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Ashley Ross: Hi, everyone. This is Ashley Ross. I'm a professor of Urology at Northwestern Feinberg School of Medicine. I'm accompanied by a good friend and colleague, Dr. David Morris, who's at Urology Associates in Nashville, Tennessee. Recently at ESMO, we saw some presentations regarding Decipher, which is the genomic test for prostate cancer.

And specifically how it might play into the decision-making regarding advanced disease, metastatic prostate cancer in particular. And this builds on some data that was shown at ESMO 2022. So we thought it'd be a nice opportunity to talk about how providers like Dr. Morris and myself look at hormone-sensitive metastatic prostate cancer, particularly at initial presentation.

And how we make decisions about therapeutics for those patients and how intense therapy should be. And then also look at what's going on at the community level in recent updates. Like how many people are using hormonal therapy by itself, or doublet or triplet therapy, et cetera? So we'll launch into this first with Dr. Morris talking a little bit about hormone-sensitive metastatic prostate cancer and the landscape.

And then we'll review some of that data from ESMO, and then maybe have a little bit of an open discussion between David and myself.

David Morris: Thanks, Ash, for having me on. I appreciate the opportunity to talk about this next frontier for some of our genomic classifiers and our mRNA-based tissue testing. It's a new space in terms of risk stratification for metastatic disease. So we're going to dive into what we're currently using in terms of risk stratification for metastatic diseases, specifically the metastatic hormone-sensitive setting.

These are the AUA guidelines I'm sharing here in terms of things that should or should not be done for patients presenting with metastatic disease. And I think most people are striving to get to this, but the reality that we'll touch on in a minute is that we're a long way from ideal. And there may be some further technology that might help us appropriately put people in higher risk categories so that then we intensify their therapy with combinations.

But combination therapy has become the mainstay for metastatic hormone-sensitive disease, whether it's de novo or it's recurrent. Other terms that are used are synchronous and metachronous depending on which literature you're looking at. But in general, we as clinicians should be striving to at least offer the majority of patients combination therapy with ADT when they have metastatic disease.

And you can see on these guidelines that are shown, that we shouldn't really be using first-generation anti-androgens. We shouldn't really be using agonists alone, unless we're at least offering the combination therapies with AR agents. So this was a recent publication and there's now multiple datasets across the oncology world, the medical oncology world, the urology-specific world in terms of what are we actually doing for metastatic patients?

And this is an interesting dataset because it includes not just the US but other marketplaces that have different accessibilities. The US, we think we have access to basically every therapy that's available, and that's a nice thing. You can see that there's differences across cultural regions. But the real call to arms here is the large blue bar that is the ADT monotherapy, or the light blue, which is the first-generation anti-androgen plus the ADT.

That are in the US, at least, still a majority of patients, and this is a relatively recent dataset. So the argument has always been, "Oh, that's data from five or six years ago, and it's going to get so much better as we let this disperse through the community." But in reality, we've reached a plateau of uptake, and we really need to shrink the bars that should be the less ideal therapies.

And really grow the combination arms, which are the green, the orange, and the red. You can see here that part of the risk stratification, probably the hesitancy from some providers to use combination and really intensify the treatment, is the benefit has been historically seen largely in high-volume disease. The low-volume disease may have more of a mixed bag response to therapy, and many of them do well.

So it's hard to sometimes argue about the additional benefit of expensive therapies or therapies that may have toxicity on top of just simple ADT. You can see here on the left side the graph of the different disease groups, the synchronous or metachronous, which is basically de novo or recurrent. And then high and low volume, which has always conventionally been done with conventional bone scan and CT.

And you can see here, median overall survival on ADT alone is drastically different depending on which risk group you're in. They are all metastatic hormone-sensitive patients, but it's drastically different if you're a recurrent patient with only one or two METs years after you've had primary therapy, versus somebody walking in with de novo, high-volume disease that's either visceral or multiple bony lesions.

So really what we need to do is what's on the right. We need to say this is the NCCN layout: high-volume synchronous disease, we really need to intensify. We're potentially down in low-volume metachronous disease, we're looking at maybe that's something where we intensify. But there may be some patients where the risk of the therapy may outweigh some of the potential benefits, if their median overall survival is eight years with monotherapy alone.

So that's the new frontier that I think some of this data that Ross is going to go over with us really can help.

