Burgeoning Non-Muscle Invasive Bladder Cancer Space: AUA 2025 Clinical Trials Presented (Doctor/Patient Podcast)

00:00:00: You are listening to an ADIS Journal podcast.

00:00:05: Welcome to this ADIS podcast in oncology and therapy.

00:00:10: The podcast is aimed at everyone interested in the latest research related to bladder cancer presented at the American Urological Association or AUA annual meeting, twenty twenty five.

00:00:22: You don't need to be experts as the discussion will be in plain language with explanations given for any technical terms used.

00:00:30: Podcast speakers include Rick Bangs, a patient advocate for bladder cancer, and Dr Roger Lee, an oncologist.

00:00:38: The views expressed in this podcast are solely those of the authors and do not necessarily reflect those of their employers, the podcast sponsor, AUA, or any of their affiliates.

00:00:51: This podcast was sponsored by Johnson & Johnson.

00:00:55: The authors received no honor area related to the development of this podcast.

00:01:00: And medical writing support was provided by Amica Scientific and funded by Johnson & Johnson.

00:01:07: Hello everyone.

00:01:08: My name is Roger Lee.

00:01:09: I'm a urologic oncologist at Moffitt Cancer Center with a clinical and research focus in bladder cancer.

00:01:16: And I have Mr.

00:01:18: Rick Baines joining me.

00:01:19: So Rick, could you also introduce yourself?

00:01:23: Hi, I'm Rick Bangs.

00:01:24: I'm a survivor of muscle invasive bladder cancer.

00:01:28: I host a podcast for the Bladder Cancer Advocacy Network and get to work with clinicians like Roger on clinical trials and guidelines.

00:01:36: And I have a two thousand and six model here, Neil Blatter.

00:01:41: Great.

00:01:42: So today we are going through some of the high level.

00:01:46: data readouts from AUA, and this year it was an exciting AUA with a primary focus on non-muscle invasive bladder cancer clinical trials with a lot of data reading out.

00:01:59: So all the trials that were covering here are potentially practice changing and these were presented in the practice changing paradigm shifting clinical trial session.

00:02:10: Roger and I selected four studies, and it was based on their significance to bladder cancer patients and clinical practice.

00:02:17: The first is a clinical trial called Crest.

00:02:20: It includes SanSanLimab, which is a program cell death PD-one inhibitor.

00:02:26: The second is Bond-zero-zero-three.

00:02:29: That includes creta-stimulgine, cadena-novropec.

00:02:35: And the third is Sunrise-one, which is... using TAR- Two-Hundred, a gem site of the intravascular system.

00:02:43: And the fourth is CISTO, which is an observational study looking at bladder preservation therapy versus radical cystectomy surgery.

00:02:51: There's a novelty here.

00:02:53: We have so many burgeoning choices that we had to select from for this podcast, and we are optimistic that guideline changes are going to follow, but they are not currently in place.

00:03:05: Right.

00:03:05: So Rick, as you know, there has been very little change in the standard of care for folks with high risk, non-muscle invasive bladder cancer over the last four decades, until very recently.

00:03:18: And certainly for us as clinicians, it's very exciting to see all these options emerging.

00:03:24: From my view as the clinician treating these folks with high risk non-muscle invasive bladder cancer, I think our first and foremost goal is to prevent disease progression to muscle invasive disease.

00:03:37: And secondly, to minimize the number of recurrences and also to control the treatment burden as much as possible.

00:03:45: So I agree from the patient point of view, what I would describe as keeping the genie in the bottle, that is going to be absolutely critical here.

00:03:54: Your first line of defense has been breached, so you want no further progression, and you certainly want to avoid radical cystectomy and the collateral damage that comes along with that.

00:04:04: Our first trial is going to be the Crest trial at San Sanlamab.

00:04:07: It's an immunotherapy.

00:04:10: And so Roger, what's this trial about and what's interesting from your point of view?

00:04:15: Rick, as you know, San Sanlamab is a type of immunotherapy called a PD-one inhibitor.

00:04:21: And in this trial, it was paired with intravascular BCG, which is a widely used first-line treatment for folks with high-risk non-muscle invasive bladder cancer.

00:04:32: And immunotherapies in general will help patients to boost their immune system to fight the cancer.

