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Alicia Morgans: Hi, thank you so much for joining us today. My name is Alicia Morgans. I'm a medical oncologist at Northwestern University and I have here with me today, Dr. Dan George, who is a Professor of Medicine and Surgery and a co-director of the Duke Prostate and Urologic Cancer Center. Thank you so much for joining us today, Dan.

Dan George: My pleasure, Alicia.

Alicia Morgans: Wonderful, so I think we really wanted to get together to talk about some of the initiatives that you've been working on, particularly in the context of Prostate Cancer Awareness Month and can you tell us a little bit about what you've been doing in terms of the IRONMAN Initiative?

Dan George: Yeah, sure. Alicia, you know, prostate cancer is a very common disease. We deal with this with ... every man in America is at some risk of this disease and some more than others. Prostate cancer can be a slow and long course, but it can also be a course that presents, at more advanced stages, or a progression to its more advanced stages, of what we term castration-resistant prostate cancer pretty quickly. And recognizing patients who have advanced prostate cancer, either metastatic disease at diagnosis or this castration-resistant prostate cancer stage are patients that have a lethal phenotype, meaning they are cancers that are likely to kill them if they live long enough.

And it's exactly that population of patients that we need to be aware about. That's why we do prostate cancer screening and education. That's why we do a lot of treatment for localized diseases to prevent patients from getting ever to that point, if possible. But, for the many men in America and, really, worldwide that do develop this advanced stage prostate cancer, there is surprisingly little information regarding the course of symptoms that progress to this disease. There's surprisingly little information regarding the extent that their germline or hereditary genetics plays a role in their outcome and there's very little insights, as well, into the racial determinants associated with prostate cancer and what factor that has in the outcome of patients. Not simply in terms of survival, but even response to therapy.

So, recognizing these gaps in our knowledge, we started this registry. We called it IRONMAN (NCT03151629), because it's an International Registry of Men with Advanced Prostate Cancer. It didn't quite fit the acronym, but it was close enough. This is something that's supported, it's an investigative-led effort by myself and Phil Kantoff at Memorial Sloan-Kettering and Lorelei Mucci, a cancer epidemiologist at the Harvard School of Public Health to really look broadly at this advanced stage of disease, both with the metastatic and the castrate-resistant populations and to understand the patient outcomes, their experiences through this process, to understand the various treatment patterns of how these patients are being managed, to collect blood samples so that we can understand both the tumor and the germline factors and racial determinants that influence the outcomes associated with these patients.

And really begin to be more precise in our definitions of these populations or sub-populations and hopefully begin to develop some therapies for the unmet needs that are out there. It's a study that is half based in the U.S. and Canada and then half based in the rest of the world and we're adding countries. Every few months we've been adding countries. We're up to 10 countries now, globally, that will be participating in this and a huge diversity of countries from South Africa to Sweden to Brazil. All three countries that have very high rates of prostate cancer mortality associated with them to countries like Australia and New Zealand and Canada and other European countries, Spain and the U.K. and whatnot. So, a broad reach of countries to really help us understand the diversity of genetics associated with advanced prostate cancer.

Alicia Morgans: What I think is so fascinating about this, besides its sheer scope, which is incredible and should be commended, is the fact that you're acquiring information in multiple ways, both on what treatments patients have been undergoing, but also you're looking at DNA information, circulating tumor DNA, but you're also then getting patient-reported outcomes, so can you tell me a little bit about how you see all of these things coming together to give you a picture of what the prostate cancer experience is like in these places?

Dan George: Yeah, Alicia, I think there's so many things we can do with this information, but as you just articulated, it's the combination of them together that makes it so powerful. So, to be able to use biomarkers and say the clinical context of the patient's presentation to put together phenotypes of prostate cancer, but then to be able to actually track how those phenotypes respond to different sequences of therapies, and what's happening to the patient, from their perspective through all of that. That combination requires a tremendous volume of participants. You can't do that in 100 people.

But, more importantly, now we're up to 6,000 patients for this registry, if we've got subgroups that represent maybe only 5 or 10% of the population, well, that's still 500, 600 patients that could be in this registry that fit that subgroup, that's tremendous insight and to be able to collect it, not just from a biologic or clinical perspective, but from an outcomes perspective, particularly a patient-reported outcomes perspective, that now we're doing things that have never been done before and there's very little opportunity to do that outside of this kind of mechanism. So it becomes a really unique and powerful resource and our hope is, is that these different sequence patterns or emergence of new therapies really make a difference.

I'll give you an example. It may be that we want to understand BRCA2, but we don't want to understand BRCA2 just in terms of the germline. We want to understand it in terms of the patients that develop somatic BRCA2 mutations independent of their germline. Well, we might be able to pick that up through some of our circulating tumor DNA and begin to look at what are the differences by germline versus somatic alterations and put that in the context of how they were treated. And by having all these different countries ... you know, we're going to see different access to therapies. There's going to be some treatments that are just not available in some of these countries and sadly we may be looking at some of the natural history of this disease where those treatments weren't available, but in other circumstances, we'll be able to show where those treatments came online and how much of an impact they changed the course, compared to these other populations.

