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Sam Chang: Hello, my name is Sam Chang. I'm a urologist at Vanderbilt University Medical Center, and we're quite fortunate to have Dr. Woody Smelser, who is an assistant professor of urology at Washington University. He actually is a 2024 awardee of the Young Urologist Award from the AUA and was asked by the AUA to present the key takeaways dealing with urothelial carcinoma. We're quite fortunate to have him. So Woody, can you give some of the highlights you gave at the 2024 meeting?

Woodson Smelser: Absolutely, and I would be remiss if I didn't also let the audience know that Dr. Chang was also the AUA's 2024 Hugh Hampton Young awardee, so he's due great credit as well for all of his contributions longitudinally for patients with urothelial carcinoma. But it was an exciting meeting. There are a number of things that have come to the mainstream in organized urology within the realm of bladder cancer. Some of these abstracts are not things that are necessarily new for those of us who deal with urothelial cancer day-to-day. But I think this represented the widespread dissemination of some of these concepts into the rest of urology, and I think it points to trends that we're going to see change over time and some results are honestly going to be practice-changing. And so we'll focus on each of those. And I've got four key takeaways that we're going to go through today and some accompanying slides to give the highlights of the meeting.

So moving on to some of the key takeaways from the AUA 2024 meeting in bladder oncology. I think the first key takeaway is that clearly non-muscle invasive bladder cancer salvage therapies are in their Renaissance Era. Not too long ago, I think most of us who've done this for even just a little bit remember that there weren't a ton of options for patients in this space. But we're really seeing a huge expansion of new clinical trials with results that are going to inform our practice. And so I like to think that urologic oncologists at this time are in their Taylor Swift era. They've got range, and we really have to keep on top of our game because the data is changing rapidly, and we don't want to be an old act where we're only offering cystectomy to patients who have recurrence or progression with non-muscle invasive disease.

And so if you look at the landscape of our currently FDA-approved options in BCG unresponsive non-muscle invasive bladder cancer, there are three things that are now available in practice: Pembrolizumab, systemic immunotherapy, Nadofaragene, which recently received FDA approval, and then the newest agent obviously, Nogapendekin, or alt, 803. And the latter agent you can see was just approved on April 22nd and is not yet really widely available in clinical practice. And then of course, there's the old mainstay, cystectomy. And if you look at the slides on the right, you can see the complete response rates at three months for two of these three agents, which have been roughly around 40 to 50% in heavily pre-treated populations. But then when you look out to 12 months, those rates fall down to about one in five patients with a durable response.

And so the first abstract that I want to highlight from the AUA was from this new forum that we have, the Paradigm-shifting, Practice-changing Clinical Trials, or the P2 Forum, which was part of the Friday plenary. And this was in regard to the TAR-200 system, which is a potential multi-drug intravesical platform that's being used in bladder cancer. And these are specifically the results from the SunRISe-1 study.

So if you're not familiar with the TAR-200, it is an intravesical pretzel stent that is deployed cystoscopically and it is designed basically for osmotic release of drug. And the key thing here is that different drugs can be added to the platform as new agents show efficacy, but this specific drug trial was looking at gemcitabine with slow release.

And so this is the design of the trial. They took patients who had high-risk non-muscle invasive bladder cancer, who had persistent or recurrent disease, or met the FDA definition for BCG unresponsive, who were either unwilling or unfit to undergo cystectomy. And they gave them the TAR-200 device. And so the specific cohort we're looking at here got TAR-200 alone, there were other arms of the trial, or the design, where people got immunotherapy, other things. And you can see that their primary endpoint was the overall complete response rate. And the key thing about this TAR-200 is it's left in the bladder, and so the dosing is not weekly like we've seen with BCG, but allows extended interval dosing.

And so here's some data from that. The results of that study show that the centrally assessed complete response rate was 82%, and that was quite durable. At the six-month mark, the complete response rate was still 75%, and at the twelve-month mark, it was 61%, so markedly better than what we've seen with other agents. And you can see from this slide that the overall durability of response was quite good. And you can see even out to 18 months with Kaplan-Meier estimate, the duration of response was 74%.

