Neal Shore: My pleasure.
Zachary Klaassen: We have some breaking news here. I mean, this is like just hot off the press May 28th, 2026. Just a huge feat to get this combination of an IO plus BCG in these high-risk patients. Can you just level set with the POTOMAC trial's high-level results for our listeners?
Neal Shore: Yeah. Well, thanks so much. And yeah, just yesterday we got the news from the FDA that they had it now approved. So essentially we've had high-risk NMIBC patients for decades that really the only therapy we've had that's been approved in the guidelines is BCG induction and maintenance based on a prior SWOG trial, about a three year where we know that only about 16, 17% ever get the three-year maintenance. And so many of these patients, 20% to 50%, will go on develop unresponsive disease, and invariably they'll go on to develop muscle-invasive disease and/or metastatic disease. Radical cystectomy being the standard of care with unresponsive disease really in most of the world.
Zachary Klaassen: Right.
Neal Shore: And an option in the US as well. We've had the luxury of multiple different approvals for unresponsive disease, but how do we stop patients from getting there? What other sort of combinations? So we designed the POTOMAC trial sponsored by AstraZeneca. The lead PIs on it were myself and Maria De Santis, a very respected, great person, colleague, medical oncologist from Berlin, Germany. We did the trial during the pandemic and essentially a little over a thousand patients looking at durvalumab, a well-described approved checkpoint inhibitor, in combination with BCG versus a control arm of induction and BCG for two years. We had a second cohort where it was just induction in that arm, as well as in the combination, patients got durvalumab intravenously for a year.
Zachary Klaassen: And then when we look at the event-free survival endpoint, just explain what that is and what you guys found in that combination.
Neal Shore: So for this particular primary endpoint was DFS or disease-free survival. Previously, we published a similar trial called the CREST trial, where we had an EFS. DFS, EFS are actually pretty similar endpoints.
Zachary Klaassen: Sure.
Neal Shore: But at the end of the day, the bottom line, we successfully met our primary endpoint. Again, these are for high-risk NMIBC patients. So high-grade TA, papillary disease, CIS, T1 disease. And the combination durva/BCG bested BCG induction maintenance with a hazard ratio of 0.68-
Zachary Klaassen: Right.
Neal Shore: ... in favor of the DFS arm. No decrement at all on OS. It's still immature.
Zachary Klaassen: Sure.
Neal Shore: And then at the AUA, just a couple of weeks ago, I got to present at a plenary session, extended efficacy analysis, and some additional safety. What we showed at the plenary at AUA was the looking at some of the additional subgroup analyses, papillary only, T1 only, as well as combinations with or without CIS. And so the hazard ratio, as I said, in the intent-to-treat population was 0.68. When we look at these subgroups now, the hazard ratios drop down to anywhere from 0.49 to 0.61. So this is really great, especially on the papillary side, where 91% of the patients in the study had at least papillary and/or combinations with T1 or CIS. So I'm thrilled that the FDA approved this yesterday. This is going to open up a lot of opportunity for our colleagues, uro-oncologists by themselves and/or working with medical oncologists, to say to patients, "Look, I now have a combination that will best BCG induction maintenance."
Zachary Klaassen: Yeah, it's absolutely brilliant. I think you kind of led into my next question. Do you see this as, this is BCG-naive, so they're coming to urologists typically? Is the urologist going to adopt both? They're going to give the durvalumab. Do you think it's going to be a partnership with med-onc? Probably a combination of both. What are your thoughts on sort of this kind of workflow?
Neal Shore: Yeah, so you make a great point. These are all BCG-naive patients.
Zachary Klaassen: Right.
Neal Shore: As opposed to the unresponsive group. So I think it's really a fabulous question, and I maybe preface it by saying, "Look, patients deserve to have a choice."
Zachary Klaassen: Yeah.
Neal Shore: So this is this very vaunted and important concept of shared decision-making. And I've had the privilege of having a debate about this at EAU and again at AUA, IBCG. And I think what I learned from that, looking at the different segments of who would be giving the combination. Will it be a urologist? Will it be working together hand in glove with your medical oncology colleagues? I think it's going to be all sorts of permutations of that. The IO therapy, the checkpoint inhibitors, or the PD blockers, PDL, PD have been approved across numerous tumor types and, of course, in bladder and in kidney, and there's even a tumor-agnostic indication in prostate.
That said, the medical oncologists are very comfortable with this, and there are toxicities associated with IO therapy, but it's very well described and very well understood. I think what I'm proud of for this particular trial, the POTOMAC trial, is it's going to really, I think, inspire our uro-oncologic colleagues to say, "I've been hearing about checkpoint inhibitors for many, many years; is now the time where I'm going to start to get more involved because of high-risk NMIBC, BCG patients?" This is the wheelhouse for urologists, not just in the US but globally.
Zachary Klaassen: Right. No, that's absolutely the case. I think when we got this notification yesterday about FDA approval, we all immediately thought, "Hey, I've got this patient; I got that patient."
Neal Shore: Yep.
Zachary Klaassen: If somebody's thinking about the first three or five patients, who do you think this is the correct cocktail for?
Neal Shore: Yeah. I mean, there's almost virtually no contraindication except for a checkpoint inhibitor IO therapy like durvalumab, maybe somebody with really debilitating rheumatologic disease, but virtually everyone can be educated on what the risk-benefit is. There's clearly the DFS benefit. I also presented a decrease in the number of cystectomies.
Zachary Klaassen: Yeah.
Neal Shore: A delay in the time to even needing a cystectomy, a time in high risk recurrence in the first year, all favoring the combination arm versus BCG, and cystectomy-free rates trending positively. So this is pretty, very exciting I think, for our uro-oncologists, particularly those who perform a lot of cystectomies.
Zachary Klaassen: Yeah.
Neal Shore: T1 patients with or without CIS, TAG3 patients, multifocal with or without CIS. And so this is many of these patients-
Zachary Klaassen: Yeah.
Neal Shore: ... that we see, and I think it's going to be very, very important for us all to, again, say, "Look, here's the clinical benefit." Obviously the FDA sees it; that's why they approved it. There is a trade-off. There is more of the traditional, well-described immune adverse reactions. And again, our medical oncology colleagues are very comfortable with this. I think we need to. We've embraced a new adverse event profiles in GU oncology, and I'm really excited that this is going to be another great educational opportunity for the field, uro-oncology, but then also, most importantly, for patients.
Zachary Klaassen: Absolutely. I think you mentioned the AUA subgroups thought that was super helpful because it helps to sort of tease out seeing those hazard ratios and having that. Neal, congratulations on the trial. Congratulations on the FDA approval. Thanks for joining us on UroToday. Appreciate your time as always.
Neal Shore: Thanks, Zach.