Alicia Morgans: Hi I'm so excited to be here at AUA 2022, where I have the opportunity to speak with Dr. Ashley Ross. We really wanted to talk today about adjuvant treatment for prostate cancer. How we think about people in the unfavorable, intermediate, and high risk setting who might need additional therapy. We just don't know the answer yet. Can you talk a little bit about the space and what's been going on in terms of adjuvant treatment and trials in the past?

Ashley Ross: Of course. And thank you for having me. So in recent years, as we've been doing surveillance for men that have lower risk disease and favorable intermediate risk disease even, the people that we take to the operating room tend to have a higher risk disease space. Some of it also may be a function of the way screening has gone. But regardless, a lot of our men at the end of prostatectomy will have adverse pathologic features. Some of them will also have other indicators that their disease might progress, have higher grade disease. As we mentioned, extra prostatic extension, some [inaudible 00:00:57] involvement. Traditionally, we had a decision of how we wanted to then intensify their therapy. We could watch them until their PSA rose. We could give them an adjuvant therapy, meaning before their PSA rises with radiation, with or without hormonal therapy in those settings.

Even more recently, we've had more tools to predict who's at highest risk of metastatic progression. One of those tools is the Decipher score, which is the genomic classifier score that was originally developed to look at metastatic progression risk and men at high Decipher scores are at higher risk of metastatic progression. And so you have some question of, if we treat these men more intensively early, is that going to benefit them long term and put them into a deeper remission? And in the more advanced stages of prostate cancer, N1 disease, metastatic disease up front, we see that intensification early does seem to have benefit.

So the question is, when you have a very low disease burden or even a disease burden that has not yet even been measured near in the adjuvant state, is intensifying them with systemic therapy with radiation, is that going to pay dividends in the long term? Or is it just exposing men to more toxicity and the number needed to treat being higher? And so there've been some studies mostly focused around radiation in this area. And then more recently, there's been the opening of studies like ERADICATE, which is a large consortium study that look at, what if we think about the benefit of intensifying with affecting the antigen axis?

Alicia Morgans: Absolutely. And to one of your very important points, I think the previous adjuvant trials have really used clinical features to identify the highest risk population. And I don't think they necessarily were able to successfully identify the highest risk or those that might benefit from systemic treatment or even radiation in some cases. But Decipher is different and actually is incorporated within ERADICATE.

Ashley Ross: I think, as you pointed out, the adjuvant trials not only didn't have as much tools to gauge risk for these men, but also in the previous trials there's always some selection bias, which is difficult to get away from on who goes on study. And to a larger extent, you had people going on study when they were comparing adjuvant to early salvage that had a slightly lower risk stint, I think, in my mind. And now that we understand that, in the appropriately selected patient, more could be better. And you're not really over treating.

I think that using these tools like Decipher to see who's at highest risk for metastatic progression emboldens us to put those people on study. But more so, you can have entry criteria that are tailored for that. So for ERADICATE, either by CAPRA and then Decipher, or on the function of having bad pathology. Those are the mens that are ending entering ERADICATE. And that study obviously is an advent study. So before the PSA rises where you're using darolutamide plus androgen deprivation therapy for 12 months for these men. And you can add radiation, you cannot, to see if that extends their metastasis free survival versus ADT alone at this point.

Alicia Morgans: Absolutely. And really, the entry criteria are that patients have to have undergone a prostatectomy. They can't have low risk disease. So we're identifying them as having higher than low risk disease by having a CAPRA-S greater than or equal to three. And then patients can get the Decipher test on trial, which I think is really nice. They could get it through standard of care as well, but they also can get it free through the trial. And as long as the Decipher score is greater than 0.6, which is identifying that high risk population, they can enter in the trial. So really hoping to capture that highest risk group.

