Exploring Racial Biases in Clinical Trials: The PANTHER Study's Findings on Prostate Cancer - Dan George

June 15, 2023

Daniel George and Alicia Morgans explore the groundbreaking results of the PANTHER study. The study addresses an enduring gap in clinical trials concerning black patients, who are disproportionately affected by prostate cancer. The PANTHER study investigates the effects of a novel combination of hormonal therapies, apalutamide and abiraterone, in castrate-resistant prostate cancer. Intriguingly, the study shows that black patients exhibit significantly longer radiographic progression-free survival, time to PSA progression, and overall survival rates compared to their white counterparts. While the cause remains unknown, these findings suggest potential biological differences in the way black patients develop castrate-resistant prostate cancer. The conversation underscores the critical need for diversity in clinical trials, urging active patient recruitment and advocacy, in order to understand potential racial disparities in treatment responses.


Daniel George, MD, Medical Oncologist, Professor, Departments of Medicine and Surgery, Duke Cancer Institute, Duke University, Durham, NC

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Dan George, who's a professor of medicine at Duke University. Thank you so much for being here with me.

Daniel George: My pleasure, Alicia.

Alicia Morgans: Wonderful. So Dan, you had a fantastic presentation at ASCO 2023 where you presented results from the PANTHER study. Can you tell me a little bit about this really unique and important study, why it is so important and then we'll get into the details of what you found?

Daniel George: Well, Alicia, historically, we have never accrued well for our black patients on our clinical trials in prostate cancer. And particularly in advanced disease and metastatic disease, we have particularly poor accrual. And it's a problem because black patients are more likely to be diagnosed with prostate cancer, twice as likely to die from this disease. So they're disproportionately affected, especially on this lethal phenotype of castration-resistant disease and yet they're not part of our clinical trial portfolio and experience. So we did this study at a time when we were interested in a combination of hormonal therapies. Apalutamide and abiraterone are two novel hormonal agents that work somewhat complimentary to block the androgen-receptor signaling pathway. And so it was thought that if we combine these agents in castrate-resistant disease, we might actually see more responsiveness, maybe even better survival. And there's two large Phase 3 studies, one by the sponsor Janssen, that looked at that combination versus abiraterone and another by the Co-operative Group that looked at enzalutamide and abiraterone versus enzalutamide.

And both studies showed an improvement in radiographic progression-free survival and a trend in overall survival, but it wasn't statistically significant. So overall it's felt that maybe this wasn't robust enough. But both studies really were done in predominantly white men. And so while the ACIS study, the Janssen's study was going on, they supported us to do a multicenter small, exploratory study with two cohorts, a black cohort and a white cohort of patients. Treated at the same centers, we had eight centers, treated by the same physicians on the same study following the same protocol. So really kind of equitable care, if you will. And amazingly what we saw was a fairly dramatic difference in the outcomes. Our black patients had a much longer radiographic progression-free survival, median of 30 months. Our white patients, in line with what we see with this combination of about a 15, 16 month median rPFS.

The time to PSA progression was also almost double in the black cohort. And even with overall survival, when we looked at two years, our overall survival rate was 86% in our black patients versus 67%. Really almost a doubling of the death rate in the white patients compared to the black patients at two years. And this really surprised us because again, this is a population of patients that historically are dying faster from prostate cancer than our white patients. But it's a trend that we've seen in retrospective analyses over and again with hormonal therapies, chemotherapies, even immunotherapies in this castration-resistant disease setting. So it really suggests that there could be something biologically different in black patients that develop castrate-resistant prostate cancer than our white patients.

Alicia Morgans: And certainly that the treatments may be differentially affecting those cancer cells. So that's so interesting. I wonder, other than the biology, is there something else going on here? Is it that intensified treatment is just going to give more to the black patients? How do you sort this out and how do you take this to the next steps in terms of further investigating and understanding what's going on?