Similarly, there's another trial on non-muscle invasive bladder cancer that was also featured in the P-2 Plenary Forum, looking at the results of the BOND-003 trial, which was using another intravascular agent called Cretostimogene. And this again was in heavily pre-treated patients with BCG-unresponsive non-muscle invasive bladder cancer.

And so Cretostimogene, or CG0070, is a conditionally replicating adenovirus, and these are a family of oncolytic viruses that naturally infect tumor cells. And this one specifically binds to a highly expressed receptor called the Coxsackie Adenovirus Receptor, which is expressed in most stages of bladder cancer. And this invokes basically a two-hit killing mechanism where there's direct oncolysis through translocation into the tumor cell, and there's also local up-regulation of immune cells through T-cell killing.

And so the trial design for this, this was a similar course to BCG, people got a six-week induction course, and then they got a second induction if they were initial non-responders. And then patients got maintenance. And Dr. Mark Tyson presented this work at the plenary, and you can see the complete response rate at any time point was 75%.

When we look here at this plot demonstrating durability of response, you can see, similar to the TAR-200, there was significant durability, and the progression-free survival at 12 months was 96.7%.

And then transitioning from there, my next big takeaway from the meeting is that in the space of locally advanced or metastatic disease, we now have highly effective agents. And the efficacy of these agents, specifically Enfortumab vedotin and Pembrolizumab in combination, is really changing our paradigm in advanced bladder cancer.

So if you're not someone who works in this space regularly, just a refresher. Enfortumab is what's called an antibody-drug conjugate and it targets a specific receptor called Nectin 4, which is highly expressed on bladder cancer cells. It then translocates into the cell and releases an agent that is a microtubular disruptor, which stops cell replication and leads to apoptosis. And then of course, Pembrolizumab is an immunotherapy agent with pancreatic cancer indications, and used in combination, it helps disinhibit the immune system to lead to further tumor killing.

And so, one of the key abstracts highlighted at the SUO portion of the AUA meeting was results from the EV-302/Keynote-A39 study. And this was recently presented also at the ESMO Congress by Tom Powells. And basically, patients who had previously untreated locally advanced or metastatic urothelial carcinoma received either standard chemotherapy with platinum-based regimens or EV-Pembro.

And what we see here is there's essentially almost doubling of overall survival and a number of patients who actually had a complete response to this therapy and were rendered with no visible metastatic disease on traditional imaging. And so I think that this is really going to have implications in the way in which we treat patients who are initially diagnosed with advanced or locally metastatic disease. And I would predict that these agents are going to move earlier and earlier in their treatment phase and will eventually supplant neoadjuvant chemotherapy with cisplatin regimens as the frontline agents.

And then moving on to the third key takeaway, this is one that we didn't really take time to focus on in our takeaway session at that actual AUA, but there's been a lot of discussion about quality of lymph node dissection and extended lymph node dissection in bladder cancer for decades. And so I think the takeaway from the newest data and the sentiment of the meeting is that you should do a quality lymph node dissection at the time of cystectomy, but it should not be at the expense of efficiency of the operation or safety for the patient.

And so just a little background on that, when we look at the SEER Database, we knew that historically up to 40% of patients didn't actually have lymph node dissection. And this has improved with time, with guidelines from bodies like the AUA and NCCN. But we know that even with lymph node dissection, you will have patients who have negative pathologic lymph nodes in both NMIBC and MIBC who will recur, and sometimes they recur quite fast. And so that has brought into question the extent of lymph node dissection of whether or not potentially more extensive dissections would've been therapeutic. But the interesting thing is, with an increasing lymph node dissection yield and footprint, we really haven't seen improved therapeutic impact or improvement in prognostication, but we do know it increases operative time and it may also increase complications.

So there's a debate at the IBCG session at the AUA where there's discussion of SWOG 1101, which is a recently accrued and reported randomized trial, where they actually compared standard versus extended lymphadenectomy. And you can see the trial design on the right. And the key thing is that the extended lymph node dissection was clearly defined, and extended lymph node dissection included the standard zones, plus common iliac, presacral, and then even distal IVC and aortic nodes. And I think the key thing in this trial design is that surgeon quality was audited by submission of photos from every case, as well as upfront credentialing, to make sure that there really was a difference in the lymph node templates. And the key takeaway is that there was no difference in disease-free or overall survival. You can see the hazard ratios there.

