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Sam Chang: My name is Sam Chang. I'm a urologist in Nashville, Tennessee at Vanderbilt. And I am here with Doctor Neal Shore, who has been one of the most preeminent researchers for prostate cancer, bladder cancer, and kidney cancer.

And recently at the AUA 2025, that was held in viva, Las Vegas, he presented actually one of the plenary sessions looking at a new combination therapy using sasanlimab, I think I said that correctly, with BCG or versus BCG. Tell us the key highlights of that, because I think it really has opened people's eyes regarding systemic therapy and combination, et cetera.

Neal Shore: Yeah, thanks very much, Sam. Yeah, what a great honor to present on behalf of all my coauthors, the CREST trial. And this was a phase 3 global trial that was really conducted largely throughout the pandemic. So kudos to so many folks who were able to get this accomplished.

What we did was recognize-- and there were actually one of, I think, another three phase 3 trials that are addressing high-risk NMIBC, so Ta G3, CIS, and T1 disease, which has historically done well with the gold standard induction maintenance BCG. But we said, OK, what if we could add a checkpoint inhibitor, a PD blocker, sasanlimab, which is interestingly it's delivered subcutaneously.

Sam Chang: Yeah, so a key point. So basically, a checkpoint inhibitor, systemic therapy, different from the intravenous regimens that we've learned about that one single arm pembrolizumab given actually for BCG unresponsive approved, uptake hasn't been fantastic. But now, actually a similar type of mechanism but given subcutaneously. So a key difference there.

Neal Shore: Yeah, I think from a practical standpoint, it could be appealing for sure for urologists, but even for medical oncologists too, because throughput in clinic, we all have person power supply chain issues. It's just quicker. And delivery system is easier with the subcu than a parenteral intravenous.

So what we looked at and the data as we presented here at AUA essentially showed that it was a three-arm study, over 1,000 patients. The combination of sasanlimab given monthly with induction maintenance for two years BCG versus the control arm, induction maintenance BCG, we met superiority in terms of our endpoint of EFS. So we're the first to report in this type of a phase 3 trial. So we're really proud of that achievement.

I think that these patients, as you know, you're one of world-class bladder cancer experts. And when these patients don't do well, when they get recurrent CIS, and/or progression of their T1 disease and/or persistent high-grade Ta G3, we're oftentimes looking at either cystectomy or some of the other approved BCG-unresponsive therapy. So there's a cascade of additional therapies.
By combining sasanlimab with monotherapy BCG induction maintenance, we now potentially, we just presented this data, we're pending publication, it could lead to a change in the treatment paradigm. So I think we always like to have options. So that's the really, to me, what's I'm really proud to have been part of the study.

Sam Chang: And tell me about the side effect profile-- combination versus the control arm of BCG and maintenance.

Neal Shore: Yeah, well, naturally, you're giving a checkpoint inhibitor a PD blocker. The class effect-- we didn't see anything that wasn't not anticipated that you see in this class effect of these agents these, immuno-oncologic agents, about 16% Grade 3, 4 events. The most common thing we saw was some thyroid or thyroiditis type things. So typically, it's more hypo than hyper, and then some rash.

And then there are other type of immune-related adverse events where pretty much low single digit percentages, elevated amylase or transaminase and things of that nature. People have asked me, so will the urologic community embrace this?

Sam Chang: Let me ask you, will the urologic community embrace this?

Neal Shore: What a great question.

Sam Chang: I think that's a question that we should-- because I think that is on everyone's minds. To be honest, I think people were surprised, because there have been other trials, as you know, not with BCG. There are ongoing trials now that we don't know the results.

But then there have been other combinations with other therapies that the addition of the systemic therapy hadn't seemed to be beneficial in terms of physiologically and mechanism of action, you would think this combination would be, in some form, be beneficial. So tell me, do you think the urologists, or what will urologists now do based upon this data, once publication is achieved, et cetera?

Neal Shore: Well, to your point, and it's a great point you raise, is that BCG has been shown to up-regulate PD expression. So now you put in a blocker. So there was the MOA synergy that was a predicate for why we did the study. And others are doing similar trials. So like I said, we're really one of four trials.

I think that you're right. I mean, I was part of KEYNOTE-057, which led to the approval of pembrolizumab in BCG-unresponsive CIS. I use it, I realize I'm a bit of an outlier on this. I think that immune-related adverse events have become very easily and well understood and managed by our medical oncology colleagues.

I have always been one to say, look, the Uro-Oncology Community, it may not be for everybody, but I think for those who really want to have all of the tools in their toolbox, as we oftentimes say, I think this is potentially a great option to have. I think it really could be a paradigm shift. That's a little bit overused word.

But yeah, I mean, I think having the multidisciplinary team of medical oncologists who might want to manage it, or a uro-oncologist who's comfortable in doing it, I think this is really a great advance for our patients. There's many other interesting phase 3 studies that are going to report out with other differing mechanisms of action and different delivery systems and schedule of events. I think it's a great time for bladder cancer patients. And I think that's to me is the really is the take-home-- love having options.

Sam Chang: And especially in this population of patients that you know that may not be healthy enough to undergo cystectomy, they clearly want to avoid the side effects or morbidity associated with cystectomy, the possible mortality associated with it, to have options, it especially appealing for me for perhaps even higher-risk patients because you are treating the entire body, so to speak, with a systemic therapy in addition to the BCG.

And so you can see where an adoption of this, if I'm a patient and I really want to do everything I can to avoid, what's my best upfront? And it may be this combination of therapy of a systemic plus the BCG. Tell me at this point, what next? Do we look at combination therapy sooner? Do we look at this combination with something with BCG? Do we look at it for more advanced for muscle-- I mean, where do we go next? What do you think?

Neal Shore: Yeah, I love the question. But I will say, just kudos to Dave Penson for getting this as a plenary presentation-- your colleague at Vanderbilt, which is really leading so much great uro-oncology research. I think the field is going to move more and more towards looking at antibody drug conjugates, like enfortumab vedotin, other ones.

I think the field is moving more towards trying to avoid cystectomy when it's safe and appropriate, so bladder sparing, try modality, different modality combinations, whether they be intravesical drug-releasing systems, other checkpoint inhibitors. I think also, too, what we're learning-- thanks to you and all the great work that you've done in guidelines, helping our colleagues to really better understand good stratification, low, intermediate, high risk.

Let's not make the mistake of overutilizing BCG. If it's not working after two inductions, it's not going to really work. And having some synergies in MOAs, so the mechanisms of action. So I think that's where the field is moving.

Sam Chang: Yeah, I think the dramatic change-- you're not much older than me at all, Neal, which makes us both old. But when we look at where the landscape is now with bladder cancer, at the very least, I think all urologists and all treating clinicians have an understanding. We've got choices.

Now, maybe we don't know all the different choices. Maybe we don't know the specifics. But having that realization that, hey, we can go beyond cystectomy, we can go beyond, I think is really the initial first educational lift that we've started. Now, the next question is, just as you say, giving the appropriate therapy options to the patient as choices and then taking the next steps.

So I applaud all the different research efforts that you've always led, Neal. It's really-- it's an honor for me to spend some time with you, seriously. And we look forward to future presentations, and more great research. So thanks for spending some time with us.

Neal Shore: My pleasure. Thanks, Sam.