Genomics Guide Treatment Decisions in Post Prostatectomy Patients - Ashley Ross

March 11, 2021

A recent systematic review assessed the clinical utility of the Decipher® genomic classifier. This genomic classifier assesses 22 genes representing multiple oncologic pathways and is independently prognostic of oncologic outcomes. During the 2021 ASCO GU Cancers Symposium, Ashley Ross, MD, PhD, highlighted this review and presented on the use of genomics to guide treatment decisions in post-prostatectomy patients. In this conversation with Alicia Morgans, MD, MPH Dr. Ross speaks about post-prostatectomy restratification and using genomic classifiers to help us make difficult treatment choices for our patients.


Ashley Ross, MD, Ph.D., Associate Professor, Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Ashley Ross, who is an Associate Professor of Urology at Northwestern University, and here to talk to us today about a presentation he's done at GU ASCO 2021 talking about post-prostatectomy restratification and using genomic classifiers to help us make those very difficult treatment choices with our patients. Thank you so much for being here, Dr. Ross.

Ashley Ross: Thank you very much, Dr. Morgans. It's really a pleasure.

Alicia Morgans: Wonderful. So, can you tell us a little bit about what you discussed in this conversation about the use of genomic classifiers first, maybe what are these and how do we actually even think about using them in patients after prostatectomy?

Ashley Ross: Thank you very much. So, genomics is the study of the expression of genes, and in terms of prostate cancer, multigene signatures based on RNA expression have started to come into clinical use, and in some practices, routine clinical use. In the post-prostatectomy space, the Decipher® genomic classifier is probably the most studied and described.

And what this is, is you take routinely collected pathological tissue, and these tests can be run on biopsy tissue, but in this case we'll talk about post-prostatectomy tissue, and it gets sent off, extracted from the formal and fixed paraffin-embedded specimens, and gene expression gets performed. In terms of the Decipher® platform, which is the one that's, again, most studied in the post-prostatectomy space, it's actually a genome-wide array, but there are different signatures that are in different stages of the validation on that. The Decipher® genomic classifier is a 22 gene signature, which covers multiple oncogenic pathways and was originally developed and validated for its prediction of metastasis.

Now, over the years, what we've seen is more than 10,000 post-prostatectomy specimens with known clinical outcomes being validated for Decipher®'s independent prognostic ability in these people. So, beyond regular clinical pathologic features, the genomic classifier can help with the prediction of mets, prostate cancer-specific mortality, and, of course, biochemical recurrence and other outcomes.

And so now the question is, how do we use this for clinical decision-making for our patients? How can this extra information, like you said, help with some of the harder decisions.

Alicia Morgans: Absolutely. I think some of the hardest decisions after prostatectomy when we see our patients are really thinking about what other treatments might these patients need as we now have them and are concerned that they are high risk based on clinical features. How do things like genomic classifiers add to that treatment choice? What are your thoughts when you're thinking about maybe an adjuvant strategy?

Ashley Ross: Yeah. So, the first big question, like you said, is like in the decision of after prostatectomy, should you be thinking about adjuvant versus maybe early salvage radiation for your men with more adverse pathologic features? And traditionally we thought about adverse pathologic features as T3 disease, so extra prosthetic extension, or seminal vesicle involvement, maybe even just a positive margin, and not in that definition of adverse pathologic features, but like higher-grade disease would give you more concern as well.

I think, first, it's just important to understand the landscape. There were three important randomized control trials that were published this year and some people could say, superficially, they solved the question of adjuvant versus early salvage radiation. So those were the RADICALS-RT trial, the GETUG-AFU 17 trial, and the RAVES trial. And they looked at should we do adjuvant or early salvage radiation for men with these adverse pathologic features?

All three of them had slightly different trial designs, but all three of them suggested that early salvage radiation was equivalent to adjuvant radiation. So, early salvage with a PSA of about 0.2 or so. But as you were alluding to, there was a deficiency to all of these trials, which is, they didn't really include men that were at higher risk, men with Gleason scores that were sums of 8 through 10, was in grade groups 4 or 5, men with seminal vesicle involvement. And then, obviously, men with lymph node involvement weren't included. So what do we do for these men?

So there has been a lot of work done, mostly in the retrospective space, looking at what really determines whether or not you're going to benefit from adjuvant radiation given a PSA is below 0.2. There's work by [inaudible] and others that showed that really it was a few independent features that really told us whether or not you're going to benefit from adjuvant radiation or not.

And those features were having T3b disease. So, seminal vesicle involvement, having pathologic lymph node involvement, having Gleason grade group 4 or 5 disease, so sums 8 to 10. And, finally, as an independent predictor with having a deciphered genomic classifier that was considered high risk, so above 0.6.

If you had only one of those features, then early salvage versus adjuvant radiation made really no difference in your outcomes, but if you had two or more of those features, then you had much better metastasis-free survival if you got adjuvant radiation, defined as radiation before the PSA was 0.2. And so that still, maybe, has to be borne out a little bit in perspective trials, but it showed that the genome classifier, as well as those other features, could help you decide, who should I be getting radiation to after prostatectomy?

There are some important clinical trials underway. One of them is, that I think, although it's really an adjuvant trial, but it looks at the hormonal piece of it, but it does allow for radiation, which is the ERADICATE study, which you're the lead on, nationally. And in this study, they're actually using the genomic classifier to pick out which men are really at the highest risk that we should give intensification for with hormonal therapy or androgen access-directed therapy.