Ashley Ross: Yeah. And as you've kind of mentioned, I mean, I don't want to forget about the people in between the unfavorable, intermediate, and whatnot, because almost everybody we operate on nowadays ends up having a CAPRA-S score of over three. And I've always been surprised in my practice at who has progression. I mean, there's some people you absolutely know. But in that intermediate space where they have some 437 and there's T3A, the margin is negative. I often have been surprised when six months later, a year later, the PSA is rising to over 0.2. And I wonder, well, maybe we could have done more early. And so the Deciphers help engage that risk. And ERADICATE is giving a venue to study, well, should we do more early? And how much more should we do? And how does that benefit [inaudible 00:05:23] free survival?

Alicia Morgans: Well, to that point, 40% of the unfavorable risk population has a Decipher greater than 0.6. And also importantly, if patients have an ultrasensitive PSA performed, as long as it's less than 0.2, they're actually still eligible for the trial.

Ashley Ross: Trial. And that's a great point. We've talked away from this discussion that, for a lot of men, their first step into their treatment is a very hard step for them. And they want to believe in you as their provider, want to believe that the first step could be the last step/. And for some of them, and even for me as a provider, I use a lot of alternative PSA. If the PSA is less than 0.01, I often feel great that there isn't disease there. Now, that might be a little bit of a fallacy, but there's some data suggests that's maybe the case. But as it rises in that ultrasensitive setting, 0.03, 0.04, I do get a lot of concern. And for the men too, I tell them we have to take that very seriously. And that's a time to intensify.

Now, at the same point, I've certainly had men that are below 0.01 for the first half year, year, and then have recurred. And potentially, although time will tell, the Decipher can identify who's in that bucket that would've inevitably recurred that we should have treated more aggressively. So I think for those participating centers, and there's many that participate with ERADICATE, that's an important criteria to know. And having the trial kind of understanding some people use ultrasensitive, some people don't, we don't fully understand what's going on in the ultrasensitive range, is good because it basically widens the amount of eligible men.

Alicia Morgans: Absolutely. So just as a final point, can you walk everybody through exactly how Decipher works? I think it's helpful to understand that.

Ashley Ross: Great. So, maybe a decade or so ago it was understood that you could take routinely collected formal and fixed paraffin embedded tissue, like when we do a biopsy, like when we do a radical prostatectomy. And you could extract RNA from that and then array that RNA. And Decipher particularly is [inaudible 00:07:28] array. It actually raised the whole genome. And then you can look at different locked signatures on the genome. And so for Decipher, it's actually the name of the platform. The score that we've been talking about is the genomic classifier score that goes from zero to one when it outputs. And it looks at about 22 genes, RNA transcripts, that have been linked in multiple studies, now over 30,000 men, with many risks that are hard endpoints for prostate cancer. The one that's most robustly been studied has been metastatic free survival, which was where it was first validated on. But now even prostate cancer specific survival, et cetera.

Now, why this is particularly important for, I think, Eradicated in the clinical trial setting is not only, for this trial, not only do you benefit from understanding how Decipher works for risk prognostics and how it would work in the combination of these therapies. But beyond the Decipher genomic classifier score, as secondary analysis on the trial, the investigators can start to look at, how about other developing scores? There's a basal luminal classifier on it. There's [inaudible 00:08:30] response classifiers on it. There's things that look at radiation response on it. And so there's a huge breadth of data. And I think that's why, for you as one of the architects of the trial, you said, "Look, we want to have Decipher not only to look at risk." The Decipher is now NCCN endorsed in that setting, but also because there's so much backend knowledge we can get to better personalized medicine for our men in the future.

Alicia Morgans: Absolutely. And anything we can learn from these trials, even beyond the primary endpoint, I think, is going to be important.

Ashley Ross: Yeah.

Alicia Morgans: So thank you so much for taking the time to talk through the adjuvant setting of these patients with prostate cancer who have gone through prostatectomy as well as really helping us understand the ERADICATE trial and Decipher testing. I really appreciate your time and expertise.

Ashley Ross: Always a pleasure. Thanks so much.