Disparities and Outcomes in Men with Prostate Cancer - Susan Halabi, Mindy Hebert-DeRouen, and Daniel George
November 11, 2019
Susan Halabi, Ph.D., Professor of Biostatistics and Bioinformatics, Duke Cancer Institute, Durham, North Carolina, United States
Mindy Hebert-DeRouen, Ph.D., MPH, Specialist, Department of Epidemiology and Biostatistics, The University of California, San Francisco
Daniel J. George, MD, Medical Oncologist, Professor of Medicine, Professor of Surgery, Duke Cancer Institute, Durham, North Carolina
Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.
Charles Ryan: Hello from PCF 2019 I have a special panel with me today. We're going to talk about disparities and outcome in men with prostate cancer. And I'm joined by three people who have published and thought a lot about the topic. To my left is Susan Halabi from Duke, a statistician. Mindy DeRouen, an epidemiologist from the University of California, San Francisco and Dan George from Duke University, Medical Oncologist. So all three of you have given really great presentations here today at the PCF Scientific Retreat and we are covering a really important area around disparities. And I'm going to start with you, Mindy, tell us a little bit about your talk and what topics you covered and what we can learn from that.
Mindy DeRouen: Sure. So my talk spanned the portfolio of projects from the DREAM Lab at University of California, San Francisco and that's what we refer to as ourselves. It stands for Disparities Research: Environment And multi oMics and it really speaks to the broad nature of the cancer disparities research that our group conducts. We have several projects that are specific to prostate cancer and we look at disparities across a number of axes in relation to prostate cancer outcomes in everything from risk of prostate cancer, to treatment received during prostate cancer, and prostate cancer survival. And we're interested in factors that influence disparities at the individual level. Things like race, ethnicity, socioeconomic status of the individual, things like individual level of education, but we're also interested in what we refer to as multilevel factors and that includes the neighborhood that individuals live in. There've been lots of studies to show associations between what we call neighborhood socioeconomic status and prostate cancer survival, which I'll focus on a little bit. And what our group does is try to extend that to other aspects of individuals, neighborhood environments that might influence how they respond to a prostate cancer diagnosis.
Charles Ryan: And this is really the key facet, right? The question of biology of disease based on race or environment in which the patient is being treated or delivery of care. And both of you, Susan and Dan, have addressed these from a couple of different angles. Susan, you've done some work and published some very nice papers in the last couple of years looking at African Americans in the CLGB studies and what have you found there?
Susan Halabi: Right. That's a very good question, Dr. Ryan. What we've done is in about 2004 by a grant funded by the Prostate Cancer Foundation, we looked at combining data from eight Phase II and Phase III trials conducted in the CLGB, and we looked at whether there were differences in outcome and men who were enrolled in clinical trials. And to our surprise, African American men did well as Caucasian men. This was totally unexpected, but the results from these studies were not really very solid because it comes from the data was derived from Phase II and Phase III trials. Some of the patients were treated with different regimens. There wasn't really a standard of care in those trials, so I was always skeptical about the results and I always wanted to go back to this important question. I had the great opportunity of partnering with the NCTN and the pharma and had access to nine clinical trials and men with metastatic castration-resistant prostate cancer.
Now, even at the time when we did the analysis, there was about 9,000 men who were enrolled in those nine trials and I limited the analysis to mostly Caucasian and African American men. The first point I want to make is even a decades later, we are surprised by the low number of enrollment of African American men in clinical trials. I think this is the 21st century and this is in my mind is unacceptable. But the other interesting thing is that African American men, even though they had different prognostic factor at randomization, when you adjust for those factors, they did equally well, if not better than the Caucasian men who were enrolled on those clinical trials.
Charles Ryan: So your data argues or begins to open the question of whether if we just normalize the treatment, put everybody on the same treatment as these clinical trials do, disparities go away? Or lessened?
Susan Halabi: Well, I would say those patients have equal access to clinical trials. So they were eligible. But I think there is an important point to underscored here, that when you look at the presentation of prognostic factors such as hemoglobin, such as alkaline phosphatase, PSA, and other important established factors of overall survival, the African American men had worst prognostic factors than white men. But when you adjust for those variables, they did better...
Charles Ryan: Better than expected based on their prognostic.
Susan Halabi: Right. So that brings up the question and really important question to answer. Is it because those patients who are treated with docetaxel, the African American men, do they respond differently than the white men? Is it really biology or not? And this is a question unfortunately that we cannot answer because we did not have access to toxicity or treatment information.
