able to witness a significant change in urologic oncology and multiple organs with the introduction of systemic and other therapies. I saw it with prostate cancer when prostate cancer was thought to be chemo-resistant and that all we had was single basically orchiectomy or leuprolide therapy, huge explosion. That's actually where I really started my career was advanced prostate cancer. Looking at guidelines for that, we saw a huge, huge explosion then with kidney cancer, with cytoreductive nephrectomy, and then all these combination of therapies, of TKIs and immunotherapy, and how you proceed with that. Now, with bladder cancer, we're seeing it not only in the advanced disease state but in the non-muscle invasive state.

I'm going to focus on two areas quickly while I've got you. Let's focus on the non-muscle invasive bladder cancer, and let's actually move away from the BCG unresponsive because we clearly have some agents that, in my opinion, probably multiple agents will be used. Let's go to the BCG-naive space or BCG-exposed space. You have alluded to the combination of systemic therapy plus BCG showing some clinical efficacy at the trade-off of some clear concerns regarding possible complications and side effects versus BCG plus maintenance. Each of those studies showed the importance of maintenance, showed some clinical efficacy. Tell me now with these new trials that are now being studied, the QUILT study, the study, looking at SunRISe-3, looking at the BOND-008 study, looking at all those, what is going to be the standard for those trials? Are they going to have to be superior in efficacy to BCG maintenance or BCG induction maintenance? Can they be equivalent and just with less side effects? Tell me kind of, now, what you think will become the kind of benchmark of, "This is what we need to be superior for for this group of patients."

Patrick Hensley: Yeah, that's a great question. As you know, the drugs in the BCG-unresponsive disease space are getting FDA approved based on single arm registrational trials. I think in a treatment naive setting, you really have to show proof of superior efficacy compared to standard of care. Now, what is the standard of care? I think it remains BCG until trials like BRIDGE read out and may usher in new first-line standards of care for treatment-naive setting. I think you have to prove superior efficacy to BCG. You could argue a non-inferiority trial design if the BCG shortage was going to remain in perpetuity, but I think that that's going to be alleviated in years to come. There may be additional BCG strains including recombinant, et cetera. BCG remains king for high-risk, treatment-naive patients, and I think that these trials need to be randomized head-to-head against BCG.

Sam Chang: Yeah. No, I agree with you. I agree with you, and I also agree that they're going to have to show some clinical efficacy above and beyond, be it duration of response, be it perhaps a shortened treatment compared to BCG maintenance. I agree with you totally. Let's go to the second area I'm going to ask you about. Clearly, the importance of multidisciplinary care is something that the vast majority of urologic oncologists, medical oncologists, radiation oncologists, they all understand, "Boy, I think all of us will need to be participating in care of patients with invasive disease and even with advanced disease with these patients now. Perhaps we're doing cytoreductive cystectomies in the future. Who knows? It's really changed quite a bit.

To me, the patients, now, I think that we are going to struggle with, and the medical oncologists have basically verbalized radical cystectomy is a thing of the past that, 10 years from now, we're not going to be doing radical cystectomies, et cetera. Tell me kind of your thoughts regarding the clinical CR for those patients that get these neoadjuvant treatments. Because I think by default and by the data, even though the study you presented was in a population of patients with ineligibility to cisplatin, these are patients that are going to get the combination of EV plus pembro. What do we do now with these patients that really have a clinical CR, that have ctDNA that's negative, the bladder looks fine, the scans look fine? Tell me your thoughts because, honestly, we're going to struggle with those patients.

Patrick Hensley: Patients are asking the tough question, right? They've achieved that clinical complete response, and they're asking about the need for surgical consolidation. My concern as a surgeon is that until we precisely define what a clinical complete response is and make that a multifactorial definition of negative scan, whether that includes an MRI with VI-RADS scaling, negative system with deep TUR biopsies of the tumor bed, you have to have some molecular residual disease markers like ctDNA, urine tumor, DNA, these kinds of things. Because our classic tools in our toolbox of scan and scope, maybe urine cytology is not sufficient enough to really precisely define a clinical complete response. There's been some really nice data that shows that even patients who achieve a clinical complete response have occult either residual invasive disease or even nodal metastasis.

If you look at the 303 data, even patients treated with neoadjuvant EV, pembro who achieved a complete response and underwent cystectomy, there's still a drop off in the survival curve in those patients. Even a pathologic complete response confirmed that cystectomy is not a durable cure in 100% of patients. You raised some really good points. I'm really excited. I think we have the luxury of some really smart people studying bladder preservation the right way in a prospective clinical trial, and I think that's how we're going to move the needle here.

Sam Chang: Yeah. No, I think you've raised really important points. Are we going to accept the possibility that we're going to understage or underevaluate a certain percentage of patients? Because we will. No matter how good we are, we'll miss some. But is that trade off worth it compared to bladder removal for perhaps a majority of patients that may not need it? It's going to be something that we'll continually struggle, continue to try to balance and figure out what is actually best for that particular patient. But it is, honestly, obviously, a very exciting time, and I can see our next steps. We're going to start looking more and more at upper tract disease. We're going to look at other areas of urothelial carcinoma, prostatic involvement, urethral. It is a very exciting time for clinicians, but also for patients that actually have these options and to have these discussions. Patrick, as always, enjoyed so much spending some time with you and always learn from you. I really think this will be one of the more exciting sessions at the SUO in December, and look forward to hearing you lead the way in that Bladder Cancer 2 session.

Patrick Hensley: Thanks so much, Sam. Appreciate the invite. I'll see you in Phoenix.