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Dan George: Thanks Jane. Thank you all for coming this morning, and jump right in with Ironman. This is an international registry to improve the outcomes of men with advanced prostate cancer and it's a pleasure for me to present this on behalf of our executive committee led by Philip Kantoff, myself and Lorelei Mucci, with Jake Vinson, our CEO and the Prostate Cancer Clinical Trial Consortium that is really leading and operating this trial. And of course Movember and Paul Villanti who played a critical role in helping us get started.

Why are we doing a registry in advanced prostate cancer? This really started about five years ago and it was with a vision to recognize that we all have our individual perspectives on this patient population that we treat. But perspective is really critical to have broad and the only way to really gain that is by collecting data together.

I really think of Ironman as a cohort study, a cohort population rather than a clinical trial. And it's really the opportunity to follow patients longitudinally over time and to do it prospectively, hopefully, being able to identify some unmet needs in the field and some opportunities for intervention in a practice setting, not necessarily a clinical trial setting. And to create a resource ultimately for the prostate cancer community to both explore and confirm new findings.

We focus on advanced prostate cancer and it's really two populations. It's men who present with de novo metastatic, castrate sensitive prostate cancer at diagnosis. And we all know who those are that come in sometimes with high burden, sometimes with low burden metastatic disease. We also have a population of men who have failed local therapy and now have disease progression with metastatic disease. And then we have a population of patients that have progressed to castration resistant but haven't started new therapy in that setting.

So it's a second window for us to capture some men who maybe missed those first two windows. It's a heavy lift. Ironman is a big study, a big cohort and we meant it that way in order to really gain the broadest perspective, we need a great number of patients in a broad number of countries. And so we have, I think, now on the last count, 16 countries represented here, over 5,000 patients planned with room for more. This isn't necessarily closed, it does get more complicated the larger we grow, but we recognize there are still large areas of the world we're not capturing and we do plan to expand further in Asia and other countries as well, other areas as well.

This is the overall study design. I'm not going to go over it in detail, but just suffice to say a couple of things I think are unique about doing a prospective cohort study versus a retrospective cohort study. One is the ability to identify these patients up front and to collect a lot of this information now longitudinally going forward in a systematic way. So that we're really careful in our database to collect the things we need and not necessarily the things we don't need, to collect blood samples. And you heard about biomarkers, we think that that is a really important aspect going forward. It's really hard to do that on a multicenter level, much less an international level, but we've been able to do that. I'll highlight some of our biomarkers that we collect at baseline at study entry, and then with each subsequent change in therapy.

PROMs are, again, a really important aspect of real world understanding of the patient symptoms and experience and I'll highlight a little bit of that data as well. And then you'll see down here, physician questionnaires. You might ask, "Well, why do we want to do that, don't we know what these people are getting for treatment?" And we do, but we don't know why, and the why is really the critical piece that's so hard to figure out. So our questionnaires are not perfect for those who've filled them out. We appreciate your patience. We're still trying to perfect these, but I think they're going to give us new insights into the why, in terms of treatment and especially over time.

Biospecimens. So we are collecting samples and it is expensive and hard to do on an international level, but we've been able to do that and we're collecting a number of different samples. Plasma and buffy, Whole Blood, cell-free DNA and PAX gene RNA. And the reason is simply we don't know where the right medium is going to be for assessing new markers and we want to be broad for the future and what might evolve. We've also collected permission for tissue. We haven't actually collected the tissue yet, but we have consent for that and that's an important aspect to have prospectively and retrospectively is something we can collect. And as you can see here, we have a number of samples we've collected along the way.

If you total those up, we have almost 38,000 specimens. Those are individual whole blood or plasma cell-free DNA. Individual time points is about 10,000 and this study is still accruing and growing. And so I do think we'll have many, many samples in which to learn from. But already there're opportunities to start studying these samples today. And I think my hope is you'll start seeing real output from Ironman in the very next year.

