Charles Ryan: Hello from APCCC 2019. I'm joined with Dr. Christopher Sweeney, who is a Professor of Medicine at Harvard Medical School and a Medical Oncologist at the Dana-Farber Cancer Center.

Chris, great to talk to you. You are one of the leading voices around the topic of hormone-sensitive prostate cancer and this emerging notion, I think, or realization that this is not one clinical entity, of course, it's multiple clinical entities. Walk us through how clinicians should confront patients with hormone-sensitive disease and how they should categorize those patients.

Christopher Sweeney: Thanks, Chuck. And thanks for the opportunity to actually have this conversation.

When a patient sits in front of you, clinicians and nurses, we all try to think through what is the best treatment plan for them. And the session I just gave and the lecture I gave, I actually focused in on two broad spectrums, the two bookends. The 55 year-old man who presents with de novo metastatic disease. He's got 10 bony metastases, he's got pain, and he's got no other health issues. And compare that with the gentleman who is now 82, he had a prostatectomy at the age of 72, but at the age of 82, he now has two bony metastases identified because his PSA went from two to eight.

They are two completely different patients, both in terms of their prognosis from their cancer and the prognosis from their comorbid illnesses. On one spectrum, I think it's still fine to think about testosterone suppression alone. And on the other hand, you want to double down on your therapies as much as you can.

So, as part of the CHAARTED trial, even back in 2004 when we wrote it, we did recognize that just simple old bone scans and conventional scans can categorize patients into a high burden, with poorer outcomes, and a low burden with better outcomes.

What that definition is, is imperfect, but like any biomarker, there's misclassification. But broad strokes, let's just think about the broad strokes. A patient who presents with de novo metastatic high-volume disease, four or five bony metastases, some in the vertebral bodies, some in the [inaudible 00:02:19] for example, more than, visceral metastases, high-burden. They haven't been in survival of only three years. And that's consistent in the LATITUDE study, the ENZAMET study, the CHAARTED study, the TITAN study. And I suspect we'll soon see that in the STAMPEDE study.

Charles Ryan:Right. I frame that observation by saying, in the high-volume patients, a third are dead in three years, right?

Christopher Sweeney: Yeah. On testosterone suppression alone.

Charles Ryan: Well, even in the, in the LATITUDE study-

Christopher Sweeney: A third, a third.

Charles Ryan: A third, 33% on abiraterone. So median survival is longer than three years, but you know, lest we think we've finished the job, we're still losing 33% of patients in a relatively short order.

But you point out this really important fact, which is there are some who will do fine with what we have, some who need more, and some who maybe need less. And that's an ongoing conversation as well. Let's talk about those who need more, those who face the greatest risk. What is the optimal treatment today for, and considering whether we should treat the primary and all of the treatments available, optimal approach for a high-volume patient today?

Christopher Sweeney: I think it depends on that patient, and it depends on what you can have access to, and it depends on their finances. I think all the options are on the table for a chemo-fit, de novo high-volume patients, because whether it's docetaxel, enzalutamide, abiraterone, apalutamide, all of them have their median survival, so their three-year survival increased from about 50% to about 70%, so all of the drugs do the same absolute improvement at three years, as you point out. You're absolutely 100%, that's not good enough, but that's where we've seen the most advance, and I think we may have actually reached a ceiling with the drugs we have. We didn't really even seem to improve that when we combined enzalutamide with docetaxel in the subset from the ENZAMET study. We may delay their progression, but we're not improving the survival yet. We need longer-term followup to see if that pans out.

Charles Ryan: Yeah, stop you on that point really quickly. For those out there who are following these trials and following you and your presentations, what is the clarity from ENZAMET around enzalutamide and docetaxel?

Christopher Sweeney: I think the answer is, if you want to get docetaxel out of the way, and you want to give it up front, you can do testosterone suppression and docetaxel, follow them closely on the testosterone suppression alone, and add the enzalutamide on. Because you'll get the same overall survival benefit of giving the triplet, the ADT, the testosterone suppression, the docetaxel, and the enzalutamide. Because once they progress on the enzalutamide, having given it upfront with the docetaxel, we really don't have many treatment options. Whereas if you go with the docetaxel upfront, we seem to be able to salvage them with adding it on. Now, in two years' time when we have longer followup, will we start to see a separation in the survival curves? I really hope so. But I'm not confident.

