Alicia Morgans: Hi, I'm so excited to be here with Dr. Lorelei Mucci, who's a Professor of Epidemiology at the Harvard T. H. Chan School of Public Health, and Dr. Dan George, who is a Professor of Medicine and Surgery at Duke University. And we're talking today about the IRONMAN study, and the data that was presented at GU ASCO 2023. Thank you both for being here.

Lorelei Mucci: Thank you, Alicia. Delighted to be here.

Daniel George: Happy to be here.

Alicia Morgans: Wonderful. Well, Lorelei, can you set this study up for us, and tell us about this ongoing study and this initial data cut?

Lorelei Mucci: Yeah. The IRONMAN registry stands for the International Registry for Men with Advanced Prostate Cancer. It's a study that we started in 2017 with the goal of really addressing a lot of the unmet needs for patients with advanced disease, so either hormone-sensitive prostate cancer, or castration-resistant prostate cancer. The goal is to enroll 5,000 patients at least. And so far, we've actually enrolled 3,200 individuals, from 14 different countries around the globe.

Alicia Morgans: Wow. That's extremely impressive, especially since this is not just US, Canada, and European countries. Can you just clarify, this is countries really truly around the globe, trying to get a diverse set of patients representing as many countries as we possibly can, right?

Lorelei Mucci: No, that's exactly right. And we picked not only sites globally, but also within the United States, to try to get as diverse a patient population as possible. So diverse in terms of geography, socioeconomic status, the type of center they were attending, as well as racial ethnic diversity as well. So we're enrolling currently in the US, Canada, Brazil, a number of countries in Europe. We have partnerships that are allowing us to enroll in the Caribbean and in Africa as well as in Australia.

Alicia Morgans: Wonderful. Well, Dan, I know this was really one of the first presentations of the data, and I know that you're aiming for 5,000 patients at the end. Maybe you're aiming for more. This is a little bit less than that, because you are still continuing to enroll, but what did you learn? What did you present at GU ASCO 2023?

Daniel George: Yeah, Alicia, I think it's really important for us to recognize that as a registry, we can take data cuts and looks at this data all the way through. It's not like a clinical trial where we have alpha to spend and things like that. So this was really one of our first looks at our first 1,700 patients or so that have been enrolled in this study. And that was largely the US, Canada, and Europe, just because those were the centers that came on first. So we're excited about the diversity that we've added, but we're limited a little bit in this setting. That said, in the US we've accrued almost, I think it was 18% black patients and a number of other minorities, Hispanics and others. So I think we are representing a broader display of patients in the population. It's still not perfect. We're still not where we want to be, but it's moving in the right direction.

And we've also accrued this study over, I think, a really dynamic period of time. So 2017 marked the start of our intensification, if you will, with androgen receptor pathway inhibitors, namely abiraterone. And already at that time, we were using docetaxel in this metastatic hormone-sensitive space. And so just being able to see how these agents are really being implemented into practice, so non-clinical trial patients was really critical. And seeing that sort of in a global sense is really kind of the first time we've been able to do that.

So what our data showed interestingly, was in the US, we have about half of our patients, about 52%, that are getting treated with a AR pathway inhibitor. Another 15% or so that are getting docetaxel chemotherapy. And still, 25% of patients that were treated with just androgen deprivation therapy alone in this metastatic hormone-sensitive setting. We saw on the castrate-resistant setting a lot less ADT alone, but still some, as well as use of these agents.

And we saw variations from country to country. In England and Australia, we saw a lot more chemotherapy and less AR pathway inhibitors. In other parts of Europe, a lot more pathway inhibitors. So it's still everywhere. There's a sizable proportion of patients getting treated with ADT alone. And understanding now the nuances of why physicians are making these choices, and what are the factors driving this difference are, I think, is really going to be one of the things we can dive into with future analyses.

Alicia Morgans: Well, just to follow up on that, Dan, there are questions built into this survey study, this cohort study. Of course, there are questions for the patients, because we need to understand how they're feeling, what they're experiencing, there are sociodemographic and there are clinical characteristics, but there are also questions for the clinicians about their decision making and why they're doing what they're doing. Right?

Daniel George: Yeah. This is, I think, one of the more unique aspects of this registry, is that we built in prospectively these questionnaires for the physicians. Now, we don't have the demographics on the physicians, they're not part of the research. But what is part of this is really their treatment decisions, and what were the factors that pushed them to choose what they chose for therapy? And we're just beginning to look at that data now in this context. I think it'd be really important to understand it in the context of the patient reported outcomes, how the patients were feeling, the socioeconomic factors that you mentioned, and other kind of characteristics of the patient, as well as the disease that influence these decisions. It's complicated.

Alicia Morgans: Yeah, absolutely. And I think we need an epidemiologist, like Dr. Mucci, to help us kind of think through this complicated data. Dr. Mucci, from your perspective, what are some of the interesting things that you found in this initial data cut? And where are you looking forward to going in the future, as more data rolls in, and you have the opportunity to dig into really just the vast amount of data that you're collecting?