Charles Ryan: Now Mindy, you may look at that data and say, well do we know where these patients actually came from? The other factors as you've described, whether they be neighborhood or other health background factors in whether we actually in those clinical trials had a representative sample of the African American community, for example.
Mindy DeRouen: Right. And I don't know about the details of the trial, but my intuition would say probably not.
Charles Ryan: Yeah.
Mindy DeRouen: I mean our randomized controlled trials are very selective in their patient populations and they represent a very small group of individuals in terms of where they are at in their disease stage at diagnosis.
Charles Ryan: And they require a lot of resources from the patient themselves.
Mindy DeRouen: They don't represent the heterogeneous nature of the individuals who are diagnosed with prostate cancer. The disease characteristics at diagnosis.
Charles Ryan: Right.
Mindy DeRouen: Or the environments of those individuals are embedded in.
Charles Ryan: Right. So now, Dan, you've taken this on in a prospective manner. Tell us about your work at Duke.
Dan George: Yeah, so, first of all, I appreciate the work that both of you have done. This is a really complex problem and we're going to have to come at it from multiple different angles. And the retrospective large meta-analyses are really critical. And I think that the demographic work, the socioeconomic work, understanding those environment factors are really critical. We've looked at it from a little bit more of a prospective analysis. If we want to get a biology then we need to identify patients ahead of time by race and we need to study them for treatment outcomes. And so what we did, what we thought was a simple trial, this was shortly after the time of the Cougar 302 study, FDA approval for abiraterone in the chemo-naïve setting. We got a grant to give free drug to patients and we studied African Americans and White patients prospectively. Same centers, parallel-group study, 50 patients each. And we said, well we'll just do this in our community centers, our outreach centers at Duke and we accrued like seven patients in the first year. So we were going nowhere.
So we went back to the drawing board. We opened this up to multicenters around the country, eight centers total. Some of our friends, Oliver Sartor in Tulane and Elizabeth Heath in Karmanos and Guru Sonpavde was down in UAV at the time, some VAs and whatnot. And we were able to get this study done in about 18 months and we equally accrued Whites and Blacks in each of the centers. And in similar to what Susan saw, we saw a difference in the outcome with these patients when we controlled for them all being on the same trial.
To Mindy's point, these are selected patients, but one of the things we tried to do was loosen that selection. So we went through a series of amendments to further and further loosen the criteria getting further and further away from the Cougar 302 selection and more into, I won't say real-world, but just more open eligibility. The other study, and we saw, again, a longer time to PSA progression in that study. Maybe some trends with radiographic progression-free survival, but nothing significant. It's not a Phase III study, wasn't meant to be, but we collected tissue, we collected blood. We're going to begin to look at what are the genetic, hormonal, metabolic, and other factors, biologic determinants that might correlate with those differences in outcome.
And then the other study was just going to mention it was IRONMAN. Our big registry, which is a big national, international registry and that's really meant to get more, a little bit more at what Mindy's doing. Where it's not the typical clinical trial patients, just patients, anybody that has the disease at that state metastatic hormone-sensitive, castration-resistant. Wide eligibility, Black or White. We're trying to get a broad selection of patients, old and young, various different histologies, whatnot. Criteria that wouldn't necessarily fit into a prospective treatment trial but allows us to begin to look at a broader cross-section of how are real-world patients being treated. Not just here in the U.S. but really all across the globe.
Charles Ryan: So in IRONMAN, are you collecting the type of data that Mindy is collecting in her very detailed analysis down to the zip code?
Dan George: Well, I don't think we got zip codes. I don't know zip codes in South Africa, but we are trying to get some, we do have some demographic data about smoking, about diet habits, about religion, education, income and things. Not the neighborhood stuff. I think that kind of granularity really takes sort of a separate dedicated trial, like the work that Mindy's doing. And again, all of these are to me, pieces to get at that puzzle, that complexity. There's no one study that's going to answer all the questions, but if we can all come from a different angle and sort of begin to see patterns emerge and begin to collect samples that help us begin to understand the biology a little bit more. We're going to get at understanding this problem.
Charles Ryan: So I would say one of the key interesting things to me is having done a little bit of work on androgen metabolism and helped to develop abiraterone in this disease is that it's one thing to talk about disparities. Another thing to talk about prostate cancer as a metabolic disease. And it's another thing altogether to talk about the specific therapy abiraterone because that is a treatment that has direct... there are polymorphisms and various genes around androgen metabolism that may drive response to abiraterone. This is Nima Sharifi's work and others. And there's a huge amount of racial difference between, in the population of people who have, for example, gain of function variants and three beta HSD1, the key driver of androgen production. And so your samples are going to be really important and you might find that there are socioeconomic variables and biological variables and that's what you hinted at in the panel.