Daniel George: Well, I think that last part is key. This is an exploratory study. I don't want to leave the impression that we have demonstrated that without a doubt black patients do better. But there's a really strong trend, it's across multiple endpoints. And we had actually done a prior study with just abiraterone alone in black and white cohorts and we didn't see that much change. We did see a longer time to PSA progression in the black cohort, but the radiographic progression-free survival and overall survival were the same. So consequently, when we compared our PANTHER patients, who were black, to our Abi race patients with abiraterone alone who were black, we saw a big difference there. When we compared the white patients in PANTHER and Abi race, we didn't really see any difference. So it does suggest there's something potentially biologically going on, but what that is at this point is unknown.

The good news is we have a lot of biologic samples to draw from. We can look at things like the metabolic profiles in patients, we can look at the DNA changes, SNP changes, circulating tumor DNA, even RNA changes. But probably in my mind what suggests the most, because the treatments are so specific for the androgen-receptor pathway is that there might be something different about the androgen-receptor pathway in castrate-resistant prostate cancer for black men versus white. And again, I'm not trying to essentialize, I mean, the reality is that these are social constructs that people self-identify with as black or white, but underlying that social construct is some genetic ancestry and that genetic ancestry may have biologic implications in this disease. And I think that's what this data is suggesting to us.

Alicia Morgans: It is really fascinating. And I think as you mentioned, Abi race was an earlier study that you did again with a white cohort and a black cohort. In that study, you found differences not only in PSA progression, but at least numerical differences in some of the development of side effects. And so I wonder was that a difference that came out in the PANTHER study as well, that there might be differences by race in terms of side effects?

Daniel George: It did. And it's really interesting because in the Abi race study we saw our black patients had about twice the rate of hypokalemia. If you think about hypokalemia from abiraterone, it's really driven by the effects on the mineral corticoids and the inhibition of mineral corticoids by abiraterone as a 17α-hydroxylase inhibitor. So that effect was there and we were postulating that maybe the patients that got hypokalemia just had greater concentrations of abiraterone in their target tissues, both the adrenal gland and maybe even the tumor.

Well, in PANTHER, we saw the same thing. We saw twice, not quite twice, but 50% versus 30% or so hypokalemia. So it was about a 20% greater incidence of hypokalemia in the black cohort versus the white cohort. What's interesting about this though is that in the Alliance trial looking at enzalutamide and abiraterone, they're able to show that enzalutamide actually induced a greater metabolism of abiraterone. So the concentrations, the pharmacokinetics of abiraterone in the combination are about two to two and a half fold lower than in patients on abiraterone alone. And so it suggests that these patients on apalutamide and abiraterone, even with potentially lower doses of abiraterone, are still getting this hypokalemic effect. So really a fascinating kind of correlative toxicity potentially with efficacy.

Alicia Morgans: It is so interesting and I think I have a lot of interest in understanding the genetic predisposition to developing these different complications. And as you said, with different ancestry, we have different genes coming into the mix. And so really I'll be curious to see how the germline genetics somehow are potentially associated with some of the development of these side effects. So fascinating. So as you think about this, and obviously as you said, this is a relatively small study, one that is so important, but is now part of a growing portfolio of work that you're doing to help us as a community certainly connect with our black patients and also help understand the biology and the history of how things will be in terms of their outcomes with treatment. Where do you go from here and how do you continue this really important line of work?

Daniel George: Yeah, I think there's really two really important lessons learned here. One is that we absolutely have to be intentional in our inclusion of black patients in our clinical trials. We can no longer really passively just wait for patients to show up and come to us and ask to be enrolled in our studies. We as a community have to actively engage them and help them meet those criteria to be eligible and to be able to make a clinical trial work for them on their lifestyle terms. Look, this is everyone's responsibility because the pharmaceutical companies don't accrue patients, clinical trial sites accrue patients. But clinical trial sites only accrue the patients that they see in their clinic and if they're not seeing enough black patients, they're not going to be able to accrue them. So we have to, number one, put clinical trialists where our black patients are being treated with castrate-resistant prostate cancer.

