Zachary Klaassen: Hello. And welcome to AUA 2025 live in Las Vegas. I'm pleased to be joined on UroToday by Dr. Brian Mazzarella, who is a urologist at Urology Austin. My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. Brian, thanks so much for joining us on UroToday.

Brian Mazzarella: My pleasure, Zach. Thanks for having me. Appreciate it.

Zachary Klaassen: So you've done a lot of great space in the non-muscle invasive bladder cancer area. And today, we're going to talk about ADVANCED-2, looking at TARA-002. So maybe just before we get into that, just highlight this really unmet need and the awesome stuff we've seen in the last five years or so.

Brian Mazzarella: Yeah. I mean, it has been an awesome five years. That's a correct summary. So to think about what's happened in those five years, we can back up and say, there were really two or three options for high-risk non-muscle invasive bladder cancer then. We had BCG and we had intravesical chemo that wasn't really indicated there. And we've seen this incredible proliferation that is ongoing right now. So there were three new approvals in that space over the last few years. And this is all because recurrence rates were still pretty high in spite of BCG being effective.

When I speak to patients, I use the general term of recurrence rates are about 60% at five years, but that's more of an all-comers number. And so when we confine that to AUA high-risk or high-grade cancers, even in the current therapies, there was a lot of need for additional treatment options, and we're seeing those come out right now.

Zachary Klaassen: And particularly because maybe people aren't fit for cystectomy or they don't choose cystectomy, these are additional options we can hopefully safely give them and even multiple options potentially too.

Brian Mazzarella: I mean, it's a complicated question. According to guidelines, for BCG-unresponsive patients, cystectomy is still the first-line treatment. But as we know, many patients are not fit for it. Many patients elect not to have it. And the FDA has really echoed this need. And so in all of these approvals—and we'll talk more in this particular context—the FDA looked specifically at this space and said, we need additional therapies because those patients need additional treatment options.

Zachary Klaassen: Absolutely. Tell us a little bit about TARA-002. What's the mechanism? How does it work?

Brian Mazzarella: Yeah. So, I mean, it's a very familiar mechanism is the short answer. So TARA-002 is actually a therapy that has some current approvals in other countries and in other types of cancer. And it is like BCG. It's a broad-spectrum immunopotentiator. And so BCG is a live-attenuated vaccine, as we know. TARA-002 is Streptococcus pyogenes that is inactivated. And like BCG, they both have a very strong immunopotentiating portion, and then they also have a direct cytotoxic effect.

Zachary Klaassen: Awesome. And that leads us to ADVANCED-2. Just tell us a little bit about the trial design, maybe the primary or secondary outcomes of this trial.

Brian Mazzarella: So the trial design goes back to what we were speaking about earlier, which is that FDA-specific need for new therapies in BCG-unresponsive disease states. And so it is a prospective single-arm but multi-cohort trial. And in the BCG-unresponsive CIS space, that's primarily what we've seen and continue to see, which is single-arm trials. And that was the FDA's attempt to provide innovation in that space.

So TARA-002's trial, ADVANCED-2, is for BCG-unresponsive CIS in one cohort—that's their registrational cohort, meaning they hope for an FDA approval from those results—and then they have another cohort that's in BCG-naive high-risk bladder cancer, and that's more of a pilot cohort for them looking at those results.

Zachary Klaassen: Awesome. And I know just a few months ago, at SUO 2024, you presented some preliminary data on ADVANCED-2, maybe just highlight briefly the summary of those results.

Brian Mazzarella: Yeah, that was really an honor to give that—that was some of the first public release of this data from ADVANCED-2. At that point, the CR rate, which is the primary endpoint of the trial—CR at any time, defined as CR up to six months—the CR rate in the BCG-naive setting was 68%, and the CR rate for the registrational group in the BCG-unresponsive was 100%—

Zachary Klaassen: Wow.

Brian Mazzarella: —at that point. Now, I'll stress, that was only five patients that were evaluable out at that point. So obviously, each patient at that point was worth 20% worth of CR. So that's very early data. And, honestly, I don't think anybody expects 100% CR to hold. But those were both numbers that are relatively in line with what we're seeing emerging in this space. And I will plug the new data by saying that BCG-naive CR has actually gone up with some further analysis.

Zachary Klaassen: That's awesome. So I know at AUA 2025, additional update is being provided. What was presented at AUA?

Brian Mazzarella: The data continues to look stronger is the short answer. So I had the honor of presenting this at the SUO back in December of 2024. And the data cut point was through November. Right now, what we're seeing is two cohorts, as we talked about. So the BCG-naive cohort, which is fully enrolled—that's over 30 patients—when I presented that data in December, had a 68% CR rate, and that's actually improved to 76% CR. So that is not only continuing to get better, but is in line with a lot of the very exciting emerging therapies.

And then in the registrational cohort, the BCG-unresponsive group, I presented a 100% CR. That was only five patients. Those patients have continued to progress, but there are still only five patients within that cohort that are fully evaluable. The 100% CR rate has held with a few more months of analysis. It won't hold forever. That cohort is designed to have 100 patients in it ultimately. So it's very early, but certainly promising early.

Zachary Klaassen: Now, that's exciting. I mean, I think even just a couple of years ago, we were looking at 50% to 60% CR rates and very excited. Now, we're getting into the 70s and even low 80s in some trials. So this is great. This has been a great discussion. I know it won't be the last time we talk about TARA-002 on UroToday. So Brian, any take-home messages for our listeners today?

Brian Mazzarella: Well, I think the take-home message I'd share is that this is a world that is about to get very complicated for us as urologists. But I think the upside to that is it's a world that is also going to get much better for our bladder cancer patients.

Zachary Klaassen: For sure.

Brian Mazzarella: And my suggestion would be two things to practicing urologists. One is, as we think about what therapies are right for these patients, don't hang our hat entirely on a few percentage points of CR, but really look at, how does the therapy as a whole fit for our patients? And one thing that I think is important about TARA-002 is that it is intravesical. Its administration scheme is similar to BCG. Its mechanism of action is similar to BCG. And I think that's worth something for our patients and for urologists for the familiarity.

And then the second point, I would say, is, as we try to answer the question, what therapies are right?, which is going to be an incredibly complicated question, an important part of that answer is urologists trying these things. And so I'm not encouraging people to be ahead of approvals and guidelines. But on the other hand, we can't understand what is right for our patients until we bring these things into our practice, administer them to the patients, understand how the conversations go, understand how our patients tolerate them. And I think that will be accessible for most urologists in the relatively short future.

Zachary Klaassen: Yeah. Great summary. Very exciting time for non-muscle invasive bladder cancer. Brian, thanks, as always, for joining us on UroToday.

Brian Mazzarella: My pleasure, Zach. Thank you.