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Zach Klaassen: Hi, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm joined today by Dr. Dan George, who is head of GU Medical Oncology at the Duke Cancer Center. Dr. George, thanks for joining us today.


Daniel George: Hey, my pleasure, Zach.

Zach Klaassen: We're going to discuss some recent data that you presented at ESMO, and we're looking at basically Enza versus Abi in the pre-chemo mCRPC setting. What was the genesis to look at this specific disease space?

Daniel George: Yeah, Zach, really, since 2013, 2014, now, we've had these drugs now almost a decade on the market. They've never really been studied head-to-head, and it probably won't be a clinical trial looking at them head-to-head at this point in time. So clinicians are really left with making a choice on which drug to use, and supplying real-world data into that space, that kind of knowledge gap, is really helpful for people just to kind of frame, does this make any difference at all? Does it make a big difference? How much of a difference? Are there certain patients where one drug might be preferable over another?

Zach Klaassen: Right. And we've seen some other studies in this space looking at some French data, the VA data, Flatiron, so the private insurance data, what have those studies shown looking at specifically Enza versus Abi?

Daniel George: It's really helpful to have multiple data sources. The French data, the French National Database, probably the largest database we have out there so far, showed a significant difference in favor of enzalutamide in terms of a longer survival associated with that treatment in this space. When we look at Flatiron, that's a different population now. That's US, and there's a little bit of a different landscape on how and when we use these drugs. We also saw that, more of a trend, but we saw that there in the VA, single-payer system. So there's not this sort of access gap that you might see in certain populations. We see a little bit higher percentage of minority patients, Black patients, in that population. There too, we see a difference in favor of enzalutamide.

So we wanted to look at Medicare. And Medicare is important because this is a database that's really focused on the elderly, 65 and older, and that's a particularly important population, one, because they are the biggest population with prostate cancer and where we're seeing this need, they're the patients that are less represented in our clinical trials. These are older patients, a significant portion over 75, and this is a population of patients that's, ultimately, at the end of the day, it's US-based. It's the largest US-based payer system that we have.

Zach Klaassen: Absolutely. So it's a great background. Setting the stage for Medicare. Take us through the study design and how you guys looked at the data.


Daniel George: There's a real systematic way, a consort diagram that we use on how we break this down, starting with just a diagnosis of prostate cancer, breaking it down to patients then that have metastatic disease and then receive these therapies. One of the critical things that we don't have in these databases is the diagnosis of castrate-resistant disease. And as you know, these drugs are now approved in the metastatic hormone-sensitive disease space. The way we got around that part in particular was to focus on patients treated between 2014 and 2017, because, really, before 2017, there was no indication, no data really to support using these drugs earlier. All of that use was in the castrate, castrate-resistant setting, and then we focus specifically on patients that hadn't had docetaxel chemotherapy. So we could really kind of pare it down to that population. And with those assumptions in mind, we could look, and we still had several thousand patients treated with either abiraterone or enzalutamide.

Zach Klaassen: It's nice. I mean, we have a huge sample size, I am an epidemiologist, at least on the weekends.

Daniel George: Oh, nice.

Zach Klaassen: I think the nice thing is you're able to set those timeframes in terms of when the approval was and try to make it, there's always going to be assumptions with these studies, but I liked how you guys picked that timeframe because that's when utilization in advanced prostate cancer was likely to be used for mCRPC. So I think that that was a strength of just setting it up from the very top.

Daniel George: Absolutely, and it gives us the long-term follow-up for overall survival. Ultimately, that's really what we want to see. Is there a difference in how long these patients live?

Zach Klaassen: Take us through the key results. What'd you guys find?

Daniel George: Top-level data, there is a difference, and surprisingly the difference is in favor of enzalutamide. And I say that somewhat surprisingly because there's an impression out there that this drug is harder for our older patients to tolerate, and we can talk about side effects and whatnot. We didn't break it down by individual toxicities and everything. This survival difference that we see, and these curves separate early and it's all the way through the population, and when we look at our forest plots, our subgroup analysis, there's really no group that isn't benefiting more from enzalutamide versus abiraterone. I found that really somewhat surprising because of this, this is real-world data, so it's taken into account both the benefits, the efficacy, as well as the tolerance.

Zach Klaassen: That's right.