Patient reported outcomes and PROM tools, we're looking at both the outcome and the experience of patients and there's a number of tools. I won't go through all of these, but it's important to recognize that the therapies we give patients have lasting impact over time, not simply during the first few months of a study period but over a lifetime. And what's really great about Ironman is that we're following these prom experiences over multiple lines of therapy. So there's going to be an opportunity to see the impact of that sequence or concomitant approaches in a broader range of patients.

This is our structure. We need governance and we have that and we built that in at multiple levels. There's no one boss in charge of everything. We have an executive committee as I showed you, and then we have a scientific oversight committee that includes all of our country PIs and representatives from our sponsors, that I think also represent a unique interaction between industry and academics. All the voting members are investigators on this study. And so it is an investigator-led effort. We have a coordinating center that's done a fantastic job helping us grow and organize and operationalize this effort. And then a number of working groups and we continue to add working groups.

And I think as this study matures, there'll be more opportunities to see grants and new efforts and even sub studies come out of these working groups. So I'll put one question as just an example of the kinds of things we can use Ironman for. So there's a lot of data coming out now and this is just one abstract, there's a number that have shown that the management, the actual use of what we might call treatment intensification, docetaxel or novel hormonal therapies in the setting of metastatic hormone-sensitive prostate cancer patients, is maybe not what it should be.

And this is just data from a single payer system in the US, our VA, Veterans Administration system that offers free care to our veterans. And you can see here in red that we have only about 20% of patients as of up to 2019, that are actually getting treatment intensification for metastatic hormone-sensitive prostate cancer. Gladly, it is increasing over time but it's still not nearly where maybe it should be. And yet we are seeing survival advantages historically in this population over time. And some of that may be from the use of these therapies in the castrate resistant space. But the fact that these numbers are changing now more suggests that that earlier use could impact it even further.

So how do we get there? So I think looking at Ironman might give us some new clues into who's getting treated, who isn't and maybe how can we improve this. So this is our population in Ironman. We have about almost 2,500 patients accrued so far. We'll be presenting our... writing up our first paper of the first 1500 patients. These are the demographics, I won't go through them all, but we have about 8% Black or African American patients accrued. We have about 66, 70% that are white Caucasian and then a number that are not reported.

And I think you'll see that in real world evidence that a number of patients don't necessarily identify with a box, they may be mixed race or they don't necessarily identify with how we view race. And I think that's interesting in and of itself. Ethnicity as well, a similar pattern. You can see we have about a 60/40 mix between the US and non US and I think that's really important for this worldwide perspective.

De novo metastatic disease, about 70% of our metastatic hormone-sensitive patients are presenting with metastatic disease. Interestingly, PSAs are not necessarily that high and performance status ranges. Many of these patients, about 40%, are symptomatic and have decreased performance status at diagnosis. The metastatic sites are interesting because we think of this disease as predominantly bone dominated. But for this population of metastatic hormone-sensitive disease, there's a substantial number of patients with lymph node disease. And I think you're going to see this number increase with some of our novel imaging and we may continue to see shifts in this population in the diagnosing of what we might term low volume or earlier or lower risk metastatic hormone-sensitive disease. And it may very well impact on our treatment approaches, but roughly half the patients have bone metastasis and then a smaller number with visceral or other soft tissue sites.

This is the treatment intensification in the US and I lumped here just in the interest of time, the novel hormonal therapies and... Well, I separated them, the novel hormonal therapies from the docetaxel use because it does vary and it varies by region in the US, and Europe have different patterns. In Canada, Australia and Brazil have very different patterns as well. And I think this is really helpful. There's a lot of factors to unpack as to what could be driving that.

But suffice it to say we are seeing a fair amount of intensification in the US and Europe. More than half of the patients in this study are getting concomitant treatment, but almost 40 to 50% are not. And our surveys may give us unique insights as to why many of your colleagues are treating patients with mono therapy today.