Dan George: Abiraterone is a steroid.
Charles Ryan: Yeah.
Dan George: It's transported into cells the same way androgens get in.
Charles Ryan: Right. Well I think of prostate cancer as a metabolic disease and patients have, overall, and patients come with different metabolic backgrounds and then we're interfacing with metabolic drugs.
Dan George: Yes.
Charles Ryan: Right? So there's going to be some difference there.
Dan George: Absolutely. Absolutely.
Charles Ryan: So what's your next step? Let IRONMAN mature?
Dan George: No. Absolutely, we need to finish that project. That needs to grow for sure. Right? But we also need to take these questions into the curative setting. It's one thing to understand how to keep people alive a little bit longer with castration-resistant disease, but now that we're starting to treat patients with locally advanced disease, with hormones and radiation, combining some of these novel hormonal agents, it's important to represent African Americans there. Susan, there was a study that looked at RTOG studies and I don't know if you want to talk a little bit about it, but there showed us a difference in outcome by race in that population as well.
Charles Ryan: I'm going to get to that. Yeah, so tell us about it. The RTOG studies that... Dan Spratt's work from the University of Michigan.
Susan Halabi: I had the opportunity to be involved also in this analysis, but this is mostly based on three different cohorts of patients to have the SEER data, you have data from the VA health system, and you have data from four RTOG trials. I think it's really interesting to me that the data from RTOG did not show that the disparity in terms of overall mortality and prostate cancer, specific mortality. And also it is important to underscore that the RTOG patient population did enroll more African Americans than the other cooperative group. It's like about 12 or 14% of the patients were African American men. Now again, when you adjust for important variables in the RTOG trials, the African American men did better. The hazard ratio was 0.81 and it was statistically significant to everybody's surprise. But if you talk to other people such as Mack Roach, he said, well we've known this for 20 years.
Charles Ryan: Just to slow down and go over that. You said the hazard ratio for African American men in RTOG studies compared to non-African American men's was about 0.81 indicating...
Susan Halabi: In favor.
Charles Ryan: In favor saying they have a survival that's maybe 20% better over time than others.
Susan Halabi: But again, I think it's very important to underscore that the data is highly selective. The patient population were eligible to be treated on those clinical trials. Those clinical trials are, you can think of them as controlled experiments. The regimens are standardized, the protocols are very well written, so there are of course a lot of caution. We need to take a lot of caution interpreting the data. Now when you look at the VA data there was some evidence of a disparity, but I think the worst disparity as you would expect was from the SEER registry because again, this is coming from the patient population.
Charles Ryan: Right, and I'll address the next question to Mindy. Looking at the study with the VA database, it actually, there was a little bit of a disparity, but actually it data kind of suggested that once you're in the VA, the care is relatively uniform and outcome disparities are corrected a little bit if I remember that data fairly correctly. But even within the VA, there's a huge amount of geographic, economic, and other types of disparities and so I would just put it back to you and say, what is the next step for this type of analysis? For those of us treating the patients and designing the clinical trials, how can we integrate what you've learned to do better work and to help patients?
Mindy DeRouen: Sure. So during my talk, I mentioned a paper out recently in a special issue of the American Journal of Public Health in the spring and one paper in particular by Agurs-Collins reviews the necessity of multilevel interventions in clinical trials. And I think that point is very important and it really takes some of what we've learned in our multilevel studies and many others to acknowledge and recognize the multilevel influences to these disparities and to clinical trial participation initially. And that could mean understanding where your patients come from and targeting those neighborhoods that your trial is not capable of reaching. And it could mean cultural competence among the individuals who were in your trial. Why might like individuals not be able to keep up with whatever treatment regimen is presented to them in the clinic. And so there are numerous ways in which these multilevel interventions could really improve upon who participates in clinical trials, who receives therapy within a nonclinical trial setting. And whether or not they're able to finish their therapy, but also what else is in their environment that's affecting their biology while they're going through that therapy.
Charles Ryan: It's a really important one. We hadn't even talked about the completion of therapy or the tolerability or safety of therapies, which is another whole separate question and hopefully we'll reconvene at some point and have the answers to those questions. It's really delightful to have a statistician, epidemiologist, and an oncologist all working towards the same end here, towards the same end on this really important question. So delightful to talk to all of you. Thank you so much for your time and congratulations on your great work.
Susan Halabi: Thank you. It was my pleasure.