And there, they're looking at the idea that some of these men are probably micrometastatic. We know that those people benefit from the intensification of androgen saline inhibitors. Perhaps we pull out these Decipher®-high men that also have a higher CAPRA-S score that we can then randomize them to androgen deprivation therapy for 12 months or intensified strategy for 12 months. So, that's one important place.

Alicia Morgans: Great. Well, thank you. And thank you, of course, for mentioning the ERADICATE study. I agree with you. I think that when we incorporate these genomic classifier risk strategies, we can pull out the highest risk patients, and validating that in a prospective way, and using those in clinical decision-making, is something that I think we all are aspiring to. And, hopefully, that trial will help us make those choices around systemic therapy.

And as we think about things like salvage therapy, one of the things that we do need to think about is whether or not those patients getting salvage radiation, if that's what we decide to do, should get intensification with systemic therapy at the same time. Is there a way to use genomic classification in that decision strategy point, or making point, or is this something that's still being studied? What are your thoughts on GCs in that setting?

Ashley Ross: Yeah. And so, I think, right now, that's probably the most validated and most important thing, because of a recent paper coming out that just came out by Doctors Fang, Dr. Tran, and the NRG group, which basically did an analysis of genomics and the genomic classifier score in the RTOG 9601 trial.

So, as you well know, and I think a lot of our audience know, the RTOG 9601 trial was an important trial, looking at whether or not androgen deprivation therapy, or hormonal therapy, in this case, in the form of two years of bicalutamide benefited men getting salvage radiation. Now, that study was positive, and it showed that you did have an overall survival benefit for men getting the androgen-directed therapy with their radiation, but there's a lot of caveats to that. And among those important caveats are that a recent subset analysis was published that said, "Look, a lot of people in that study had really high PSAs. Let's look at where we're really getting the overall survival benefit."

And that overall survival benefit was really seen only for the men with PSAs above 1.5 at salvage. In fact, if you had really low PSA's, like below a 0.7, the other cause mortality started to increase in those men. So, how do we make this decision about whether or not to add our hormonal therapy for our guys in that salvage space?

So, what they did was, the NRG group took 9601. In a subset of those patients, they were able to get the genomic classifier scores from. And it was about 352 of those patients, so it was a fairly significant subset, and they looked at what happened, particularly at these guys who were getting salvage at lower PSA's. So if you're going to get salvage radiation therapy, and your PSA was lower than 0.6 in that analysis, and you had a low genomic classifier score. So, a genomic classifier score that was less than 0.45.

What they found was, in that setting, there was really minimal benefit oncologically. So, minimal metastasis-free survival benefit, minimal prostate cancer-specific mortality benefit, but, very importantly, there was a large detriment to the man's overall survival. So, if you're considering salvage radiation at a low PSA, and your Decipher® genomic classifier score is low, now compared to level one evidence, we're seeing that you could be hurting the gentlemen by giving them that androgen deprivation therapy, certainly two years of bicalutamide, which was the trial.

Now, it was different if you had a high genomic classifier score. If you had a high genomic classifier score, then your metastasis-free survival prostate cancer-specific mortality, and overall mortality, were still benefited from adding that hormonal therapy. So, this is a critical finding, and, actually, I think it is bringing genomics into routine use in that setting because you're now pairing it to level one evidence from a randomized clinical trial.

Alicia Morgans: I completely agree. And I think that, for many of us, basing these decisions on PSA levels alone can be really complicated because we know that men start with all different PSA levels. They can have all kinds of responses to hormonal therapy and their PSA may be more or less tied to the aggressiveness of their disease, with sometimes more aggressive disease having even lower PSA.

So, knowing that we can use a genomic classifier that's looking molecularly at these patients, really, I think, makes me feel more confident that what I'm looking at is the biology in a little bit more of a specific and directed way than something as, I guess, less tied like the PSA. So, really, really interesting.

Ashley Ross: I agree. And I think that this is one use that's already now getting kind of firmed up, but they have plans. My understanding that genomic classifier Decipher® people in collaboration with NRG and others have plans to also profile the RTOG 0534 trial, which is also looking at androgen deprivation therapy with salvage radiation in earlier space with or without pelvic radiation.

And they're also partnering to look at trial results of intensification for people with high PSAs. My understanding is, for some of the salvage enza trials, for example, they're going to look in that setting too. So I think there's more to come. And I often think about breast cancer and where they are in using their multigene genetic signatures to help guide decision-making about chemotherapy or not, or intoxication or not, and I'm glad that prostate cancer is really catching up quickly.

Alicia Morgans: I 100% agree. So if you had to give an overarching message to folks who were thinking about these genomic classifiers in this space, what would that message be?

Ashley Ross: I think it's that the Decipher® genomic classifiers test is now kind of a primetime test. It's easy to get, it's very accessible, covered by many insurers, covered by Medicare, and in the setting of salvage decision-making for salvage radiation, I think it's now become a must test in my practice in that setting.

I think there's still work to do for restratification and you can use it to help with that in the adjuvant setting, but particularly in the salvage radiation decision-making, it's a test that deserves strong consideration for use, and I think we're going to see that reflected in guideline statements that build upon the recently published work.

Alicia Morgans: Great. Well, thank you so much for walking us through this, because I think it can be really complex when people are just trying to get into using the Decipher®-type platform or other risk classification systems. This one, as you said, really seems to be the one that's most heavily tested and really seems to be the one that is most clearly linked to these post-prostatectomy decisions, which are so critical to our patients. So, thank you for taking the time to walk us through this.

Ashley Ross: It was my pleasure, Dr. Morgans, and thank you very much for having me in to have me talk about this important work.