Lorelei Mucci: Yeah. Well, one of the thing I think that when we were initially planning this study was, we assumed that we'd have a much higher percentage of patients who are CRPC, compared to hormone-sensitive prostate cancer. That is not the case, where actually currently to date, 61% of our patients have newly diagnosed hormone-sensitive prostate cancer, 39% are CRPC, and that's actually pretty consistent across countries. So I think that was something that was surprising to us.

One of the strengths of our registry though, is we're going to be able, we enroll patients within 12 weeks of their diagnosis of advanced prostate cancer. We're going to follow them prospectively. So we're going to be able to follow those patients when they do, or if they do, transition from hormone-sensitive prostate cancer into castration resistant. So I think that was something that was surprising.

The other interesting thing that's happened is, since the COVID-19 pandemic, which definitely impacted our enrollment, the types of centers, particularly in the US, but really globally, that are enrolling patients now are much more the community-based centers. And I think that's going to be a great opportunity for us to understand, what does the patient experience look like? What are the treatments looking like? In the more community setting, how does that compare to more of the traditional cancer centers? And then, as I mentioned, we have a large number of individuals who reported serving military service, some of whom are in the US are being seen at VA centers, and some of whom are being seen in more traditional settings. And so those kind of comparisons, I think, are going to be really interesting.

Alicia Morgans: That that will be fascinating. And I know, in addition to the stuff that we've just talked about and the survey, data points that you've mentioned, there are a number of sub-studies and a number of additional initiatives within the IRONMAN cohort. Dr. George, can you speak to any of those?

Daniel George: Yeah. We view IRONMAN as kind of a platform. Platform to then layer on top of some additional questions. One of those questions really kind of came out of work that was presented earlier in a chemotherapy setting, and that is, what's the impact of these serial patient reported outcomes on the physician care of the patient, and even the outcome of the patients? And does this information really change care and change outcome?

And then, at least the settings of chemotherapy, repeated patient reported outcome tools have been shown to actually improve outcomes, including overall survival. So we wanted to look now in this more chronic setting, these patients getting therapies, many of them oral therapies, or hormonal therapies over time. And so, we've embedded into IRONMAN a prospective Phase II study of centers that would receive additional, more frequent patient reported outcomes, and have that information fed back to the treating physicians, so that they can act on it. Particularly, when there's a change in those patient reported outcomes, when there's a deterioration and a functional status in some way. And that may allow better care of those symptoms. It may change the tolerance of that treatment, and even the outcome in these patients.

And we'll have within IRONMAN, sort of our contemporary control populations, where we're collecting the same kinds of patient reported outcomes, maybe in a little bit less frequency, but to be able to compare it without that sort of immediate feedback. And so, it's really a great opportunity to have these kind of control populations built in.

Another one that we're looking at is the PRODIGY study, where we're really looking for these rare genetic alterations that have been associated with homologous recombinant repair defects, but a non-BRCA2, BRCA1 type mutations. These less common ones that were part of, say the PROfound study, but were underrepresented. And to be able to see how a drug like olaparib really impacts in this population now on a broader scale. And it allows us to bring these rare patients into IRONMAN, even if they haven't been part of it to begin with. So it begins, again, sort of a platform in which to pull patients in, and be able to start asking questions that honestly, would be too difficult to find in a broad population of patients.

Alicia Morgans: That is, that's really great. And I think that this is a cohort study that is going to continue to really help illuminate our understanding of these patients, their care patterns, their quality of life, their disease control outcomes, for so many years to come. Dr. Mucci, if you had to sum it up, and give a message to listeners about this first data cut, and where you expect to go in the future, what would that be?

Lorelei Mucci: Well, one thing that I wanted to say is that, when we set this study up, we really wanted it to be a resource for the community. And so, we want people to come in with their ideas of projects to propose. So definitely reach out. If you go to the IRONMAN registry website, there's information you can contact Dan or myself and Alicia. I know you're very engaged in our PROMs working group, including the sub-study on patient reported outcome measures. So I think that's one thing that really, really want to echo.

And then the other part is, I think there's so much in this population of individuals who are on average, older but potentially now are living many years with a diagnosis of advanced prostate cancer, we really need to be thinking about, what are the things that in their lifestyle could help them flourish despite having advanced disease? So I think that's another area that we're really excited about.

Alicia Morgans: Well, certainly the community is excited about all of that too. And we will have information for the IRONMAN website next to this recording, to allow people to really easily communicate. And Dr. George, if you had to sum this up, in terms of the first data cut, and the message to listeners about where you want to go in the future, what would that be?

Daniel George: Yeah, there's a lot of heterogeneity in how patients are being treated. And I think we need to understand the implications of that in these real world settings, both in terms of those initial outcomes in long term. And ultimately, what we need to be able to find is, are there patterns of care that are superior than others? And make sure that we optimize the outcomes for these real world patients as much as possible. And I think tools like IRONMAN, maybe not alone, but in collaboration with other efforts that can really make a difference in our ability to improve the outcomes of our real world patients.

Alicia Morgans: Absolutely. And not just improving the outcomes at Duke, or at Harvard in Boston, but really trying to address this global problem of prostate cancer, and ensure that every voice is heard. So thank you so much for your time today.

Daniel George: Thank you.

Lorelei Mucci: Thank you so much.