Our hope is, is that this allows us to get those therapies into those countries that don't have them, quicker for those populations. We're not simply doing this registry to publish some papers and describe some populations. We want to change practice. We want to do practice informing research. We want to do research that can ultimately more quickly expand the use of these drugs in countries that otherwise aren't making them available.

Alicia Morgans: That's fantastic and also then at the same time, to be collecting feedback from the patients directly, I think, is fantastic. So, as you're looking at the efficacy changes that we can't access here because there are so many ways to get drugs through clinical trials or off-label or whatever way, you know, you're going into these places, you're getting efficacy data in fresh areas where these patients have not had access before and then you're also getting their direct report, so you can hear in many situations, I think, firsthand and new information for patients who are not on a routine, randomized, phase three clinical trial, you know, how does this really affect your day-to-day and that's a fantastic aspect of this whole program, too.

Dan George: You know, I think so, too. I think we've undervalued the importance of the patient experience. And I'm not saying this simply from the patient's point of view. I'm saying it as a clinician. I want to know when somebody's really changing in terms of their quality of life, what does that mean in terms of prognosis? That may be more important than three new bone mets on their bone scan. That may be more important than a doubling of their PSA. And if it's in the context of both of those things, that may be much more significant than it's in the absence of those markers. So, being able to kind of really have now, systematic patient-reported outcomes, not just on the course of say six months or a year of a therapy, but over the course of three years of multiple lines of therapy. That's really going to help us understand where that change in that quality of life makes a huge impact and what specific parameters within those patient-reported outcomes matter.

So, I'll give you another example. I mean, we may have patients that we say, well pain is really important. We know that patients who develop prostate cancer pain, have a much worse prognosis and we imagine patients who are having a lot of pain are going to do poorly. But, what about patients that have some fatigue and how do we quantify that fatigue? We don't really know how to do that and, yet, that may be much more common and it might be much more of an earlier effect in their life expectancy in this advanced stage than pain, which might happen in just the last six months or so of life. This may be an earlier indicator of somebody that's going to run into trouble and we need to be thinking about sequencing their therapies much more rapidly or even layering their treatments because of this fatigue effect now that's happening, or it may be, Alicia, that these are the patients that can't tolerate that kind of aggressive treatments.

The treatments are what are hurting them as much as the disease and we need to be thinking about unmet needs, newer therapies that don't cause fatigue that can treat those patients and control that cancer. So, these are the things, I think, that could be really insightful based on these patient-reported outcomes that no one's really been able to answer that kind of question because we just don't have any data regarding that on a broad enough level or a longitudinal enough level.

Alicia Morgans: I agree. You know, one of the things that I also am so fascinated with about this particular program ... something that you and your team at Duke brought to light at ASCO this year, really understanding whether there could be differences in efficacy or a response to particular therapies, based on the genetics of the patient and also whether there might be different side effect profiles, again because of differences in metabolism or polymorphisms in the androgen receptor or whatever it might be and I'd love to hear your take on whether some of the work, looking at those differences, might be possible through this IRONMAN initiative.

Dan George: Absolutely. You know, Alicia, you were referring to a small study we had done, a multi-center study done, looking at parallel groups of African-Americans and Caucasians treated with abiraterone and prednisone for metastatic castration-resistant disease, really a simple study just looking prospectively at these groups by race, but at the same centers, accrued by the same physicians, treated in the same healthcare system, so equal access for these patients, free drug for everybody, same treatment approaches and then blood samples collected at baseline and on treatment so that we can really begin to interrogate what are sort of the genetic differences associated with race and do they have any bearing regarding outcome. And what was, I think, really interesting to us was the patterns that we saw were consistently better responses by PSA and by time to PSA failure and even to a lesser degree by radiographic progression through survival.

For African-Americans, this is a subgroup of patients we've always identified with as having a much higher risk of dying from prostate cancer and here we have, in a metastatic castrate-resisted setting, a prospective study showing consistently, by every cut point we used of PSA, a greater response rate and a greater duration of response through the abiraterone than in white patients and so it really opened our eyes up to this hypothesis which, at the time, was just based on some retrospective anecdotal data, but now really looks much more consistent with a biologic effect of the racial determinants associated with these patients.

And this happened in the same time that Susan Halabi and many investigators, including myself, had one a meta-analysis, looking at number of docetaxel trials by race and although African-Americans only represented about 7% of the population in these large phase three docetaxel-based chemotherapy trialss, there was a 20% proof survival, longer survival for African-Americans versus Caucasians and that meta-analysis again sort of turning on its head, this notion that African-Americans have a much more aggressive disease and it really suggests that access to these therapies, use of these therapies and maybe some biologic determinants could be making these patients perhaps more responsive to these types of treatments. And I think it really begs the question of should we be thinking about using those therapies in that patient population sooner, because we know that African-Americans get diagnosed with higher grade and higher stage disease, that the use of hormonal therapy is later and that these patients are at a much higher risk of dying from this disease, so if these therapies work better in castrate-resistant prostate cancer, could they be working better even earlier?

