Peter Black: Thanks, Ashish. Always a pleasure to join you on UroToday.
Ashish Kamat: We've chatted about a lot of things over the years and really enjoy every time we get your perspective. There's a huge influx in interest and bladder-sparing paradigms across the spectrum of bladder cancer, right, but especially when it comes to non-muscle-invasive bladder cancer. With all the new trials reading out, all the new studies coming in, even in the BCG-naive space and the BCG exposed and unresponsive.
So, I just wanted to have you join us today to get your perspective, see where you think the field is headed and a few practical tips for the listening audience, which as you know, is made up not only of experts, but also young urologists across the globe. So, first off, thank you for taking your time and looking forward to hearing what you have to say.
Peter Black: Perfect. Thank you, Ashish. I put together a few slides just really to hit some of the high points of what we need to be thinking about when we're thinking about bladder-sparing for high-grade non-muscle-invasive bladder cancer. I did add high-grade in there because it is quite different for low-grade intermediate-risk, non-muscle-invasive disease.
So, let me start with the four main take-home message that I want to provide you with today specific to bladder preservation. So, the first is that first-line therapy is so key to preserving the bladder. We have to get it right the first time to maximize the chance that the patient goes without recurrence and potential progression and gets to keep their bladder.
Secondly, high-grade non-muscle-invasive bladder cancer recurrence after first-line therapy, so meaning after BCG, essentially, at this point in time, can be treated with second-line therapies, and we'll go over some of the second-line therapies and how to manage those, but we have to be careful. We can't just treat over and over again if the treatment is ineffective.
The third point I want to make is that trimodal therapy is a consideration for T1 tumors and we shouldn't forget about this. If we're thinking cystectomy, we should also be thinking trimodal therapy, and that certainly will preserve some bladders with good outcomes.
And finally, even though we like to preserve the bladder, we need to remember that removing the bladder is actually part of the treatment algorithm and we should not be trying to preserve the bladder at all cost. So, let me dive into each one of these just a little bit.
Optimal first-line therapy, these things are familiar to us. There's not really anything new in this regard, but we need to do a complete high quality TURBT. High quality means ideally with enhanced cystoscopy, even though we recognize that the vast majority of urologists in US and Canada are not necessarily using enhanced cystoscopy, but doesn't increase the quality of resection. We need to be doing our re-TURBTs when indicated, especially for T1 disease, and we need to be treating with optimal BCG induction and three years of maintenance for the high-risk patients.
So, these are the givens. And the question is, where are we going in the near term future, potentially, that will enhance first-line treatment even more? And so, we've seen the three trials, POTOMAC, CREST, and ALBAN, comparing BCG alone versus BCG plus systemic immune checkpoint inhibitors. And we've seen some very intriguing results and the question will be really how are we going to adopt that into practice?
So, we're anticipating that durvalumab plus BCG will be approved in the near future by the FDA. And then, as a community, we're going to have to figure out exactly which patients get that. And I think we're most likely to gravitate to the patients who may have an indication for cystectomy, so the highest risk patients, and pursue BCG plus IO in that setting, recognizing that we should still be doing cystectomy in those patients whenever acceptable to the patient.
The other first-line change that we might see in the not too distant future is gemcitabine/docetaxel instead of BCG. And this, of course, would really help alleviate the BCG shortage issue, but it also just in general gives an alternative of patients who don't tolerate BCG or have a reason not to get it. And, the BRIDGE Trial comparing Gem/Doce to BCG has completed accrual and we just need to give it time to accumulate events so we can see what the outcomes are.
And another treatment that I personally find very intriguing is BCG plus N803, the interleukin-15 superagonist, just because it's building on the BCG backbone that we know is effective, but potentially making it more effective. And this trial is ongoing comparing to BCG alone in the BCG-naive high-risk setting. And the company had put out results from the first nine patients in a phase 1b trial and they essentially had 100% complete response and remarkable durability. Now, we can't make too much out of nine patients, but it is a potentially impactful treatment going forward, not considering the cost, of course.
So, second point is just patients with BCG-unresponsive non-muscle-invasive bladder cancer. This is probably where we've seen the most activity in the last few years and we have, on the bottom in gray, these three new treatments that are all FDA-approved. Importantly for the international audiences that these drugs are for the most part not available outside of the US. Nadofaragene has actually been approved in Canada, where I am, but is not yet available or funded. But it's important to remember that these drugs were tested in the CIS population and not in the papillary only population. So, one dilemma is what do we do with patients who have BCG-unresponsive Ta/T1 disease only? And Ashish and I were just talking before this started. There was an FDA sponsored workshop on this on the weekend and a lot of the urologists in the room certainly thought, although there are biological differences between these two, clinically, we tend to treat them the same. And so, hopefully we'll be allowed to use these drugs also for papillary-only disease.