And I suspect that will change as we see concomitant therapy show even greater benefits even in the early disease settings, potentially even the curative disease settings, or these low volume disease settings. So I think much to come in this field and I think having this baseline perspective here in 2022 will really help us go forward.

I think PROMs are going to be another important aspect to this study, a unique aspect of this study. And there's a number of questions we can ask that we just haven't been able to ask in many of our other disease settings. Some of the things I think that we've found very interesting already in our prom data is that our patients who are non-white do not necessarily have the same reported symptom profile as our patients that are coming in from our white Caucasian perspective. And we're seeing a worse quality of life in our population there.

And there again, many factors to unpack there, race is a cultural phenomenon, less so genetic. So it'll be important to recognize some of those factors in there. But it's not simply quality of life, it's also pain and pain associated with disease is again disproportionately affecting some of our minority populations. And recognizing that and how that biology may differ and why that is important is really critical. It's mostly bone pain and interestingly it's not related. So again, a lot of insights are gained from these phenomena that may help us understand how we might begin to think about and treat patients differently, or at least raise our attention to what some of those differences might be.

And we're used to seeing these quality of life tools just flatten out. Patients go on study, the quality of life goes down and then it flattens out and it looks the same over and over time. And that's because of attrition. Patients drop out who have progression and you're left with the patients with stable disease but there's no dropout and not a lot of dropout in Ironman. And one of the things we're seeing is a difference. We're seeing actually things like fatigue worsen over time, over six to 12 months, in this blue line here is our castration sensitive population.

So recognizing there are cumulative effects in these patient populations over time is really important. And not just weeding out the patients that are progressing and focusing on the stable disease patients, because I think it gives us an altered perspective of the overall population. So I think in summary, this is a large contemporary, to me it's a prospective cohort study, it's an opportunity for us to follow patients longitudinally. I think it's uniquely designed and supported by investigators.

Industries played a key role. We have seven industry partners and I could not have launched this scope and scale without them. Advocacy groups play an absolutely integral role and you've heard about Movember, but there are others as well. On a smaller scale on a country scale, we invite you as country PIs to embrace your local advocacy groups and include them in your population. I think this can inform our practice patterns, gaps in care and unmet need.

I think the potential to explore and confirm biomarkers is really huge and we really hope as we continue to amass this collection of specimens with outcomes, there's a lot we can learn from it. And I think embedding future prospective sub studies, I didn't get a chance to talk about that but we have two already and there'll be more to come. I'll just like to acknowledge again our executive committee, our sponsors, many of whom are represented here at the APCCC, Movember of course, who, again, was integral from the start of the study. Our staff, of course our country lead investigators and for your continued support of accrual and data that really make Ironman possible. Thank you all.

Jane Fisher: Thank you Dan. That was a great update on Ironman. It's really impressive in this coming out of the post-Covid era, I suppose, to see studies like this continue to recruit and do so well. So what are you seeing as major challenges in that space at the moment?

Dan George: Yeah, let me just say I think Covid was a huge challenge for us because people view this from a regulatory perspective, from an IRB perspective as a clinical trial. But it's considered a low priority clinical trial because its non interventional, and so we were really put on hold at a number of sites around the country, really around the globe. And maybe rightfully so because of the scarcity of resources, of staff and whatnot. But coming through Covid now and recognizing that this is something that we're going to continue to live with for a long period of time. We've seen the accrual rebound at some sites but not all.

So I think it's really critical for us to understand the importance of this data and how one clinical trial will come and go. But Ironman is something much larger that I think could feed our field for a decade or more. It's really important that we as custodians of this time, of patient care, buy into this and continue to accrue.

