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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. Matt Cooperberg, Urologic Oncologist at UCSF. Thanks for joining us today, Matt.

Matt Cooperberg: It's a pleasure. Always a pleasure.

Zach Klaassen: We just had ESMO recently. There's been a lot of data about EMBARK. Obviously it was presented first at ASCO, presented PROs at ESMO, recently published in the New England Journal last week. So just for a high-level overview, obviously there was the enza plus leuprolide versus leuprolide alone in these high-risk non-metastatic hormone-sensitive prostate cancer patients. We saw an MFS benefit hazard ratio of 0.42 for the combo group. But then we had a very interesting group looking at enza alone versus leuprolide, and we also saw an MFS benefit there. And if we just summarize the PROs, we saw basically it's well tolerated in the combo group. Interestingly as you'd expect, the combo group had some issues with sexual dysfunction, but the enza group tolerated it quite well. So with that very quick overview, what are your initial impressions of both the oncological efficacy as well as the PRO data?

Matt Cooperberg: It's a big study, obviously very long awaited. This has been going on for a long time. I think to an extent, maybe some of it is not surprising. Every single context where we have intensified treatment, we have seen better efficacy, and this has been true from late stage advanced disease on through every step to the left. So the better efficacy for combination treatment in a group who were previously castrate sensitive makes perfect sense and is, I think, kind of predictable. You still have the questions of timing and the optimal patient population and whom to intensify. This was a relatively aggressive group of patients starting on therapy.

But it's funny, from the time that the trial launched to today, I think a lot of us are more conservative about starting ADT in general for patients who do not have metastatic disease. Ten plus years ago, we would put patients on ADT, maybe intermittently, maybe not, more or less indefinitely based on a somewhat low PSA after surgery and radiation. These days, we're really waiting for a higher PSA. For PSA PET findings is the huge change of course. So I think finding the right patients to intensify is still going to be a bit of a question, and as always, I'm hoping that that is going to evolve to a genomically or otherwise biomarker-driven decision rather than one driven just based on PSA kinetics or availability of drugs. The monotherapy arm, like you said, maybe it's the most interesting.

Zach Klaassen: This is the interesting one, yeah.

Matt Cooperberg: Yeah, this maybe is the most interesting part of the trial. Again, long awaited. There is a similar trial ongoing with darolutamide. I think patients have been excited about this for a long time because the idea of so-called castration sparing androgen-deprivation therapy obviously has a lot of appeal. High dose bicalutamide, which was tested ages ago even before my time, and there's enough gray in my beard that actually means something these days, didn't pan out, although it was a very popular concept at the time. Clearly this is different with the second or third depending on how you want to count generation AR antagonists.

So I think it totally stands to reason and would be predictable that you're going to avoid all the side effects of ADT. I think what's interesting is how well tolerated the drug was as monotherapy, not too much in terms of fatigue. There was fatigue, but maybe not as much as I think some might have anticipated. I will say for all the horrific press that the enzalutamide in Active Surveillance trial got a couple of years ago, that was one of the side findings is that men who were otherwise naive to treatment actually tolerated it quite well. There are adverse effects, but they were not debilitating, and the drug cessation rate was relatively low.

I think it will be interesting as the darolutamide one comes out, there is some data, not a randomized head-to-head, but there are a few studies showing better tolerance in terms of asthenia and fatigue and this sort of thing. So in a patient population who are going on treatment for maybe years, these what might be subtle differences maybe will become more important and will be amplified. The flip side, of course, is that the cost is a major concern as we talk about potentially years of treatment. Abiraterone is finally coming down a little bit. The AR antagonists have not. And I do think from a stewardship and financial toxicity standpoint, we need to think carefully about this. And, of course, we live in this crazy system where the patient's exposure for an injectable is very different than the patient's exposure for a pill. So that unfortunately has to be weighed together with the differences in efficacy and in side effects.

Zach Klaassen: That's a great overview. I think a couple of spinoff questions from that.

Matt Cooperberg: Sure.

Zach Klaassen: In your mind, do we have to have OS benefit in this population to give it in the clinic?

Matt Cooperberg: Not only do we not have to, I think it's a totally impractical goal at this point because you're talking about patients who have years in front of them. That's a good thing, right? That's a testament to all the progress we've made in the last however many years. We've got 10 drugs now between this trial and overall-

Zach Klaassen: And MFS, it's a good endpoint.

Matt Cooperberg: It's a good endpoint, and it's as good as we're going to get.

Zach Klaassen: That's right.

Matt Cooperberg: I mean, literally the number of possible combinations of treatment that the patients might get between progression on EMBARK and mortality, 10 to the... The number of possible paths is going to get totally unmanageable very quickly. Not to mention the stuff that's in the pipeline, which is going to hit between now and when these patients ultimately-

Zach Klaassen: Absolutely.

Matt Cooperberg: ... reach the end or don't. I mean, a lot of these patients, I would expect a lot of the patients in this EMBARK-type population ultimately will not die of prostate cancer actually, and that becomes an important-

Zach Klaassen: All these things.

Matt Cooperberg: Exactly. Exactly. All the usual things. Which does raise the point too, overall survival is important to track as a secondary endpoint because the guy that goes on ADT doesn't really go on antiresorptive therapy, gets accelerated osteoporosis, has a hip fracture and dies of a PE a week later.

Zach Klaassen: That's right.

Matt Cooperberg: That patient's not counted as a cancer mortality, but the mortality is more or less directly attributable to the treatment and therefore to the diagnosis. So it's definitely important to track these long-term distant outcomes, but I don't think the standard of requiring proof of overall survival delta is realistic.