And of course, in blue at the top, I have gemcitabine/docetaxel, which a lot of us use. There are obstacles to its use as well from just logistics and practicalities, but it's inexpensive. It's relatively easy to access and give, although there is a burden on the patients with two drugs given sequentially on the same day, but this is used widely despite good evidence. And so, we really need better evidence to validate that it is actually as effective as some of the alternatives.
But the big question is, what do we do when we have a high-grade recurrence after one of these? So, we're now into third line BCG. There's a recurrence after BCG. There's recurrence after second line treatment. When do we proceed with cystectomy versus another intravesical therapy?
And my own opinion is certainly a high-grade T1, I want to do a cystectomy, and otherwise, even for the CIS and the papillary disease, if I'm on third line, I'm already thinking a cystectomy because the risk of progression is rising and we shouldn't just fall into this trap of one drug after another.
So, just quickly on trimodal therapy for T1 tumors, just something to be thinking about. If the patient requires... If you think, as urologist, patient requires cystectomy, we should also be thinking of trimodal therapy. And what does the data show us? So, there was some retrospective data, for example, from Erlangen in Germany with reasonable results with chemo radiation.
We have one trial, the RTOG 0926 trial. There's only 34 patients. It took a long time to accrue. The primary outcome was basically cystectomy-free survival. 88% of patients preserved their bladder at three years, but I would say there's a relatively high rate of metastasis. So, you can see 12% at three years, 19% at five years. Overall survival is difficult to interpret because these are older, frailer patients, but there were certainly local recurrences, 12 out of 34 and there were deaths from bladder cancer, eight out of 34. So, there are some concerns here.
There's an ongoing trial that I encourage everybody to support. It's an NRG trial called the PARRC trial where any patient with high-grade T1 considered for cystectomy is randomized to radiation plus chemo, sort of the usual, versus radiation plus IO. And these are patients who have persistent T1 disease on a ReTUR or they have adverse features such as lymphovascular invasion or a histologic subtype or they're BCG-unresponsive.
And then, finally, I just want to make the point that even though the context is to preserve the bladder, some patients I think really do need their bladder out. Very high-risk patients, which are those I just alluded to, positive LVI, histologic subtypes, those types of patients, they do warrant upfront cystectomy. They have a very high-risk of progression. Those who receive BCG, the risk of progression goes up with each round of ineffective bladder preserving therapy, and we know that cystectomy is the most definitive management with the lowest risk of progression, metastasis and death.
And the one new thing I would just like to highlight are the results of the CISTO trial. This was a pragmatic trial where patients chose their treatment, either bladder preservation or radical cystectomy, for high-grade disease after prior BCG. 570 patients enrolled around the US and it was really, really interesting to see that a lot of the quality of life and patient report outcome measures were better in the cystectomy population than the bladder-sparing population. So, physical function was worse after cystectomy at three months, but was already equivalent to the bladder-sparing group by nine and 12 months and the cystectomy population had better emotional function, generic health-related quality of life, reduced financial burden, less depression and anxiety, the clear negatives of cystectomy related to bowel function and sexual health, and of course, there are postoperative or perioperative complications and even perioperative mortality. But the bottom line is, we should not write off cystectomy as one of our treatment options.
And so, just to reiterate the take-home message again, optimal first-line therapy is key to preserve the bladder. High-risk recurrences after BCG first-line therapy require judicial use of second-line therapies. Don't forget trimodal therapy for the T1 tumors, and especially don't forget radical cystectomy as an important part of the treatment algorithm.
Ashish Kamat: So, Peter, I love the fact that you started with, or you ended with the CISTO trial because I think it's very, very important for us to listen from our patients. In fact, I'm sure you're aware, at the AUA or right before the AUA at the National Press Club, we had a joint event with the IBCG, BCAN, World Bladder Cancer Patient Coalition, of course, our partners from J&J, to announce the results of the bladder burden effort that we looked at. Urologists, then physicians and patients and their caregivers, and one of the things that really came out is that the radical cystectomy is not as bad as people might think, so long as patients are counseled appropriately on mental health aspect and the financial and economic toxicity of it. So, I'm really glad that you brought that up.
