Ashley Ross: Hi, I'm Ashley Ross speaking for UroToday. I'm a urologist at Northwestern at the AUA 2022. This year. We had some interesting discussions around the use of decipher in unfavorable, intermediate risk, prostate cancer. Genomics has played a larger role in our practices as urologists. Particularly at initial diagnosis. For a while, we were using its prognostic ability to help guide us on decisions regarding active surveillance or active treatment for men with localized prostate cancer, mostly in the low and favorable intermediate risk space.  They published some retrospective, an analysis of prospective randomized data in the RTOG 0126 trial. And this was with intermediate risk patients getting radiation for their prostate cancer. Many of which were unfavorable, intermediate risk patients. And they showed that you could use a genomic classifier to stratify those patients into low risk or into high risk categories. And by that stratification determine whether or not they would have benefit from adding androgen deprivation therapy to their treatment. In those studies men without androgen deprivation therapy, who were genomic high risk had metastasis rates of about 20%.

And that was about fivefold more than those that had low risk disease, indicating that for some men with low risk disease, androgen deprivation therapy could be omitted. There's an ongoing prospective NRG trial called guidance, which is testing this in a prospective fashion. And right now many of us, including myself, are using genomics in our practices to help guide decisions about utilization of androgen deprivation therapy with radiation, for unfavorable, intermediate risk patients. Following this, we'll see a discussion with me and a few of the urologists out in academic and community practices and talk about their use of genomics in unfavorable, continuous prostate cancer for decision making. Thank you.

Hi, this is Dr. Ashley Ross. I'm a urologist at Northwestern Medicine. I'm delighted to be here today with Dr. Jason Hafron and Dr. Katie Murray. Dr. Hafron's from the Michigan Institute of Urology and Dr. Murray is from the University of Missouri. We're going to talk today about the treatment of unfavorable, intermediate risk prostate cancer. And for the men with those disease, how we can use some new tools like genomics to help understand how we should intensify or potentially deintensify their treatment, particularly in the radiation space. Dr. Hafron, Dr. Murray, pleasure to be here with you today. And I'll start the discussion off by saying for you, Dr. Hafron, for our men with intermediate risk prostate cancer, they're broken into two categories, favorable intermediate risk unfavorable, intermediate risk, at least by the NCCN and AUA. Can you talk about that discrimination?

Jason Hafron: Yeah, I mean, if you look at the intermediate risk group, it's the most heterogeneous group of all of our risk groups. We have favorable and unfavorable, but if you think about the treatments of how we treat these patients, we have the opportunity to do active surveillance all the way up to ADT plus RT. So there's a widespread of options. So it's a very much more, I think, much more heterogeneous group than the, our low risk or very low risk group, because there's less options or less variability to treat these patients. So if you look at the favorable risk group, as you know, what we all know based on NCCN guidelines, you know there's options for therapy there. And then if you look at the unfavorable risk, based on NCC and biopsy scores. Four plus three, typically grade group three, that typically is how we categorize them is based on their biopsy and PSA scores.

Ashley Ross: And Dr. Murray for the... Let's focus now on the unfavorable intermediate risk category and say that men have greater than 10 years to live. And you're thinking about treatment. And again, these are men with Dr. Hafron just said, Gleason grade group three disease and above PSA greater than 10, for example, are there other ways that they can be risk stratified?

Katie Murray: Yeah, I think that's a great point. Right? So like he just mentioned, there's so much heterogeneity across intermediate risk, but even if we narrow it down to the unfavorable, intermediate risk. Right? So how do we determine that person who is going to be an actor like the high risk people, who's going to act closer to that favorable risk categorization, because like you said, it's four plus threes, it's a PSA greater than 10. And so it's across the board. So we do have opportunities now and it has come up in the guidelines as well for genomic classifiers that help us determine so that we determine how to categorize those patients and intensify, or potentially deintensify a treatment and also show those numbers to the patient. Right? Where do you fall in this spectrum from low risk to high risk? And so I think genomic classifiers are here to stay, especially fit a gap in this unfavorable, intermediate risk categorization

Ashley Ross: And Dr. Hafron, for genomic classifiers in general or genomics, can you speak a little bit towards what that means? Some urologists have not started using them? Maybe enlighten us on what those are and maybe a little bit about how you use them in your practice.