00:04:39: In this trial, there were three arms, but the presentation focused on the arm that combined BCG induction plus maintenance.

00:04:50: with Sasana MAP versus RMC, which is BCG induction plus maintenance alone.

00:04:57: RMB had BCG induction without maintenance plus Sasana MAP and wasn't covered as much during the presentation.

00:05:07: So what the investigators found was that there was statistically significant prolonging of event free survival.

00:05:14: And what that means is there's no major health problems that occurred, including recurrence of cancer in the patient cohort who were treated with the combination of Cisandamab plus BCG induction plus maintenance versus those patients who were treated with BCG alone.

00:05:31: So the event free survival rates for the combination arm at two years was eighty five percent versus eighty percent seen with BCG alone and at three years eighty two percent in the combo arm versus seventy five percent in the BCG arm.

00:05:49: And significantly, for those patients with carcinoma in situ, non-muscle invasive, flat tumor that's extremely aggressive, three-year complete response in those patients were treated with the combination was impressively higher than those who were treated BCG alone at ninety-two percent versus sixty-eight percent.

00:06:13: So the trial results brings into question whether or not Sasanumab or other immune checkpoint blockade agents, which are systemic agents, should be brought in as a combination treatment for patients with high risk NMIBC.

00:06:30: And this has potential impact on changing the standard of care, which is currently just intravascular BCG.

00:06:39: However, We did see that with the combination of SusanaMap plus BCG that there was increased number of grade three or four severe life-threatening toxicity that we're seeing.

00:06:52: At twenty-nine percent with the combination of BCG plus SusanaMap versus only six percent in the arm that was treated with BCG alone.

00:07:01: And furthermore, discontinuation of the study due to adverse events was also higher in the combination at thirty-two percent versus ten percent in those patients were treated with BCG alone.

00:07:14: So I think even though the EFS, which was the primary endpoint for the study, was shown to be superior for the combination arm, but in the clinical practice, we still have to take into account whether or not the higher rate of adverse events that we're seeing with the combination is justified by the improvement in the event-free survival.

00:07:36: You've seen the data, Rick, so what stands out to you?

00:07:40: So the first thing I noticed was the delivery mechanism because it was subcutaneous delivery, which is fairly unusual in bladder cancer, but it's not the only unusual delivery that we're going to discuss today.

00:07:52: And it's layered on top of BCG induction and maintenance.

00:07:56: So this kind of delivery should be more convenient.

00:07:59: There's no incremental time in the clinic because you're getting the BCG as well.

00:08:03: It should be less painful than intravenous delivery, and that should help enable wider access and adoption.

00:08:11: To date, this is the only application of this particular agent, the toxicity, meaning the side effects or the safety profile, similar to the two agents, BCG and Sanalumab administered separately, and quality of life similar to BCG induction and maintenance.

00:08:30: For the patients who have carcinoma in situ, that's that aggressive flat tumor on the surface of the bladder, those patients that receive Cethylamide plus BCG versus BCG alone have a higher probability of continued complete response.

00:08:46: Okay, our next trial is the Bond-Zero-Zero-Three.

00:08:49: That's Cretostimaging, Gnadinorevpec, and Roger, what's this trial about?

00:08:55: Bond-zero-zero-three is a trial that used creta-stimaging, which is an alkalitic adenovirus, as treatment for patients with high-risk BCG, unresponsive, non-muslim-vasive bladder cancer with carcinoma and situ.

00:09:12: So there are several notable points that were reported at the AUA.

00:09:17: Overall, there was a seventy-six percent complete response rate seen at any time.

00:09:22: And that actually includes patients with TA or CIS who are underwent a re-induction course of the treatment.

00:09:31: And then more notably, forty-six percent of the patients overall had maintained a complete response at twelve months, which is quite impressive.

00:09:40: Moreover, they reported twenty-four months long-term durable response in thirty-four percent of the patients as well.

00:09:49: And as mentioned before, of the patients who had undergone a re-induction or a repeat course of the six weeks of treatment because they had disease persistence at three months, fifty percent of those patients actually converted to a complete responder.

00:10:07: Over ninety percent of the patients had remained free from progression to muscle invasive disease at twenty four months and over eighty percent of the patients had avoided radical cystectomy by that time point.