And then we have to build infrastructure to support those champions in those sites to be able to accrue those patients, those patients, then it's their responsibility to participate in this as well. And ultimately for us as a community to come around and be able to do the subgroup analysis to see are there differences in black patients and white patients on trials? Because if we don't look, then we don't know and if we don't know, then we assume that there's no difference and that's a big problem. So my hope is that this PANTHER study just opens our eyes up to the possibility that we may be missing something in a patient population that maybe needs us most of all in terms of better treatment options.

And then I think the second thing from this study is that this combination, we really need to study this further. We need to understand now, can we independently confirm these effects? And that's going to be hard to do in metastatic castration-resistant prostate cancer because many of these drugs are now being used in earlier disease settings. But in settings where patients have prostate cancer that is androgen-receptor signaling inhibitor naive, they haven't received abiraterone or apalutamide or drugs like it, there's an opportunity to study in black patients, can we see a better outcome in patients that get a doublet versus patients that get a single drug like abiraterone? So I hope there's a broader lesson learned here so that we don't miss this. And who knows, with chemotherapy, immunotherapies, even PARP inhibitors, could there be differences associated with race? And I hope we can ask those questions in the future. And I hope particularly for this regimen, we can have an open mind to reevaluate this combination in some other settings and really see if there is a difference associated with black patients in a greater benefit.

Alicia Morgans: I couldn't agree more, especially since I think the trend in the field has been to not combine these AR signaling inhibitors in our general practice. So we may be missing a really important opportunity for our black patients to do very well with a regimen that's well tolerated.

Daniel George: It is. It's not adding a lot of extra toxicity, there is some, but it's manageable. And I think the important thing too is that we're not using these drugs in sequence. At least we shouldn't be. There's not really a clinical benefit to doing apalutamide after abiraterone or vice versa. So if we're only going to use one line of this novel hormonal therapy, we really ought to use the best line we can, the best combination, if it's justified. And there was a signal there in a broad population, it just may be stronger in a more defined population.

Alicia Morgans: Or a population that's more sensitive and benefits more from the particular combination?

Daniel George: That's exactly right. And ultimately, if that's true, we need to understand why. Because there could be other patients, non-black patients that could benefit from that. And that's important too. But to do that, first we have to see, is this signal real? Can we reproduce it?

Alicia Morgans: Absolutely. So what would your final word be? What is your message to listeners on this really important study and the work, of course, that you've done previously, even with Abi race and other work?

Daniel George: Yeah. I think it's so important for our black patients out there, and even non-patients, just people that are black in the community just recognize that we see that there's a disparity in outcomes and we care and we want to find out why. And yes, there are a tremendous amount of social determinants that are driving the biggest differences here and we're not ignoring that at all. And those are the bigger issues that need to be addressed. But in doing so, in looking at our clinical trials, we have to make an effort to include a broader population of patients because if we don't, there really is biology that we're not taking into account when we think about our overall population here.

And that's going to be hard going forward, but it's going to be something that I think we all need to own. And I hope patients will give us a chance to do that. I hope centers where they haven't necessarily been included in clinical trials and supported with infrastructure are willing to take that on and champion this because it's the right thing to do, not just for black patients, but potentially for all patients.

Alicia Morgans: Absolutely. I think that the continued work that you and your team are doing and the continued engagement that we're so grateful for, for all of the patients that are participating in your trial, but particularly the black patients who overcome maybe social determinants of health, maybe concerns from cultural history that have been challenges and whatever it is that they're overcoming to participate in these trials, we are grateful for that and really look forward to continued work in this area so we can, as you said, treat all of our patients to the best of our ability. So thank you so much for your time and your expertise today.

Daniel George: My pleasure. Thank you.