You always give such a succinct presentation that it really leaves no room for questions, which is really odd, but I still want to put you on the spot and maybe ask you a couple of questions. So first off, let me ask you about Gem/Doce, because in academia and even in Europe, we tend to use gemcitabine/docetaxel because of the abundance of evidence from multiple centers that have been pulled together. But our community folks in the community will often say, as you mentioned, that they lose money on it, they can't make money on it and hence they don't use it. You mentioned the BRIDGE study. What if the BRIDGE study shows that Gem/Doce is equivalent to BCG? Do you think our community oncology urologic folks are going to use it? I mean, they don't use it in the BCG-unresponsive space. How do you think the BRIDGE study is going to change treatment paradigm?
Peter Black: It's a difference between the practicalities and logistics of delivery, which I must say are quite different everywhere else other than the US. So, it would impact treatment in other places, but, I mean, I don't have the answer for the US. I think, if it's a money loser, then you would think that they just have to change the fee schedules and the reimbursements that it's perhaps not a money loser. I understand that these are cheap generic drugs that if it's based on percentages or yeah, it's just not easily fixable.
So, I think that's a logistic problem they don't have a solution for, but I think scientifically, it's important and it gives us options. And even in community settings, if you have the choice, you might... I mean, we're talking about BCG versus Gem/Doce and so BCG is not going to be a big money winner either, but in that context, in the first-line, if it's easier and cheaper to give BCG, then why not? But, in the patients where you can't, then you have an alternative. So, it'll be important data regardless.
Ashish Kamat: I mean, again, kudos to the investigators and the patients and everybody that participated. I'm very supportive of the study. And speaking again of kudos to people for doing the studies, it's CREST and POTOMAC and of course even ALBAN, even though it was negative, with the hazard ratio of 0.68, everybody is looking to see how can we better distill down which patient population that has a ratio is justified in, right, because clearly toxicity, 25, 30% long-term toxicity in a young patient with TA high-grade disease with addition of IO, is that justified? Probably not. So, Peter, how are you thinking about... If and when it's approved, which we all think it will be, you're going to use durva with BCG? Which is that patient?
Peter Black: Yeah. Well, it's a very good question. And I mean, I would say, just as background, I was very skeptical about these trials and I thought there's no way they're going to show a benefit. And I thought that the control arm was going to do too well, and indeed, the control arm did remarkably well. I mean, BCG alone in these trials proved to be markedly efficacious, but still, there is this hazard ratio, 0.68, as you say, is driven primarily by high-grade recurrences though and not harder outcomes and the toxicity is real.
So, I was initially super enthusiastic, and certainly more tempered now. I think, for the general population, I think it's going to be hard to justify it, given the toxicity. I would love to see... And then, in the trials, originally sasanlimab in the CREST trial was presented and some of the subgroup analyses look really interesting. Maybe it works best with non-tie strains. Maybe it works best with CIS. These different groups where you're sort of piecing together how you might use it.
But then, with the Potomac trial, it came out a few months later, none of that held up. So, there's very little clinical to go by, except there was a subsequent report at the EMUC meeting in the very high-risk group for CREST. And there, it looked like the hazard ratio was wider. I think it was 0.5 something. So, as I said in my slides, I think that might be a population.
I don't think the evidence is very clear that we should limit it to that population, but that's a population that has a lot to lose, so maybe it's more worth the risk. What I'd really like to see, and I think the best we've seen yet was a biomarker study from Matt Galsky at GU ASCO that I thought was very compelling, looking at primarily RNA sequencing signatures, so immune signatures and that type of thing, and really picking out a group of patients who did particularly poorly with BCG and had a bigger differential benefit with the addition of immunotherapy. So, if we had a validated marker like that that would say, this subgroup of patients really benefits a lot from it, then I think that would really change practice.
Ashish Kamat: Yeah, no, I agree. I think we need something like that. And, of course, you and others have been working on this for gosh, now, what, more than two and a half decades, right? So we definitely need something because, as far as the POTOMAC study's concerned, Neil Shore presented at the AUA just this last week and he was the exact opposite. The patients that did well on CREST with CIS, if you took them out, then you showed a benefit with durva. And again, the hazard ratio was similar for the very high-risk population, but obviously, with small numbers, none of these read statistical significance.
Peter, I've known you for a long time and we could always chat for a long time, but I just noticed the clock and in the interest of time, I'm going to say thank you for taking the time and let's have you back to continue this discussion.
Peter Black: Thanks for having me. It's always good chatting.