I think before we get there, we need to confirm these findings and IRONMAN is a great opportunity for us to look at this, not simply between African-Americans and Caucasians, but between Africans from South Africa and not just European Americans, but Europeans, themselves, and Brazil and all the diversity that that represents. Ideally, we're going to add an Asian country to give us a full spectrum of some of the different racial groups with prostate cancer and understand how all of these factors influence, as you said, things like hormone metabolism and transport to immunotherapies. There could be a whole range of diversity associated with the host here, that could impact how responsive they are to therapies and, to some extent, side effects as well. We did see differences in side effects associated with race, twice the level of hypokalemia in African-Americans than what we saw in white patients, so it really suggests that there are powerful effects of this host genetics on the outcomes of these therapies.

IRONMAN is going to be diverse. It's going to have a lot of different treatments, but it's big enough. I think we're going to be able to do some really important confirmatory studies.

Alicia Morgans: I agree, you know, and as you were talking really about integrating these earlier therapies, it reminded me and just more data just to sort of substantiate this hypothesis, it reminded me of the VA study. I think it was VA-533 or 553. Dan Lynn presented it at AUA and I think that the manuscript is pending, but you know this subgroup of patients that benefited from adjuvant chemotherapy in that population included, among other patients, African-American men. So this is definitely something that we should continue to delve into. I am glad that you're delving into it with IRONMAN and if there can be differences in drug efficacy, then why in the world would there not be differences, potentially, in side effects, toxicity and even in patient-reported outcomes because these drugs are potentially having slightly different potential effects in these different patients, so really, so much to be learned. And very excited to hear about this data as it comes out.

So, what do patients and clinicians do, who want to become involved with the IRONMAN project? Is there a way for them to do that?

Dan George: Yeah, that's a great question, Alicia and we're talking about how to bring this more public or to the public in terms of awareness and access to IRONMAN. First of all, people should know that we've opened this study up at 38 centers around the country. Many of those centers with sub-sites within them, so we have broad geographic representation across the United States and we're open to adding more centers. We have a website. It's called www.ironmanregistry.org. It's sponsored by Movember, one of our key sponsors, who's a really important foundation in supporting our research in prostate cancer and through that website, people can learn a little bit more about the project. There's also information on the website to contact us if they're interested and through clinicaltrials.org is another mechanism that you can search IRONMAN and we'll come up and you can see sites that are available in areas near you. We're not hard to find in most directories and you can reach out to myself or Phil or Lorelei directly.

We're run by an organization called the Prostate Cancer Clinical Trials Consortium, the PCCTC, and we also have a website there and can be reached through that mechanism and would be more than happy to open up availability of this either to patients and help connect patients or to investigators that want to be part of it. I will say that, since you brought this up, I think there's tremendous value in this field, not just to the researchers and the drug developers and the scientists interested in prostate cancer, but to the patients and I think for patients who participate in this study, we view this as a platform. Ultimately, our goal is to create a community that patients feel tied to. You know, 5,000, 6,000 patients going through this same disease state that they are and we are working with the Us Too organization to create some chat rooms and websites within us, specifically for IRONMAN participants or people that are like them, but are not part of it.

As much as possible, I think what we're trying to do is create a culture of collaboration between patients and investigators to help us understand what we need, what we've been missing in this field, help us treat you better and help us figure out how we can improve the outcomes of our patients.

Alicia Morgans: Well, thank you so much, Dan. And I think we can do better and I sincerely appreciate that you and the IRONMAN organization is trying to help us do that and, as I said, I look forward to hearing some of the results. Our center here at Northwestern, actually just opened for IRONMAN and the registry, locations that are listed online are always being updated, so if you don't see a place near you, then please do reach out to the organizers like Dan or Phil or Lorelei and do get involved because it's only by working with patients that we, as clinicians and investigators, can actually move the needle, so we all need to work together on this one and, like I said, we can do better. Dan, do you have any closing thoughts before we sign off?

Dan George: Alicia let me just end by saying, you know, there are a tremendous amount of clinical trials going on the field today and they all need involvement and support. But this is really a one-of-a-kind study and this is the kind of study that there isn't this sort of immediate feedback for either the investigator or the patient to participate in. So, it's not an easy sell, if you will, for people to do this kind of work. But, I would argue, when we look back 10 years from now, this may be the one study we remember from this generation more so than any other single drug study that's going on today. So, when you're thinking about what studies you want to open or participate in, what studies you want to be part of, think about the landmark studies that you know of in whatever field it is. It can be cardiology, it could be urology, it could be oncology, but think about those studies and they're usually the really big global studies and if you want to be a part of that, let us know.

Whether you're a patient or investigator, this is the time to join and not just join but really accrue. And for those centers out there that have this open, please, the first couple of years are always the most critical for these studies in terms of getting things done so, whatever you can to prioritize this work, we really appreciate it.

Alicia Morgans: Well, thank you so much, Dan and thanks for raising awareness of the study, of prostate cancer generally, for helping us to move the needle and a great conversation for Prostate Cancer Awareness Month. I really appreciate your time.

Dan George: My pleasure. Thank you very much.