Jason Hafron: Yeah. So there's a couple of different products or classifiers on the market. I'll start with Decipher, which is a 22 gene genomic classifier that involves seven different cancer pathways. It's typically can be obtained off of the biopsy. And it's essentially a whole transcript zone of results that predicts likelihood of progression. And it classifies the patients into intermediate, medium risk or high risk. So in our practice, we've over the years become very comfortable using these genomic classifiers in the active surveillance space. And I'm in Michigan. I'm part of the music collaborative. And one of the requirements or variables that we measure in music as well as in our practice is if a patient meets criteria for active surveillance, we recommend and monitor that those patients have a genomic classifier or a multiparametric MRI within six months.

So it's pretty rare that we put patients on active surveillance without one of those. Now we, I think as urologists, we have to expand and revisit this intermediate space because it is, like I just said earlier, a very heterogeneous space with a lot of questions on how to appropriately manage these patients, where we never really had good data to support it. It was kind of like a shotgun approach. What these genomic classifiers, specifically Decipher give us, is exactly that precision medicine on how much therapy to apply to these patients, how intense the therapy should be. Do we need ADT? How long do we need the ADT questions? We challenge ourself every day in the clinic, but never really had good information or good tools to make those decisions.

Ashley Ross: That's excellent review. And for Dr. Murray, just like Dr. Hafron was saying, for our unfavorable, intermediate risk patients that have greater than 10 year survival, for surgery we don't usually modify what we do that much. But with radiation, if you go that route for the patient, now they have different choices they have to make that are somewhat risk dependent. Do you do the radiation with, or without androgen deprivation therapy for some period of time? Can you talk a little bit about how you make that decision in your practice? At least up to the point of recently, how have you been making that decision?

Katie Murray: Yeah. So I think we've had our routine standard of care. Right? So these patients are our patients as urologists. Right? You've seen them. You saw them with the PSA. You did the biopsy. They're coming back to talk to us about their results. Right? What do I do from here, doctor, is kind of their scenario. You talk to them about surgery option. You talk to them about radiation option. Right? If they're leaning towards radiation, you're going to refer them to one of your radiation oncology colleagues. And that may be in a multidisciplinary clinic that you do that, or on the outskirts. No matter how it happens. But, again, this is our patient. And so we're kind of setting that up for, what do we think that intensification or do we think they're going to need ADT?

How long is it going to last? And a lot of practices, the urologists continue to own the ADT portion of it while the radiation is proceeding with radiation therapy. So, routinely that's been four to six months of ADT for those patients. And that's been kind of across the board. It's the best that we've got and that's what we were doing. But hey, maybe there's a group of patients that don't need that ADT and that impact on their quality of life without that. And I think that's where this genomic classifier can come in. And that's what we've seen now recently in some retrospective is that may absolutely be the case.

Ashley Ross: Yeah. And so maybe to stick to that, to that point a little bit as you were mentioning the clinical trials that showed oncological benefit for addition of hormonal therapy with radiation in the mostly unfavorable, intermediate risk men. The benefit was there. It was statistically significant. The absolute risk reduction in metastasis and death was however small. And in some cases you wonder, is it clinically significant and should be using it as all comers approach? And like you're saying, probably not. At GUASCO, this past few months, they presented results of the 0126 trial. Studied from the prism of genomics. So they looked at that trial was one where nobody had hormonal therapy. They were all getting radiation for their intermediate risk prostate cancers. And they look to see, were there people in the setting of unfavorable, intermediate risk who did better or worse based on their genomics? And maybe Dr. Hafron, you can just walk us through. What were their findings? Yeah.

Jason Hafron: So RTOG 0126, the value of the trial was not the results of the trial. It was that subset analysis that they did. 0126 was looking at radiation intensification, adding nine gray five extra sessions. Does that make a difference going to 79 gray in this patient population? It's kind of a moot point. The trial took 15-20 years. Now everyone's getting pretty much 79 gray. The trial didn't show any benefit to overall survival. But the interesting, cool thing about the trial is that they had tissue available and they ran tissue, it was 110 patients in each arm to look at. Does a genomic classifier like Decipher impact the prognosis of these patients. And also does it affect the appropriate therapy that should be applied? And what we found is that when you look at the patients outside of their NCCN risk categories and look at them based on their Decipher scores, that it is predictive in all major end points.