Ashley Ross: Thank you for that. The idea is, and maybe this will change practice patterns, but the idea is that, like, well, some of us may need to have more tools to risk stratify patients to see who's going to benefit, like you said, from often beneficial but sometimes toxic additional therapy, and certainly financially toxic therapies. When we talk together, we'll get into some of the sense of why maybe there may be barriers for that.

And as I mentioned, at ESMO, a lot was presented around the Decipher Genomic Classifier and how it might be able to be used in these advanced states. A lot of us, as urologists and other radiation oncologists and med oncs, may already be familiar with Decipher. It's a genomic test that, at least in the clinical use right now, primarily reports a signature, which is based on about 22 transcripts.

And has been heavily validated across many studies to be prognostic for outcomes. And it can guide decisions like for a low-grade prostate cancer, should we survey it or not? For an intermediate-risk disease, should we add ADT? For high-risk disease, how long should that hormonal therapy be? But it has been evaluated in the metastatic setting as well. There's been some recent reports from the STAMPEDE investigators around the Decipher led by Dr. Attard and others, that are pretty provocative.

First ESMO a couple years ago, Dr. Parry presented on behalf of the STAMPEDE investigators, and they looked at STAMPEDE Arm G, which was a randomization to abiraterone or not, in addition to androgen deprivation therapy. And they looked there at two different cohorts. One was patients that had very high-risk, localized, or N as in Nancy, lymph node metastasis disease but not metastatic disease, and then people who had metastatic disease.

And these curves, the green and the red, are broken across the median Decipher, which was about 0.77 in these studies. So what they were seeing is for localized disease or lymph node-positive disease, among the people with lower Decipher, so lower than that 0.77, the absolute benefit of adding abiraterone for a couple of years with their radiation was mild.

Whereas if you had a higher Decipher, even in that setting of localized disease or locally advanced disease, you were getting some benefit in metastasis-free survival. For metastatic disease, the Decipher genomic test again is stratifying the risk and the benefit. But the investigators made the point then and again in the last ESMO Conference, that because there's benefit across all the ranges and the stakes are higher, there's almost no Decipher score that would make you want to omit adding a second agent. Like you may have mentioned, ADT plus abiraterone in this metastatic population, at least in general.

And this shows this: on the right is your N1 or very high-risk N0, M0 patients. And you can tell if the Decipher is low, which is the green scores or lower, I should say, there's not much absolute benefit from adding abiraterone.

If you look on the left-hand side, the Decipher low, you do get an over 10% benefit in overall survival by adding the abiraterone as you go towards six years and more. Obviously, the benefit's even greater if the Decipher's high, which is the red parts. They actually this year at ESMO, they analyzed also STAMPEDE Arm C, and that was the ADT plus or minus docetaxel.

And Dr. Grist presented for the STAMPEDE investigators, and looked at Decipher and some other signatures as well that are available on the Decipher platform and how it predicts sensitivity to docetaxel. And what they saw is if the patients are Decipher high, like in the top quartile, Decipher is above 0.8, they get a benefit from adding the docetaxel.

They're sensitive to the docetaxel almost as a predictive signature of sensitivity. Decipher low, you're not seeing any benefit; the hazard ratio is like 0.96, and that was true in high or low-volume metastatic disease. So where this plays a role, and we're going to go just into the discussion, is also what we just touched on is you had the early trials. And the AUA calls them out that are showing Level 1 evidence for adding ADT plus abiraterone, enzalutamide, apalutamide.

But then you have more recent trials where you're looking at triplet therapy, so like the PEACE-1 type, ADT plus abiraterone plus docetaxel. Or the ARASENS trial, ADT plus darolutamide plus docetaxel. And some of this Decipher data can play into what are our thoughts about adding the docetaxel? So just to step back and then I'll start the discussion.

The new thing again for our audience is that for me, at least, I'm used to using Decipher from diagnosis of Stage 1, Grade 1 disease, all the way through my locally advanced, maybe occasionally a lymph node-positive disease. But this is new in terms of showing at least in this retrospective analysis of a large Phase 3 trial, Level 1B evidence that Decipher seems to have really good utility in stratifying people in the metastatic setting.

I'll take it back a little bit more and I'll first start out and I'll say, how do you use Decipher in your practice right now, David? And then if you were going to use it across the setting, how would you implement this new data in your decisions for metastatic hormone-sensitive prostate cancer?