And if you look at some of the characteristics of the patients here, you can see they were quite balanced between the two groups. And really the biggest difference was just in the frequency and grade of complications. Seth Lerner has given a nice talk about this that I think has actually been featured on this platform as well. And when we look at differences, really the only big differences were in mortality and extent of complications.

And then moving on to the last takeaway, and I think this actually dovetails off of the last point where lymph node status has served as a poor prognostic indicator overall. There are only a few abstracts in the 2024 Program Book that discussed circulating tumor DNA in urothelial carcinoma, either in the upper tract or the bladder.

Here's an example of one which was looking at genomic profiles coupled with circulating tumor DNA. And there were three or four other small ones on the topic, but this really was not a huge focus. But recently at the EAU Meeting in Paris, Tom Powells presented data from the IMvigor study, which you can see summarized in a Kaplan-Meier plot on the left. And the key in this IMvigor trial is that patients underwent cystectomy and then they had landmark circulating tumor DNA testing, meaning it occurred at a set point and were then stratified to different arms of the trial including receipt of immunotherapy. And the problem with this design, and looking at the results, is that with landmark testing, even in the patients who were initially ctDNA negative, about 30% of those patients eventually had a recurrence event. And so that's led to the question about whether or not we should actually be doing serial investigation of circulating tumor DNA, meaning that short intervals every three to six weeks, or even every three months, and then utilizing things like immunotherapy if there's a conversion to detectable levels.

And so IMvigor011, which is highlighted here on the right, is using exactly that design where patients are going to undergo serial plasma collection and imaging, and then only be randomized and receive adjuvant therapy in the setting of positive circulating tumor DNA.

So my crystal ball prediction for AUA 2025, which is in Las Vegas, is that we're going to see a lot of abstracts about this, we're going to see a lot of major trial data starting to accrue, and the utilization of both circulating tumor DNA and even urine tumor DNA will guide our escalation or de-escalation of therapy intensity after all of our major extirpative surgeries. And I think really this is the biomarker that we've been looking for that we have not seen with lymph node dissection extent, and this is going to help us have a better idea of whom we can ramp up therapy or ramp down depending on those results.

Sam Chang: Woody, that was a fantastic summary of some of the key takeaways from the AUA 2024. I'm going to ask you just one question. I'm going to focus on diagnostics and therapeutics. So what for you is the most exciting in terms of diagnostics? Is it a urine-based study? Is it a serum-based study? Is it DNA? Is it proteomics? What do you see, as you went through the abstract, seem to be most promising from the diagnostic standpoint?

Woodson Smelser: Well, I think it really is in the realm of circulating tumor DNA, both urine and plasma. And I think really, if you divide the major disease spaces that urologists manage day-to-day, non-muscle invasive disease and muscle invasive disease, there's tremendous promise with urinary tumor DNA to reduce the burden of surveillance, particularly cystoscopic surveillance, which we know is uncomfortable for patients, costly, potentially financially toxic, and also sometimes poor at detecting, through white light, subtle CIS lesions or other things like that. And so I think the ability to use a urine marker with high fidelity to determine if one of these salvage therapies that we highlighted in the earlier abstracts is working well or if we need to consider a change in therapy is extremely helpful.

And then if we look in the realm of muscle invasive bladder cancer, both pre and post-treatment, I think the circulating tumor, or plasma studies, again, are really going to give us the opportunity to figure out, who do we need to engage medical oncologists for adjuvant therapy? Because even though these adjuvant regimens or metastatic regimens are effective, they do come with significant cost and potentially toxicity. And so I think really, we're ushering in this era of personalized medicine that, for years and years, we've talked about. And I think that's actually going to be in the hands of the treating urologists very soon.

Sam Chang: Woody, thanks again for those key takeaways from the AUA 2024 focused on urothelial cancer, really is an exciting time and really appreciate you being able to distill it down to some of these key points, and look forward to talking to you again soon.

Woodson Smelser: All right. Thanks.