Charles Ryan: There was always this, I want to say myth, about the challenge of the problem of using more potent, AR-targeted therapies earlier because you're going to create some, you know, you're going to potentiate the development of high-grade neuroendocrine, whatever you want to call it, subsequent disease and people were going to die faster and we've pretty much dispelled that with every study you just mentioned, right? Where earlier is better.

Christopher Sweeney: Absolutely. I'm going to double down on that. You are touching all my hot buttons. Absolutely, Chuck.

Charles Ryan: That's my job. But I think that what you're pointing out is that you're going to find out over time from ENZAMET whether early enzalutamide versus deferred enzalutamide ... Correct? Is that correct?

Christopher Sweeney: Correct. Yeah. I think so.

Christopher Sweeney: And given with docetaxel, in that setting.

Charles Ryan: Yeah.

Christopher Sweeney: So to double down on that, you're absolutely right, Chuck. Even if you took all the studies we're intensifying the hormones in the hormone-sensitive metastatic setting, everything is a benefit. Everything's been going ... So we're delaying the emergence of resistant disease, but we're not inducing it more rapidly. We're delaying its emergence. And now the question is, can we develop new therapies to prevent that emergence? That's the challenge. The other thing is, it's even more evident that when we're giving hormones and radiation for locally advanced disease, we're curing more people.

It wasn't the hormones inducing this disease they're going to die from. So I think that story, that myth has been put to bed.

Charles Ryan: I agree. And we need to also be focused on the molecular evolution of the disease because this disease is going to evolve unless we hit it early. And I think that, you know, treating somebody with ADT alone is going to potentiate all the old well-known actors of evolution of the disease to a more aggressive phenotype, RB1 loss, et cetera, et cetera. AR amplification. But hitting it harder is going to reduce and probably, we hope, kill off some of those clones early, so that maybe the CRPC of the future will still exist, but it'll be different. Qualitatively different.

Christopher Sweeney: Yeah, I think that's a very, very sound hypothesis that you, me, and all our academic colleagues should be excited about the opportunity, to discover, explore, and refine.

Charles Ryan: But I think patients, for example, based on ENZAMET and other studies, may get aggressive upfront therapy, their disease progression will be delayed, and when it progresses it will be a different phenotype than it was if we had started on ADT alone. It may be more evolved, more resistant, but may not be, because you may have with chemotherapy and others, you may have eliminated those more aggressive subclones and RB1 loss, et cetera, et cetera. So you may end up with a more, if you will, "bland" tumor at the time of progression. We don't know. It's speculation.

Christopher Sweeney: But you're absolutely right, it's speculation but it's definitely a question. I'm hopeful our technologies on circulating tumor DNA can actually help us with that. Because as we get greater coverage and more refined, we can get the minimal residual disease, if you would. So we've got samples at six months and a progression in CHAARTED and ENZAMET, where we'll be able to actually look at that evolution that you're describing, at least in the circulating tumor DNA level. And maybe some of these methylation assays that are being developed from the circulating serum and plasma, we can actually, is it going to be a mutation profile or is it going to be an epigenetic profile? So I'm excited about the advances in the technology, but fortunately, when we wrote the studies in 2004 and 2013, we actually future-proofed it by getting the samples to be able to actually come back now the technologies are emerging.

Charles Ryan: Well you and I have been doing this together a long time.

Christopher Sweeney: Oh my gosh.

Charles Ryan: And we're beginning to see the results of these long studies. I mean-

Christopher Sweeney: It's a long run, yeah?

Charles Ryan: We complain about how long these studies take, but when they finish, and when we get data, having samples and having the retrospective analysis that we can do, really allows us to move forward, certainly with more certainty into the future. And congratulations for all the work you've done, and it's always a pleasure to talk to you, Chris.

Christopher Sweeney: Always a pleasure to talk to you, Chuck.