David Morris: So I think you touched nicely on risk stratification for localized disease is a very different answer, a different question. I think the active surveillance ship has sailed for many low-grade tumors. We don't need validation that they're candidates for active surveillance. We've been doing it for years. But for a borderline case that's low risk, it certainly can help push a patient one way or the other.

For the intermediate risk, it's been very helpful in trying to intensify with ADT or not, especially in the setting of radiation. For the higher risk, we're generally getting more aggressive with those patients upfront, and so it may tell you this is someone who maybe we could avoid being as aggressive with the standard patient. So that's how I've been using it currently.

I do recognize with more and more data like this, the mRNA signatures like Decipher are probably going to play a role, part of our upfront somatic testing and germline testing, looking at how do we risk stratify these metastatic patients for doublet combinations, triplet combinations, combinations that include other DNA-targeted mechanisms?

There's so many other combinations coming, and we're going to need things that can help us pick out other than just they're young, they have visceral disease. They have really high-volume disease or they're low volume, because all low volumes don't all act the same either. All high volumes are not super aggressive.

So these definitions that we've inherited from CHAARTED that are just based on technetium bone scans, I hope honestly we can move away from. Because that technology is slowly going away and being replaced with PSMA and targeted imaging. And with that, we're backtracking to then say, "All right. We need to get conventional imaging to figure out which volume group they're in."

Ashley Ross: Yeah.

David Morris: It would be simpler to have some sort of signature that could say, "I don't care what volume group they're in, they're going to act high risk or they're going to act low risk."

Ashley Ross: Yeah, and I think a couple of important points you made to expand on. With the Decipher test, when it showed a high Decipher, it really had sensitivity for docetaxel in whichever setting, low volume, high volume. There are also layered-on genomic signatures that the investigators showed that are also in a separate platform, like the Luminal Bs were shown in CHAARTED and in the folks from STAMPEDE to be more sensitive.

You sometimes wonder if I had high-volume disease that had a high Decipher, I'm really going to go towards triplet therapy. Even low-volume disease, high Decipher, I'm going to go towards triplet therapy. If I had high-volume disease and the Decipher was a little bit lower, maybe that's someone that I got to think about a clinical trial because there's still people that fail triplet therapy.

And like you mentioned, maybe that's someone that if there's a trial with a radioligand therapy or something else, I have to think, "Well, what can move the needle on that patient?" You also brought up a little bit of PET-PSMA. And I'll tell you one way that I would use this data is, as you mentioned, the guidelines state and there's good evidence that your go-to should be doublet therapy.

And when we say doublet therapy, you and I obviously are meaning some kind of androgen receptor signaling blocker, Abi, Enza, what have you, and androgen deprivation therapy. Even in the person who has low-volume, metachronous progression after local therapy, now we're using a lot of PET-PSMA, so it's a little bit of a different landscape. And there's always a wonder of do they need that sort of therapy?

And do they need it for a long duration when I'm doing stereotactic radiation or whatnot to someone who's that metachronous, PET-PSMA-only guy? And I think the Decipher is going to help me a lot there too. If I have a low Decipher, particularly if it's well under 0.8, like it's 0.6 or 0.5, I have to think in a lot of candidates I might omit the doublet.

And that might be—I don't want to encourage that because we've already seen that there's only about... Instead of it being it should be flipped in the curves you showed, but there may be these opportunities to just use ADT alone. And similarly, for my older men that have low Deciphers, that I have over 75 and I'm really worried about frailty, there may be a use for ADT alone.

So I'll get your thoughts on that and also why you think the curve is not flipped. It should be like 80% of our guys can't use the doublet, and it seems like it's almost the other way around.

David Morris: I would say, so two questions. The first is if you don't want to go to monotherapy, I think there's a real whole push as a field to use intense, upfront therapy and then back off therapy. So we do a lot of that in clinical practice. I have to explain to people, "It's not really in the guidelines, but there's a lot of trials looking at induction phases of doublet and then sticking with a monotherapy."

So that's an easier transition than just monotherapy, but I agree with you. There's people that we probably don't need to keep on medicine. If your median survival is eight years with monotherapy, that's eight years that you've been on combination therapy where you maybe didn't need to be on eight years of AR agent along with it.

So that's my answer to that one, is there's probably a subset where we back off some of the therapy. And then it's hard to know where the field is going to move in the future with this. But I do agree that the trials are going to push us to really try to have signatures that help identify people that are more likely to benefit from one thing or more likely to get harmed. And frail men is an example.