Okay. So we have validated Decipher in intermediate risk, but what's also very interesting is that there was differential responses based on their Decipher score. So even though we said in the initial trial, that there was no benefit to radiation intensification, but when you separate it and you look at it based on Decipher score, we do see differences in outcomes. Okay. Exploratory, not the end point of the trial, but very thought provoking and foundational for urologists in the community is that this is laying the groundwork for using genomic classifiers to determine how best to treat the patient also what I, what I see, and I'm sure you would agree with this is that we see the limitations of our NCCN categories. The NCCN categories are good, but adding a genomic classifier is better.

Ashley Ross: When I looked at that data, what I saw was, if you were unfavorable to be at risk and you had a high decipher score and you got radiation alone, your chance of metastasis in 10 years was about 16%. If you got radiation alone and you were Decipher a low risk, it was about 4%. And so that built on some other data that came out of the princess Margaret, where they were radiating also without ADT for these men. And they similarly were seeing most of the bad events happening in the genomically high risk folks. So Dr. Murray, with that building data, has this made it into your practice now, or are you waiting for more data for these unfavorable, intermediate risk men to use the genomics to stratify what you do with them?

Katie Murray: Yeah, I think that's a great question. And the answer is yes. In a simple terms, it has made its way into my own practice. And part of that is in collaboration with my radiation partners, because, if I'm seeing the patient up front and I did the biopsy, I can send that score off right then and there. Even if we're going to proceed down a surgery route. That score can still be impactful to us for making decisions, as you noted. It's not going to necessarily change anything from a surgical standpoint, but it also gives some numbers.

And it helps that patient classify that, do I fall in the high? Do I fall in the low? Where am I in this grand schema of things? And so absolutely, for a majority of the patients, I kind of think that middle ground, I'm getting Decipher scores on for the patient's benefit. And now hopefully for our benefit and the benefit of my colleagues in radiation to help them then educate. Can we do less? Do we need to do more? And this is just the very beginning of this. Right? It's going to continue with intensification de intensification. Right? The way I treat patient X, it could potentially be very different than patient Y and guess what? They're both absolutely in that unfavorable, intermediate risk prostate cancer category.

Ashley Ross: Yeah. It definitely gives you another tool for personalization. And we didn't talk about this much, but obviously you're taking into account patient age, frailty, other things as well. And I think you were hinting at it there. Even the 0126 analysis, even though it was an analysis of a phase three trial, it was a retrospective analysis. And as you're hinting, this data's just going to become sharper and sharper. Dr. Hafron, they're just starting to launch at some sites, the energy trial called Guidance, which is around the unfavorable, intermediate risk group and looks at genomics. Can you just speak to that a little bit and what the design of that trial is?

Jason Hafron: Yeah, it's a very exciting trial and it's kind of like a picture of the future of what urology's going to be. The trial is basically looking at intermediate risk prostate cancer, and then using a genomic classifier Decipher to randomize the patients. So depending on their Decipher score in Guidance, if they're below 0.45, they're considered low risk. If they're above 0.45, they're considered high risk. And then it's like a two by two forearm trial. If the patients who are below 0.46 will have RT plus or minus six months of ADT. So that's that low risk patient population. And then in the high risk patient population, they're going to get RT. Plus six months of ADT is one arm. And then that fourth arm, which is very exciting, is going to be RT ADT plus darolutamide.

So we are covering this massive spectrum from RT all the way to ADT plus novel hormone, all based on a Decipher score. So I think as a community urologist, we have to start thinking about these scores because we know as this data accumulates, that's going to probably, we don't know for sure, but be the basis for the treatment decisions on how we manage these patients. So very cool trials. And this is just one of a few that are coming down the pipe.

Ashley Ross: So thank you both. This was a great review. I think that the theme is that we have these tools that have been validated as prognostic of outcomes. And they help us to personalize medicine in our men. We're seeing growing evidence, that's maybe allowing us integrated into our practice now, like you, Dr. Murray, I use it in my practice. Now that way, just like you said, Dr. Hafron and these other trials, whichever way Guidance turns out, it's likely that the same things that you do in music where you say, well, for active surveillance, they have to have a genomic score to help us understand, should we be intensifying therapy, or maybe having them on surveillance? The same kind of criteria might apply to a lot of our unfavorable, intermediate patients in the future.

Thanks for walking in the audience and walking me through this discussion. It was really a delight to have both of you, and hopefully this will benefit both providers out there and our patients.

Katie Murray: Thank you.

Jason Hafron: Thank you.