Zach Klaassen: Another question. So you get a patient on enza monotherapy, they progress, they're not castrate resistant yet.

Matt Cooperberg: Correct.

Zach Klaassen: For our listeners, this is something I've had to try to rationalize in my mind, we can't predict what lines of therapy they're going to get, but how do you categorize that? How do you explain to the patient what they are in terms of their disease state?

Matt Cooperberg: We just created a brand new health state. Okay. We did. As we do this, we are creating a brand new disease state for prostate cancer that has not existed before. Everyone that looks at that diagram of the progressive disease states in prostate cancer has always started with ADT and then ADT resistance. So now we have something new and we're going to have to deal with it. First of all, I think we have to characterize it molecularly.

Zach Klaassen: Yeah, great point.

Matt Cooperberg: It'll be really important to get follow-on tissue on these patients, ideally from the prostate if they still have a prostate or from distant sites as they progress and figure out what is going on at the genomic, at the molecular level that is different from patients who are progressing on ADT. And I would expect that some of the patients will be predictable to respond well to then ADT. Other patients, I think will probably not. Just like we see very low rates of response from switch therapy between ABI and the AR antagonists, if I had to predict, I would predict it would be a little bit better adding ADT to enza or daro or whatever. But it's also probably still not going to be the kind of response you would see de novo, right?

So trying to make those predictions in advance based on biology is going to be more and more and more important. As we add to the armamentarium and to the number of combinations, targeting those combinations in a rational, biologically-driven way to the patients is going to be critical. For all the talk about, again, financial toxicity and patient preferences and side effects and all the rest of it, those are all important, but at the end of the day, this becomes more and more of a heterogeneous disease, the more it's treated and we've got to recognize that and go after the heterogeneity and meet the cancer where it is with the right drugs.

Zach Klaassen: No, that brought up two good points. I think the fact that by the time these patients actually hit another endpoint, there's going to be, it could be Lutetium in this disease space, could be all sorts of stuff coming down the pipeline.

Matt Cooperberg: Absolutely.

Zach Klaassen: So that's going to play into it. But I think the point about biology is important because if that patient, when we see, we'll probably see it in the next couple of years, or even hopefully sooner than that in terms of what the genomic profile of these patients are, particularly the ones that progress, that's going to really drive whether they're going to get a PARP inhibitor plus ADT. We don't know at this point, right?

Matt Cooperberg: We don't know. We don't know. Look, I can tell you what we do know is some of them should get PARPs. Some of them should get chemo. Some of them should get more AR-directed treatment. Some of them should get whatever the next bispecific in the pipeline is and choosing those treatments and matching them to the tumor, that's our job going forward. I mean, the work at this meeting is incredible in the number of agents that are being added to the armamentarium, but then there's the equally important work of now trying to use these very cool, very expensive, limited availability drugs in a rational way.

Zach Klaassen: Great conversation. So just to summarize, anything we haven't hit on and maybe a couple of points. You're seeing this patient in the clinic tomorrow. How are you counseling them?

Matt Cooperberg: That's a great question. Paper's out. The drugs are on the market. I don't have a sense yet. Neither I, nor anyone I know has tried to do this yet. So I don't know if there's going to be payer obstructionism initially, but I think for the patient that is starting on treatment, this is going to be part of the conversation.

I will say, like I said before, we are doing less and less empiric ADT anyway because of PSMA-PET. And, of course, EMBARK is yet another one of these beautiful trials that started-

Zach Klaassen: Conventional imaging.

Matt Cooperberg: ... in the old days before 2020, right?

Zach Klaassen: Right.

Matt Cooperberg: PSMA-PET has changed everything about this-

Zach Klaassen: That's right.

Matt Cooperberg: ... what was always an artificial M0/M1 split. Now we stage migrated that a little bit to the left. So now we have a different split, but we're practicing differently already. So the number of men who we're going to have this conversation with honestly is smaller. And we do see patients, I mean, I can think of them right now, the ones in my practice with the pretty quickly rising PSA after all local therapies, PSMA negative. Actually negative. Everything we can do negative, we really don't know what to do with them. I don't know when to start hormone therapy in those patients-

Zach Klaassen: But those are the ones you may be having this conversation with.

Matt Cooperberg: Well, that's exactly right. As the doubling time goes up or goes down and the PSA continues to rise, that's exactly the patient where we will have this conversation.

Zach Klaassen: So I'm going to put you on the spot. You're giving them enza plus leupro or are you giving them enza alone?

Matt Cooperberg: Depends on the details. How fast is the PSA going up? How bad was the tumor to begin with? What are the details? What's the grade? What were the tumor parameters? I think the worse the cancer was at diagnosis-

Zach Klaassen: The cancer patients too, right? I mean, we clearly know that sexual functions better with enzalutamide as well. Right?

Matt Cooperberg: Absolutely. Absolutely.

Zach Klaassen: Some of that shared decision making that'll come in as well.

Matt Cooperberg: For sure. For sure. This is going to be very much individualized, and even now we add to the, who's going to get relugolix instead of an injection and all. So now this old-fashioned like, "Hey, we're just going to start ADT," now, this in and of itself is a-

Zach Klaassen: Absolutely.

Matt Cooperberg: ... six combination nuanced kind of discussion, which is good. It keeps it interesting.

Zach Klaassen: Sure. And I think the patients are going to, like you said, the paper's out, they're going to be reading about it, and I think we're going to have to start to think about these conversations.

Matt Cooperberg: No, absolutely.

Zach Klaassen: Thanks so much for your time.

Matt Cooperberg: Yeah, of course.

Zach Klaassen: I know people enjoyed it.

Matt Cooperberg: Always a pleasure.

Zach Klaassen: Thanks.