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Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from Houston, Texas. And I'm joined today by Professor Wassim Kassouf, who is joining us from Montreal, Canada. Was, welcome.

Wassim Kassouf: Thank you for having me, Ashish.

Ashish Kamat: So at the recent debates that we had, you and Mike O'Donnell did a nice little debate at the AUA, talking about the different treatment options for patients with BCG unresponsive disease. Of course, you're in Canada, so we understand that many of these current options available in the US are not approved. But with that in mind, how do you approach, or how would you approach counseling a patient today that has BCG refractory, or BCG unresponsive disease?

Wassim Kassouf: So that's a good question. I think that it depends on the context. It depends on where you're practicing. So at least from the debate point of view, we were posed with a typical patient situation, BCG unresponsive carcinoma in-situ in a patient with a reasonably functioning bladder. In Canada, the only option we have available is actually pembrolizumab in that space.

And the difference between Canada and other areas of the world is, in Canada, you have an approval by Health Canada. But we also have another body for reimbursement, since we're practicing in a socialized medicine system. And if you have approval but no reimbursement, pretty much, there's zero uptake. And that's what's happened actually in this country. So we have approval for pembrolizumab but no reimbursement.

And there's really zero uptake to have used that drug for BCG unresponsive disease. And so we're left pretty much with the gemcitabine docetaxel approach, as the only potential intravesical salvage treatment for the BCG unresponsive patient, who does not want a cystectomy. And most centers have used that in Canada.

Ashish Kamat: Yeah, so again, for the sake of the debate, let me put on Mike O'Donnell's hat and I'll be saying that, gem/doce really has shown benefit in multicenter studies, of course, in pooled data analyses. And really, if you look at the numbers of gem/doce, it looks remarkable at one and two years. And I know I'm taking your side in some ways here, but let's debate the opposite.

People will say that, well, gem/doce, even though it has all these numbers from small single center studies, when you pool the data, it still holds true. And that's why gem/doce should be the standard of care. What's your counter to that if you had to take the counter?

Wassim Kassouf: So if you want to be more critical-- and again, I commend Mike O'Donnell for pioneering that regimen because a lot of us are using it just because it's available. The data looks quite good. And it's a cheap regimen. And cheap is important when we're looking, particularly, at these novel agents, where, in many areas of the world, actually, the cost is becoming prohibitive. For sure, in Canada, it will be prohibitive.

But if you look at the literature of gem/doce, a couple of things to highlight. So the landmark paper by Mike O'Donnell first author Steinberg that put that on the map, the number of patients that's been analyzed in this study. And it's a retrospective study across 10 centers is 276 patients, median follow-up, two years.

But the retrospective nature is important because we've learned recently that although we love the efficacy data that, that study has shown, which is roughly around 50%, two-year, high-grade, recurrence-free survival, we've all recently have adopted for many, many years, for example, extended node dissection of bladder cancer. There was much, much more strong retrospective data, numerous, numerous publications on that. We've published on that, me and you, when I was a fellow and you were attending an MD Anderson. But there's many, many centers.

And then Lo and behold, when you look at it and study it in a randomized fashion, it was negative. And in fact, it actually harmed patients. So not to say that this is going to be the same for gem/doce, but we really need that prospective data to really evaluate if these results, if these exciting results, mirror what's happening in a prospective fashion than what we see in retrospective data.

The other thing I want to highlight, if you look at the landmark article, out of the 276 patients, the majority actually were not BCG unresponsive. And there was no mandatory biopsies. So we're looking at, again, a smaller subset of roughly around 100 patients. In that retrospective study, the 7.6% disease progression, a two-year bladder cancer mortality of 4%, stuff that we did not see in those recent readout of many of those novel agents out there.

Now, there has several retrospective studies that have corroborated the findings of Dr. O'Donnell's landmark paper. But they all suffer from a similar issue-- heterogeneous patient population, a mixed bag of BCG naive, BCG relapsing, BCG unresponsive, various follow-ups. If you look at the subset of BCG unresponsive disease, it's really 30, 50 patients in each. So yes, there's several papers out there. But at the end of the day, small series, retrospective design, and heterogeneous patient population essentially.

Ashish Kamat: Yeah, so, Was, you raise a good point, obviously, about the landmark paper and the fact that we're banking on a subset of those patient population. But of course, more recently here, put together the IBCG consortium and he published on this-- and I think, you were part of that as well-- that showed that even in a well-annotated BCG unresponsive population, gem/doce does have excellent response rates.

So again, just like you, I counsel patients. And that is, in many ways, our de facto standard. But of course, we have, as you said, prospectively studied drugs that are approved. Pembro is one of those. Nadofaragene, of course, is one of those. And Anktiva is one of those. And we can't forget that we have these drugs approved. And there's different ways to go about looking at them and using them, of course.

One of the issues we have with these prospective studies is that they're single arm. And even though the companies are following our guidance and AUA guidance and, of course, the FDA guidance, we have to remember these are single arm studies and not randomized studies. So of course, patient selection is a key factor. Share with me a little bit, your thoughts. Should we be still doing single arm studies? Should we now be randomizing, again, something? How do you feel this field can actually move forward with everything that we know now?

Wassim Kassouf: Well, listen, I mean, I think, it's time and credit to the combined FDA, AUA workshop that stemmed this whole field forward. The need for randomized trials is probably ripe right now. So we got a bunch of data out there. We got several FDA approved drugs. I suspect two more is going to be FDA approved within the next year.

I think, it's time that we need randomized data to really tease out the magnitude of benefits of all these agents. And the question is, what is the control arm? I mean, ideally, I'd love the control arm to be gem/doce. But that could be up for debate. But I think it's time to start looking into randomized data in this patient population.

Ashish Kamat: Yeah, no, absolutely agree. And that's a recommendation we made in our recommendation consensus paper from the IBCG retreat that you were a co-author on. Was, I want to thank you for taking the time. We will have the link to the full debate at the bottom of the screen here on UroToday. I commend you for taking the stance against gem/doce. Even though you use gem/doce, that was a challenge. But you certainly rose to the occasion. So thanks once again.

Wassim Kassouf: Thank you, Ashish, and thanks for having me.