00:10:20: And overall, the treatment was found to be quite well tolerated with no grade three or higher treatment related adverse events.

00:10:29: And this potentially can also impact the standard of care.

00:10:33: As you know, there are a couple of agents that have been approved by the FDA for bladder sparing approaches for patients with BC drone responsive disease.

00:10:43: And of course, based on these data, I think created stimaging may become another option in the near future.

00:10:50: So what about you, Rick?

00:10:52: What stands out to you?

00:10:54: Well, the delivery here is similar to BCG intravascular therapy in number of doses.

00:11:00: We've got an induction arm and then a maintenance arm.

00:11:04: Induction may be times two, but it's very similar.

00:11:07: The high rate of progression-free survival, which is the length of time the person lives after starting treatment without their cancer getting worse, and the avoidance of radical cystectomy are certainly noteworthy, and that's a durable response potentially, which is great.

00:11:22: The low rate of adverse events is also noteworthy.

00:11:26: Most of them were grade two or grade one.

00:11:29: So they're very low on the adverse event scale.

00:11:32: And there's also a quick response to those adverse events.

00:11:36: There were no treatment discontinuations and no dose delays and no dose reduction.

00:11:42: So all of that's good.

00:11:43: Our next trial is Sunrise One.

00:11:47: That's using TAR-U-Hunter, a gym-side of being an intravessical system.

00:11:51: So Roger, what's Sunrise One about and what's interesting to you?

00:11:55: So Sunrise One is a very interesting trial where for the first time, there is a complete data reported out for the intravessical drug system, which is designed to provide sustained local delivery of the cancer treatment within the blotter.

00:12:13: The gym cytobine intravascular system for the treatment of BCG, unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma and cytoo, with or without papillary tumors, was looked at in the context of treatment with TAR-II.

00:12:30: And two separate presentations were made in the paradigm shifting practice changing session.

00:12:37: The first one reporting one-year data for the TAR-II model therapy in patients with BCGR-unresponsive CIS with or without papillary tumor.

00:12:48: And this was cohort two within the study.

00:12:50: And then there was a separate report for the papillary-only cohort who were also treated with TAR-II hundred.

00:12:57: And this was cohort four within the study.

00:13:01: So a few noteworthy points for each of these cohorts.

00:13:05: For cohort two or the patients with carcinoma and situ who are BCGR-unresponsive, the overall complete response rate was very impressive at eighty two percent and that's the highest of any of the model therapy trials to date with ninety six percent of the patients with complete response being achieved at month three.

00:13:27: and notably for this trial there wasn't allowance of a re-induction if there was disease that was found at three months.

00:13:36: at twelve months Forty-six percent of the patients were able to maintain their complete response.

00:13:43: And fifty-three percent of those who had a complete response initially had a durable response by month twelve time point.

00:13:53: And overall, TAR- two hundred was quite well tolerated with most of the adverse events being grade one to two with only five patients with greater than or equal to one serious treatment-related adverse events.

00:14:08: In addition to that, there was quality of life questionnaire, or the EORTC, quality of life questionnaire throughout the study, and it was found that the assessment of physical, psychological, and social well-being was all maintained throughout the trial.

00:14:26: So, relatively few side effects and also having the patients, for the most part, maintaining their quality of life.

00:14:34: And then in cohort four, those patients with paplar-only BCG-unresponsive disease, progression-free survival and disease-free survival at nine months were ninety-six percent and eighty-one percent.

00:14:48: respectively.

00:14:50: Again, overall, TAR-II was found to be well tolerated with most of the adverse events limited to grade one to two and only three patients with more than one serious treatment-related adverse events.

00:15:03: In September of twenty-five, the FDA granted approval for TAR-II's use in patients with BCJR-responsive CIS.

00:15:13: So what stood out to you, Rick, about this study?

00:15:18: Well, this is that second unique delivery mechanism.

00:15:21: So we install through the urethra.

00:15:24: It's done every three weeks, through week twenty-four, and each time we're moving the prior installation.

00:15:30: Then you shift to every twelve weeks through week ninety-six and you get sustained drug over the time period that it's in the bladder.

00:15:39: In and of itself that delivery mechanism creates some interesting possibilities and raises important questions to consider about other agents.