Daniel George: Because if a patient's not tolerating the drug, if they have to stop it, we looked at the time to drug discontinuation. We could go look at that data, we looked at crossover, we're able to look at patients that only got one drug only as their treatment. As you know, in this space, especially during that time, many patients were just treated with one agent in the castrate-resistance space. All of these factors trended in favor of enzalutamide over abiraterone, and in fact, what we see is abiraterone patients are living about 10% shorter survival. And that was statistically significant. That, to me, it's important.

Zach Klaassen: Absolutely.

Daniel George: When you have a year to 2 to live, 10% matters.

Zach Klaassen: Yeah. Let's talk a little bit more about those comorbid patients because you alluded to the forest plots looking at greater than 75, looking at the really comorbid patients, and frankly, there's no great treatment for any of these patients because they're going to have side effects. But there's the perception of extreme fatigue with enzalutamide, the brain fog that some of these older comorbid patients can get. When you're sitting in the clinic looking at, let's say that 76-year-old guy that has diabetes, has had a heart attack, and you see that the enzalutamide data is better, how are you counseling the patients about these options, specifically for that patient?

Daniel George: Yeah, no, this is really important because I think you can recognize that, probably, across the board there's probably somewhere between 10-20% of patients that are not going to tolerate these drugs. So recognizing that upfront, I talk to patients that this is still, for first-line castrate-resistant prostate cancer, the best last option we have to treat these patients. It's not that we don't have other drugs, but they're going to be harder for the patient you described. The elderly patient over 75 with comorbidities, harder to tolerate chemotherapy, immunotherapies, radiotherapies, or the like.

So we're really looking at this hormone, androgen receptor-targeted strategy as really our best therapy, the one we want to maximize, and so best survival benefit matters. And then we talk a little bit about side effect management, and we do talk to make sure they're aware to look for these kinds of things. But, look, I don't want to say the brain fog doesn't matter at 75, but everyone's probably a little bit down from their peak at that point.

Zach Klaassen: Been on ADT for a long time already, right?

Daniel George: That's right. So I think a lot of these patients are, they've coped and that's, hey, listen, we do that in life all the way through. So that's something that as long as they're aware of it and recognize it's not a life-threatening complication, but it's a quality of life thing. Disease control, PSA under control, no progression, no progressive symptoms, those things are greater impacts on their quality of life than the side effects associated with these drugs.

Zach Klaassen: I think you hit on a good point, that you're talking about expectations, and I think if you just say, "Hey, we're going to do this and we'll see you in 3 months," and they all of a sudden experience all these things, but if you can sit down if it's 5, 10 minutes and say, "This is what to expect, it's going to work, but you're going to have this," and just set that expectation for that next 3-month visit or 6-week visit and then reassess where they're at, right?

Daniel George: I think that's exactly right. I think helping patients sort of preempt this and prepare for that is really critical.

Zach Klaassen: As we wrap up, anything we haven't hit on that you want to talk about? Maybe a couple of take-home points for our listeners to take to the clinic tomorrow?

Daniel George: Yeah, I think there's two things here. One, don't be afraid to treat patients who are elderly with these drugs. Don't be afraid to treat everybody with these drugs. There really isn't a patient that I can think of that's absolutely contraindicated for these treatments. It's all relative. If we look at things like diabetes and stuff, it's sort of natural to avoid prednisone. We want to use the enzalutamide-type strategies. But it's something you can feel confident is done in a broad population of patients and shows benefit.

I think the second thing is, really, where does this data go? What's the extrapolation? Because where we're using these drugs now more often is in the early metastatic castrate-sensitive, if you will, space, and I think to some extent the biology, the benefits here could extrapolate over. We obviously want to see that data in the future and we will, but that's an earlier data set. It's going to take time to mature and we're going to have to sort of see how that plays out, but right now there's reason to suspect that these benefits could also play out in that setting as well.

Zach Klaassen: Particularly as we move back with EMBARK going really earlier in the disease space, the sequencing question's always going to be relevant as we move forward, isn't it?

Daniel George: That's exactly right. Yeah.

Zach Klaassen: Dr. George, thank you very much for your time. Enjoyed the conversation.

Daniel George: My pleasure. Thanks.

Zach Klaassen: Thanks.