Tian Zhang: Welcome to this episode of UroToday. I'm so excited to be joined here at ASCO 2025 by my wonderful friends and longtime colleagues, Dr. Benjamin Maughan, who's associate professor at University of Utah Huntsman Cancer Institute, and also Dr. Michael Harrison, who is also associate professor at Duke Cancer Institute, my prior institution. So thank you so much for coming and joining in on our recording today.

Benjamin Maughan: That's fantastic to be here. I always enjoy the conversations with you, and it's great to catch up with Mike and be here in Chicago together.

Michael Harrison: Yeah, definitely. Thanks for having us. Looking forward to the discussion.

Tian Zhang: Fabulous. So we're talking about partner posters at this year's ASCO. Great presentations, both of you. But one that, Mike, you're presenting, is called "Real-World Quality of Life in Patients with Metastatic Renal Cell Carcinoma on Active Surveillance in the ODYSSEY Prospective Observational Study." And Ben, yours is "Real-World Quality of Life for Patients with Metastatic Renal Cell Carcinoma Treated with Systemic Therapy on the ODYSSEY Study." So tell us about ODYSSEY. How did it start? Why are we enrolling patients to ODYSSEY?

Benjamin Maughan: Well, Mike, this is your baby. So why don't you take off?

Michael Harrison: OK, yeah. And Tian's also been involved in you as well, but sure. So at Duke, we have this history of having done these—we used to call them registries—in renal cell carcinoma. So we did a retrospective registry when I came on faculty around 2011. Then we did another prospective registry that was a single-sponsor, smaller registry called MaRCC. And this one is the next logical iteration.

So this registry started being planned right before ipi-nivo was approved, and then ended up opening right after the approvals of the major IO-TKI agents. But the idea is that we really wanted to focus on the patient's journey, and that's why it's called the ODYSSEY. So whereas randomized controlled trials appropriately focus on important endpoints like overall survival, progression-free survival, et cetera, we wanted to take a little bit different angle.

In ODYSSEY, we're not trying to recapitulate trials. We're trying to look at the patient experience from a different angle. And so that's why we think it's unique. So appropriately, then the primary endpoint is actually patient-reported outcomes—specifically, FKSI-19 and then the subscale, the FKSI disease-related symptom subscale, and then as well as FACT-G.

So we're looking at that. But also, we want to see how patients do in the real world. So we know that trials aren't necessarily reflective of real-world patients, and so we want to look at how are these drugs dosed in the real world, how do patients do, how do patients feel and function in the real world. And that's really the gist of it.

Benjamin Maughan: And if I can, some of the other—and it's so great to be involved with this project—some of the other fantastic things about this ODYSSEY prospective registry is that it has a lot of the same advantages of what we lean on for prospective clinical trials. It's prospective data. The time points of when we're analyzing and evaluating these things are consistent across the patients. It's multi-institution.

There's quite a number of centers really reflective geographically across the United States that are involved, and that allows us to enroll a broad range of patients demographically, ethnically. But also, it allows us to enroll a fairly large number of patients as well. So there's a lot of really good things that are going to come from this.

Tian Zhang: So remind our audience again. So this is all patients with metastatic kidney cancers, starting their treatments or not. And, Mike, your project, your poster analysis is really delving into those patients without treatment. But how are you all thinking about bringing patients on ODYSSEY and that timing of how—when are we starting to look at their disease course?

Michael Harrison: So we tried to make ODYSSEY really practical. So there are really only probably four inclusion and exclusion criteria. So like you correctly said, Tian, it's really patients who have metastatic disease, who have not been treated with systemic therapy. They have to be followed at a PCORnet site because that's what we take advantage to collect data, and they can't be under treatment for another cancer. But those are really the four points.

And so at Duke, I'm trying to enroll any patient that meets that criteria. Importantly, that also includes not just patients who are selected to get systemic therapy, but patients for whom we may defer systemic therapy, as we've started to call it. So that deferred systemic therapy group could include active surveillance, but it could include other instances. For example, a patient is getting a metastasectomy, like a lung resection or something like that. So we wanted to make it very broad. We also don't select any histology; any histology of metastatic renal cell carcinoma is allowed.

Benjamin Maughan: And I think you've done a great job of this particular point, Mike. One of the really significant advantages or learning points that we're going to be able to get from this registry is understanding that active surveillance or deferred systemic therapy group. It's already one of the largest collections of patients to date, even larger than the prospective trial that Brian Rini was able to do a few years ago. So there's a lot of information we're going to be able to learn about that specific patient population.

Tian Zhang: And those patients don't necessarily go on trial by definition. They're not exactly going on systemic therapies and clinical trial cohorts. So great. Well, tell us a little bit more—well, first about PCORI and PCORnet. Because I don't think that our audience all know about PCORnet. So maybe just a quick update about what PCORI-PCORnet centers are.

