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Zachary Klaassen: Hello, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center. I'm delighted to be joined on UroToday by urologist Neal Shore. Neal, thanks so much, as always, for joining us on UroToday.

Neal Shore: Thanks, Zach.

Zachary Klaassen: We've had a great GU ASCO 2025 in San Francisco. You had some interesting data, always all over the place, but tonight focusing on ABLE-32, which I think is a really interesting Trial in Progress that you presented at GU ASCO 2025. Maybe before we get into the trial, just take our listeners through what exactly is AUA intermediate-risk non-muscle invasive bladder cancer and what the current unmet need is in this disease space.

Neal Shore: Yeah, thanks, Zach. So intermediate-risk NMIBC is sort of not low risk, not high risk—everything in between. Another way of thinking about that, AUA/SUO guidelines is you get a recurrence within a year of a low-grade Ta, a solitary low-grade Ta that’s greater than 3 cm. Of course, there's always some subjectiveness to that. A low-grade Ta, multifocal, so more than one lesion. Much more rare is high-grade Ta less than or equal to 3 cm, and the incredibly uncommon low-grade T1, which— but so mostly really what this is is your recurrences of low-grade Ta within a year of a resection, low-grade Ta greater than 3 cm, and multifocal disease. So there's a lot of those patients that are out there.

Zachary Klaassen: Yeah. And if we look at the guidelines currently, it's a mixed bag about what we do. I mean, obviously with TUR, what we do afterwards is—maybe it's chemotherapy. Maybe some people get BCG if they can get it. But there's a lot open to interpretation, correct?

Neal Shore: Absolutely.

Zachary Klaassen: So let's walk through the ABLE-32. I'm going to pull the slide up because I think it will help our listeners.

Neal Shore: Yeah. So I mean, just to—this is a nice version of the study schema. But nadofaragene firadenovec, first intravesical gene therapy approved by FDA for high-risk BCG-unresponsive NMIBC with CIS with or without papillary disease. So that's already approved.

Nado—I'll say call it “nado” instead of “nadofaragene firadenovec,” it’s a little simpler. It's a non-replicating, non-integrating adenoviral vector that delivers a human interferon alpha-2b gene into the urothelial cells. It has an excipient called Syn3, which enhances viral transduction into the urothelium.

So this local gene delivery leads to this really ramped-up expression of interferon alpha-2b and its sustained production. The great pioneering work was done by SUO-CTC, the Phase II, the Phase III, which we published in JCO and Lancet Oncology. So there's apoptotic and antiangiogenic and immunomodulatory effects, which thus prevents recurrence of the disease. I think that's the key thing from an MOA standpoint.

In ABLE-32, we’ll expect to enroll about 454 patients—100 urology sites, global, US, Europe, and Asia. And so we're really excited about that. Essentially, these are patients who have that definition of intermediate-risk NMIBC. It’s screening; they undergo a TURBT with or without perioperative chemotherapy, as the schema is describing here. And then they get randomized to observation versus Q3 month intravesical nado. And that’s the schedule you see for it in the BCG-unresponsive high-risk NMIBC patients with CIS with or without papillary disease. One-to-one randomization. The patients can get up to two years of nado. The patients in the observation arm, if they recur, they can cross over.

So it's an exciting study. There are no FDA-approved therapies in the intermediate-risk population. There's a whole bunch of other studies that are pretty exciting, too, that are going on in this space. I think this is really one of the ongoing unmet needs in NMIBC. So real excited to be part of it. We were happy to have a Trial in Progress poster at ASCO GU 2025 this year.

Zachary Klaassen: Yeah, great overview. And I think you mentioned there's really nothing right now, but we have a lot coming. And I think this has become sort of the new hot space for these non-muscle invasive bladder cancer trials.

We just talked about ABLE-32. There's the PIVOT-006 looking at cretostimogene. There's the ResQ132A looking at Anktiva plus gemcitabine—all in intermediate-risk. And so I think over the next three to five years, we'll probably have options there. Let's say all of these get approved, and we're sitting here having this discussion in several years. Where do you think nadofaragene fits into that? Obviously, there's this quarterly dosing, which may be attractive to patients and clinicians. How do you see that fitting into what could be a busy landscape in the next few years?

Neal Shore: Oh my gosh, it is going to be busy. And not just in intermediate-risk alone, but clearly, in the BCG-unresponsive we already have multiple approvals. There's nado, there's pembro, there's N-803. As you say, N-803 is now moving into intermediate-risk. In front of the FDA in the next couple of months is going to be UGN-102. So your earlier comment is spot-on. This is super exciting.

I think that the nado is nice in that, from a schedule of events, it’s once every three months. And that's pretty convenient and very patient-friendly and clinic-friendly. All of these therapies, I love it. The 006, we're doing that study with CG Oncology too. I think that I've always been a fan of just saying the more options we have for patients, the more options we have for clinics.

Some things require freezing, refrigeration. Some studies or administrations require endoscopic insertion of devices. Oh, yeah. Let's also bring in the intermediate-risk: there's the drug-releasing system, also known as the TAR-200, the TAR-210. So gosh, I mean, it's just this sort of embarrassment of riches in the clinical trial pipeline.

And I think that for our colleagues who treat bladder cancer—whether it's intermediate-risk or high-risk, BCG-naive, BCG-unresponsive—and then, of course, we get into the whole perioperative strategies of neoadjuvant, adjuvant—this is where urologists are going to play an absolutely key role. For some of them, these therapies are just within our field, and some of the other ones potentially with our medical oncology and radiation oncology colleagues. So I think this is wonderful.

For so long, Zach, bladder cancer was sort of like a little bit of an orphan disease state. But now, you look at ASCO GU and upcoming AUA 2025, there's going to be a ton of great presentations.

Zachary Klaassen: No, you're right. You took the words out of my mouth. If we look at SUO, AUA, GU ASCO, this has become a multidisciplinary, busy space, which typically was, again, very few options. Now we have rad oncs, med oncs, urologists all involved. It's going to be great. It's going to be fun to follow this over the next several years.

Neal Shore: Yeah, yeah.

Zachary Klaassen: Great discussion as always, Neal. Any couple quick take-home points for our listeners today?

Neal Shore: Oh, no, I think we covered it just to set. I really hope—my biggest worry, Zach, is folks are just so darn busy, right? I mean, everyone's seeing so many patients. Oftentimes, it's hard to get to these meetings. And I hope programs like this, which are concise and short, get people stimulated to say, “Hey, maybe when I have some time, I'll learn, I'll read more about it.”

The field is changing rapidly in GU Oncology—prostate, kidney, bladder now that we're focusing on. And maybe it's time that the group, the shop, the clinic that you're in, you think, “OK, maybe we need to sort of really work better together within my organization so we can really push towards that, especially for the community folks, a true center of excellence.” And part of it is just divvying up responsibilities, and it's a different model depending upon where you're practicing.

Zachary Klaassen: Yeah. Well said, Neal. Always great chatting with you on UroToday. Thanks for your time.

Neal Shore: My pleasure. Thank you.