Bertrand Tombal: One potential solution is... You know there are plenty of randomized control trials amongst academic group and hopefully 20 to 35% of patient, they don't go in these trials. So more and more, I mean large group are building TWICs, meaning trial within cohort. And one of the problem we get with these patients losing is that many times we don't have any registry to put in the patient that don't go in the randomized trial. They may not be the perfect patient because they will be unselected. But there are also a lot of questions about, how treatment works outside the criteria of randomized controlled trials. So that would be, especially if you take Europe, that would be a huge opportunity to say "Listen, if your patient can go in a large RCT, we could offer the possibility still to collect the data," because when you see the schedule and the material you collect, it's very similar to what sent to do in clinical trials.

Dan George: It's a great point, Bertrand, thank you for bringing it up. There are two aspects to that. One is to say, "Look we can share data, we can confirm independently data and other data sets." And I think that's a really good opportunity. And then we have Spain as an example where we've been able to marry two registry efforts, Ironman and a local effort together. And so there're opportunities for patients not to have to do multiple reporting and outcomes tools, but to be able to share that data prospectively. So I think we're very fluid in this study recognizing that again it's not restrictive like a clinical trial and we can adapt and expand through efforts like that. So happy to follow up offline on that.

Jane Fisher: And just to quickly add to that, I think that's a really good point. And having worked in clinical research for a number of years, I think a study like Ironman is a great first study for centers that aren't typically involved in clinical trials that want to dip their toe in the water and get some experience. So maybe looking at less academic centers that are interested in this space would be a venue as well.

Dan George: It is, it's a platform as the way we look at this. And I think especially for some of these countries, developing countries and whatnot, it's an entry into this network that we all value here in this community, but is closed off unwittingly to us, to a lot of other centers and stuff. So it is a real opportunity to network with this investigational community.

Jane Fisher: Great.

Aurelius Omlin: And Dan, are you still open for additional contributors, collaborators who want to join Ironman? Because we have a lot of people online and people in the room.

Dan George: Yeah. So it is a bit complicated because there is a limit to our infrastructure to implement. So we're happy to hear from you. We will be happy to work with you and I think with persistence, we can. But it does require support and it does require some infrastructure. But being a champion of this cause and being interested in being part of this community is a critical first step. So we welcome that hearing from you if that first step is there.

Jane Fisher: And I think maybe last question to Caroline.

Caroline Clark: Thank you. Hello Caroline Clark, UCL. That was really interesting. I'm sorry I was a few minutes late so I hope I didn't miss any critical bits that I'm about to ask about now at the beginning. So with your data collection on race and ethnicity, is there any scope for free text box for the 20% who are missing? Because you're right, it would be really interesting to know why are they missing? Is it because they're white and they think, "Oh nevermind, whatever." Or is it because they don't want to report for some reason? So if there was a free text box?

Dan George: It is a good question. There is a free text... I don't know how much it's used and I think one of our challenges is privacy and this is something that we respect the boundaries of. So there may be some questions we can't answer right now, but again, maybe an opportunity to go back to people if they're open to that 20%, with a new questionnaire. So it's something we can explore.

Caroline Clark: I've got more. So the question about pain levels being different in different ethnicities. I've read an interesting paper about this a couple of months ago where it talked about the amount of pain relief given to mothers during childbirth, which obviously is a different population in the UK. And apparently black mothers were offered less pain relief because there's this perception that somehow they feel less pain and that's quite a dangerous road to go down.

So there was some research into what are the perceptions of what you should offer the patient? Which people are always susceptible to these cultural, and historical problems. So I don't know if that's something that you might be able to factor in somehow. And, obviously, I can't not mention that you can map the EORTC to the EQ5D, should you so wish? Thank you.

Jane Fisher: Great way to finish. Thank you. And I just wanted to say thank you again to everyone and to Dan in particular for making an effort to get here by train, plane and automobile yesterday. Thanks everyone.

Silke Gillessen: Excellent platform, man. Thank you very much. So everyone who's already part please recruit, if I understood correctly-

Dan George: Yes.

Silke Gillessen: ... as fast as possible so we can do all this fantastic project and everyone who's not a part of it and wants to recruit, has to write to Dan and to Jane.