Michael Harrison: Yeah. So PCORI, of course, is the Patient-Centered Outcomes Research Institute. And then PCORnet is an initiative of that group. So the idea of PCORnet is it's a network of networks. So they're hospitals and health care centers in different networks across the country. And what we're taking advantage of is that they have a common data model.

So all of their electronic medical record systems, you can get certain kinds of data from them. And so the innovation of ODYSSEY, if you will, is that we realize that all of these sites are used to doing trials. And trials are very expensive, but we don't need to have that kind of trial-grade follow-up necessarily to get what we want. So basically, the innovation of ODYSSEY is we're enrolling at the sites, and there are certain baseline data entered.

But then the follow-up is handed over to the DCRI, the Duke Clinical Research Institute, patient-reported outcomes group, who will call the patients and administer the PROs via phone every three months for the first two years, and then every six months thereafter. And then furthermore, we can get their data from PCORnet. So that's where that network of networks that has a common data model comes in. We can do these data pulls every so often.

Tian Zhang: Great. So it's really far-stretching also to those multicenter approaches, right? So I think it's great. So let's get into your analyses. So, Mike, you want to go first with your active surveillance, deferred systemic therapy population? What are we seeing at ASCO this year?

Michael Harrison: Sure. So like you said, we're looking at basically a kind of a preliminary analysis. This is the first 392 patients overall accrued. And basically, that breaks down into 299 patients who got immediate systemic therapy, 93 patients who did not. Of those patients who did not get immediate systemic therapy, physicians that enroll patients will fill out a questionnaire.

So if they got systemic therapy, they fill out one questionnaire. If they did not get systemic therapy, they fill out a different questionnaire, and it essentially says, why are you doing what you're doing? And so that questionnaire allowed us to narrow this down into the active surveillance cohort. And there's really two active surveillance subgroups.

One is active surveillance disease-stable, so implying that they have metastatic cancer present, but it's stable, and the physician is going to watch them, or active surveillance NED. The former is by far the largest group, so we're focusing in this analysis on those 53 patients. And because we don't have very long follow-up—so the follow-up is only about nine months at the moment—we're focusing on baseline factors.

And so what we did is we compared those active surveillance patients to patients that got systemic therapy in terms of all the baseline demographic factors. And then we also looked at their PROs. So really briefly, in terms of the demographic factors, active surveillance patients were about the same age. They had a lot of similar features. What was a little bit different, though, is that while there were more favorable-risk patients who got active surveillance, it was not 100% favorable-risk. A lot of people assumed that. There were still plenty of intermediate-risk patients.

Some other things that were just kind of, interestingly, different that you might suspect—so active surveillance had fewer poor-risk visceral sites—so like lung, brain, bone—and had more endocrine organ sites. So they were more likely to have pancreatic mets, for example. The other two kind of interesting findings—one of which you might expect, one of which you might not—is that compared to the systemic therapy patients in ODYSSEY, active surveillance patients had better quality of life, whether you looked at FKSI-19, the disease-related symptoms subscale, or FACT-G. So that's expected.

But what we thought was interesting was if you took those active surveillance patients—these 53 patients—and you compare them versus the pivotal trials, in terms of FKSI disease-related symptoms subscale, which is the one that was done all across the board, their PROs were actually pretty similar. So we thought that was an interesting finding because that really suggests—possibly, there were patients treated on those trials that might have undergone active surveillance. That's a kind of hypothesis-generating statement, provocative statement, obviously, but we thought that was really interesting. We'd like to look into that further.

Tian Zhang: That's really interesting. Yeah. And just tell us a bit about—so there were actually a few of the intermediate-risk population that were treated. Do you know if some of them were the ones that you mentioned earlier who received metastasectomy or radiation, pancreas mets? Could they have gotten some SBRT, for example?

Michael Harrison: Yeah. So we haven't really looked at the patients who are planned to get the metastasectomy or the kind of undergoing future therapy—that's about 25-ish patients—but that's in the future plans.

Tian Zhang: Sounds great. We'll turn our attention to the people who got systemic treatment, Ben. So tell us a bit more about that population and what you found with their quality of life.

Benjamin Maughan: Yeah. So just to briefly highlight a couple of points, the analysis was very similar because all of these patients are collected in the same process and way. So about 300 patients received immediate, if you will, systemic therapy, as opposed to what Mike was talking about with delayed systemic therapy or active surveillance, whichever terminology you prefer.

And again, this was not prospectively randomized or whatever in any way. All we did is allow—the treating physician and the patients decided themselves what the treatment was going to be, and we just simply collected that information and observed how they are doing with it—how effective is it, what's their quality of life on treatment, as well as the baseline. These two analyses that we're presenting here is all about baseline information.