00:15:47: Is the delivery hindering some of our agents?

00:15:50: Are there other interesting agents that might use the same delivery mechanism?

00:15:55: Can we give new life to agents that are already familiar and effective?

00:16:00: Are there other delivery mechanisms that should be explored?

00:16:04: Okay, our last trial is the CISTO trial, and this is a prospective observational cohort study of intravesical bladder preservation therapy versus radical cystectomy surgery funded by PCORI.

00:16:16: This is the only trial here that we're covering that does not center around a specific agent.

00:16:22: So, Roger, what's this trial about and what makes it interesting to you?

00:16:27: Rick, as you know, this was a very significant and well-designed study aimed at answering one of the most important questions in this disease space, which is, how does removing the bladder impact the patient versus giving folks intravestical therapy repeatedly for the objective of helping patients to preserve their bladder?

00:16:51: So what the investigators found, interestingly enough, is that overall physical functioning was very similar between these two different approaches for folks who are undergoing bladder sparing therapy versus those that have radical cystectomy or bladder removal surgery, twelve months after being diagnosed with recurrent high-grade non-muscle invasive bladder cancer.

00:17:13: In addition, global health as well as emotional well-being.

00:17:18: So their anxiety level, their depression level, as well as their financial well-being were actually better for those patients who had their bladders removed versus those that continued on bladder sparing therapies.

00:17:33: And finally, not surprisingly, bladder cancer-specific survival and overall survivals were very similar between these two groups.

00:17:42: So to sum it all up, I think this study was quite surprising in that it actually found better outcomes in certain aspects for the patients who underwent upfront mastectomy.

00:17:55: And it points out that for these patients, maybe removing of the bladder is not a bad way to approach the disease.

00:18:05: So what's stood out to you, Rick, about this study?

00:18:09: Like you, I thought this was very patient-centric.

00:18:11: They recognized the impossibility of randomization in a context where patients would be extremely reluctant to accept it, so they designed it accordingly.

00:18:21: As you mentioned, it centers on some of the most difficult questions for clinicians and patients with high-risk non-muscle-invasive bladder cancer to answer.

00:18:30: When should radicals to stectomy be prioritized over bladder preservation?

00:18:34: Is bladder preservation really the holy grail?

00:18:37: And it's not necessarily going to be the be-all and end-all.

00:18:40: It's coming with a cost at least today.

00:18:44: It delved into the complexities of bladder preservation.

00:18:47: And these are going to become increasingly more critical to understand as we attempt to replace radicals to stectomy as the gold standard.

00:18:56: Deon Sanders, that well-known professional football and baseball player who was diagnosed with bladder cancer, he demonstrated what some of us suspected, which is that bladder preservation isn't everything.

00:19:08: He did not choose it.

00:19:10: These kind of decisions are not one, not two, not three-dimensional, but they are multi-dimensional decisions, and they go beyond data that you can capture in the electronic medical record.

00:19:22: It nicely reflected the current state of treatments and treatment outcomes, but it did raise some additional questions and results should hopefully further refine the approach that's being used in the clinic.

00:19:36: Yeah, absolutely interesting study.

00:19:38: And I think just to sum it all up.

00:19:40: I'm super excited to see so many different options now available for patients with high-risk non-muscle invasive bladder cancer in the treatment IE, as well as in the treatment refractory setting.

00:19:53: A lot of these agents have shown great promise in achieving the efficacy goals that have been set out in the beginning.

00:20:01: by the FDA as well as by some key opinion leaders.

00:20:05: And these are implying new possibilities for existing agents as well.

00:20:11: And then finally, the implications for these studies in terms of changing the guidelines and also how we practice management of high risk bladder cancer is still waiting to be seen in the future.

00:20:25: And I think we've also got a reminder here that navigating bladder preservation has been and continues to be nuanced in each of these settings.

00:20:34: And there's a reinforcement of something that is so critical, which is a goals of care conversation and offering shared decision making.

00:20:43: Roger, it's been fun.

00:20:44: I want to thank you for the opportunity.

00:20:47: I really want to thank you as well, Rick, for sharing your insights and much more to come on this subject.

00:20:52: I'm sure.

00:20:54: Thank you.

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