I think that's part of the hesitancy from a lot of people to move from monotherapy to doublet combinations, is just they come in and their PSA has done well. Why would I then intensify therapy? So it's multiple steps. It's involving a specialty pharmacy. It's the out-of-pocket costs that were a huge concern a few years ago that are getting better.

It's even in oncology literature, their usage is not perfect. So it's not like medical oncologists use 90% doublet and urologists use 20% doublet. In reality, all of us in smaller communities, it's hard to have the expertise in areas where these patients live, to be able to get them combination therapy that does take a certain bit of nuance to manage. So it's not an easy thing to just write the drug and go down to the local pharmacy and pick it up.

Ashley Ross: I think that another, there's a couple of points. One is one of the things that's hardest for me to think about when I see my patients, particularly the person who, like you mentioned, from the CHAARTED definitions, they were good but had some arbitrariness to them. Who do I want to send to triplet versus who do I want to send for doublet? Triplet meaning adding docetaxel.

Particularly as the men get a little bit older, as you explained it before, a young guy, I'm like, "Let's just hit him with everything." That's a big place where I see Decipher guiding the decision that if they're not going to be sensitive to the docetaxel, the Decipher's less than 0.8 or out of that highest quartile, I'm not going to really push that.

Whereas if the Decipher is up in that highest quartile, it was quite dramatic response that we were seeing from that analysis from ESMO, and I would say, "Well, that's going to push me towards the chemo." The other point that you were saying is I wonder in a lot of urban areas and things like this or places that they have lots of expertise like where you are, where I am, that decisions between singlet and doublet.

And I wonder, like we were talking about implementation of doublet, is it cost? What is it for these patients? And a lot of these are oral therapies. They do have costs. There has been some reform acts that are going to take place soon that are going to decrease catastrophic coverage. But I've had some providers tell me, "Well, I just want to give my six cycles of docetaxel because the patient will be compliant."

And the cost is going to be less for that older population if they think they can take it. That's the other thing that's been shown is for the abiraterone, if there was benefit from metastatic disease, even if your Decipher was lower, adding the abiraterone or another oral, there's benefit. But for the docetaxel, the benefit was really only there if the Decipher was high.

So if you had a guy who the Decipher is not really high, but they have metastatic disease and you're thinking between a doublet, which this has actually fallen out of the guidelines somewhat of ADT plus docetaxel, or ADT plus some oral agents, it should be pushing you to ADT and the oral agents. And similarly, and we mentioned some of the STAMPEDE Arm G data, I'm using the high Deciphers with my lymph node-positive after surgery.

My oligoprogressive, if Decipher is high like 0.8 and above, I'm really pushing them to say you need doublet therapy upfront. But anyways, I think it's very exciting to have this kind of tool. Because as you mentioned, the next-gen sequencing now is helping us identify who could be a candidate for second line, so like PARP inhibitors and things like this.

But we really haven't had a tool to help us understand how much therapy to layer on, who we can deintensify on. And this just seems more robust than a lot of the characteristics we had before. Certainly, that whole low/high-volume designation, Gleason grade, that kind of thing. Maybe you could give us just some final words and I'll give one final word to people too, but let me get some final words from you and we'll go on.

David Morris: Sure. I think what we're talking about is really the icing on the cake. The cake is really just having a conversation about intensifying to begin with. This is the icing to figure out the small percentage that you may move one way or the other, either more intense or even slightly less intense.

But the easiest lift for everyone is just getting people on combinations with AR agents. So I don't want to miss the forest for the trees here. We want to personalize medicine, but sometimes the simplest thing is just getting people on ADT plus something else.

Ashley Ross: Yeah.

David Morris: That's the easiest.

Ashley Ross: Quite frankly, that was my major take-home too, that while this is going to help us a lot with the therapeutic decisions and Decipher is really moving into this metastatic phase, it's alarming to see that people are not on this Level 1 combination therapy evidence, and that's the absolute first step.

As a second part from my practice, I don't know if I'm pushing people towards chemo enough and talking about chemo in a positive way enough. It's like it has a different connotation. And for my Decipher high people, I'm really going to have a very low bar to push them towards triplet therapy. So always love talking to you.

I always learn something talking to you, David. Thank you so much, Dr. Morris, and thank you to UroToday for having us. And for everyone who's watching it, thanks for your attention.

David Morris: Thank you, Dr. Ross.