And that's also true for the patients that went on to systemic therapy. So in terms of baseline characteristics, when we compare—one of the things we were interested in is why are these therapies selected and chosen in the first place? Because there's a number of combinations you can pick from. We did categorize them, though, in terms of pure IO—so ipi-nivo—versus TKI and IO. We didn't get into the baseline analysis too much, but there are some patients that receive TKI monotherapy. But if you compare the two combinations together, as you might predict, there are some differences in the baseline characteristics.

So patients treated with TKI-based combinations had a higher incidence of visceral disease, a higher incidence of bone metastases, a slightly higher preponderance of factors that add into the IMDC risk categorization system. If you look at the reasons—one of the interesting things we also did was ask the physicians why they chose what they did. And if you look at the reasons that were selected for ipi-nivo, for instance, it was somewhat different from the reasons selected for the TKI-based combinations. Patients that were chosen to go on to TKI-based combinations more frequently had reasons like they were symptomatic.

There was a concern about short-term prognosis, effectively. We use slightly different words, but fundamentally, that's what the questions got to. So that was fairly expected because that's one of, I guess, if you will, performance characteristics of that combination—high response rate, quick onset of action. And so we predicted that that would be the case, but it was interesting to see it objectively and how much more frequent that was the driving reason for the patients to choose that type of therapy.

In terms of the quality of life scores, very interestingly, similar to what was done with the delayed systemic therapy approach, we compared what the quality of life scores were when we compared to the prospective studies—like, for instance, what the FKSI-19 was for the ODYSSEY population versus the FKSI-19 scores for patients on the CheckMate 214 study. Largely, many of them were fairly similar, but we did see consistently that there were worse quality of life scores for the ODYSSEY patients than the registrational trial, which was also fairly expected because not all patients meet those strict criteria required by the studies.

Some things that we commonly saw were things like fatigue scores were typically worse, more significant, or severe. Pain scores sometimes were also more significant or severe for the ODYSSEY population, as opposed to the trials.

Tian Zhang: So more symptomatic disease burden correlating with—do you think a poorer disease presentation than those who would otherwise go on those registrational trials?

Benjamin Maughan: Yeah, great question. I can't tell you for sure that that's the case, but I suspect it is. We still need to delve into that a little bit further. I also suspect that it's a higher comorbidity index as well for those patients. There's a lot of restrictions about cardiovascular health. Patients can have cardiovascular comorbidities, but they have to be typically mild and manageable—

Tian Zhang: To go on trial.

Benjamin Maughan: To go on trial. Right. So I think it's really a multiplicity of factors that leads to that.

Tian Zhang: Yeah. So it sounds like ODYSSEY is really putting together a real great, real-world database for us to follow patients with a lot of patient-reported outcomes, and we're learning a lot. What's next for ODYSSEY?

Benjamin Maughan: So there are a couple—in my opinion, if I can just jump in.

Michael Harrison: Yeah.

Benjamin Maughan: There are a couple of big next steps that I think will be exciting to follow through on. One is, to Mike's point, we're collecting these patient-reported outcomes repeatedly over time. So seeing what that does over time with the therapies is going to be helpful, right? Qualitatively, does that change with one type of therapy versus another? For the active surveillance patients, how long can they maintain that high quality of life? And then, certainly, following the efficacy will be another interesting thing. In a real-world disease population, how effective—

Tian Zhang: As patients cross between first line to second line to third line, how are they doing?

Benjamin Maughan: Yeah, exactly.

Tian Zhang: And those sequences, we really can't test on trial, for example.

Benjamin Maughan: Correct.

Michael Harrison: That's right.

Benjamin Maughan: There's the blood-based tissue collection as well.

Michael Harrison: Yeah, I think that could be an interesting aspect. I think the main thing is we just need more follow-up—our follow-up time at this point is about nine months. And so we just need more follow-up. We need the data to mature to see how those PROs accrue over time, and then we'll have more power to look at longer-term outcomes like survival and time-to-treatment discontinuation.

Tian Zhang: Great. I think that's a great summary of ODYSSEY. Both of your analyses sound super important for our patient populations, and how we're thinking about getting patients either deferring or going on systemic therapy and monitoring them. Any other things to add that we haven't talked about?

Benjamin Maughan: I think that covers the key parts of what we're doing now. There's just so much more that we're going to keep being able to mine out of this rich data set. I'm really excited for our future analyses.

Michael Harrison: Yeah, we have a number of publications underway right now, so I think that'll be the first step—looking at some early outcomes data.

Tian Zhang: Fantastic. Yeah. I'm sure ODYSSEY will teach us a lot over the years to come. Thank you both for coming.

Michael Harrison: Thank you for having us.