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Ashley Ross: So this is a patient who underwent a radical prostatectomy, about 18 months before presentation. At surgery, he had T3a disease, and he was Gleason grade group 3, 4 plus 3 equals 7. He had a positive surgical margin. Initially, his PSA was undetectable, but then it started to rise. And by the time he was presenting, his PSA was 0.21. A Decipher was gotten, and he was found to be low risk.

And as you mentioned, Dr. Spratt, a Decipher is a very validated prognostic signature. When we look at point estimates for individuals like him with adverse pathologic features, Gleason grade group 3 disease and T3a, we can see when they Decipher low risk, their overall risk of metastasis at 5 or 10 years is relatively low. Their prostate cancer mortality is low, and indeed for this gentlemen, if we look at the Decipher report and we look at men with similar characteristics to him, he's in the lower quartile of risk, for sure. And his overall risk of metastasis is relatively low at 4%.

As you mentioned earlier, there was work that I had published previously and then work that built upon that afterward, that looked at PSA level and risks of metastasis after post-prostatectomy radiation. And if you look at it stratified by Decipher score, like for this gentleman with a lower intermediate-risk Decipher score with a PSA in the 0.2 to 0.5 range, his risk of metastasis is actually relatively low at about 3%. Indeed, even when his PSA rises to above 0.5, if we look at a population basis, his risk of metastasis isn't much more.

And this brings up some provocative questions. One is if I send him to you... And I will start with you, Dr. Dal Pra, if I send him to you and say, okay, his PSA is rising. I think there should at least be a consideration of salvage or early salvage radiation therapy. How do you counsel him on two strata, he's a healthy 65-year-old with these disease characteristics. Does he need the radiation at all? And two, if he should get the salvage radiation, how intense should it be? How are you going to implement it with hormonal therapy without other treatment planning considerations?

Alan Dal Pra: Thank you, Dr. Ross. I think this is a typical case that will require a close discussion with radiation oncologists with regards to early salvage. I think I usually explain to patients that this is potentially one of the only curative options they have after prostatectomy failure. And I would offer salvage radiation, and I wouldn't wait. I think as mentioned before, the PSA is one of the most important factors for a response to radiotherapy results. At this time point, it's not only prognostic but a predictive factor for hormonal therapy responses as Dr. Spratt presented before.

So assuming that this patient has a long life expectancy, which is for a 65-year-old patient, I will offer salvage radiation to the prostate bed. He has a low-risk Decipher, as we saw before, less than 5% risk of distant metastasis. I would discuss still, the role of hormonal therapy based on these two randomized clinical trials, the RTOG 9601, and the GETUG study, but I would tend to give radiation only.

There is another question, where is the intensification with pelvic radiation treatment? This is hopefully going to be clarified in this RTOG-0534 study that is in publication. So it seems that there is an intensification, an incremental gain if you add not only hormonal therapy but [inaudible] radiation. But this patient with a low Decipher risk, I think he can be cured with salvage radiation to the prostate bed only.

Ashley Ross: Great points. And actually, so that brings us to the second case. The same sort of presentation, a guy also with T3a disease, 4 plus 3, 7, Gleason grade group 3, PSA is 0.2, 0.21. Margins were positive, and now his genomic risk was high. It was 0.79. And as we saw earlier in both of your talks, that his genomic risk really stratifies beyond the clinical pathologic features. This patient has now about a 20% risk of metastatic progression at 10 years.

And if we look at him across the different PSA strata, his risk of metastasis increases with that predictive and prognostic biomarker of PSA as well, such that even as he goes from 0.2 to 0.5, his risk went from 5% to 16%, and from 0.5 to above 0.5, it's going to be 21%. So this is actually, one question I'll start off with Dr. Spratt, then I'll go back to you, Dr. Dal Pra, is in my practice, I will say this is a prime example, these two cases, of why when I have adverse pathologic features at prostatectomy, I will order Decipher early, so I can understand the trajectory in where they are.

I will not wait until the PSA reaches 0.2. Now we have ultra-sensitive PSA's. I can even order it up front before I even get my first PSA to understand what and how I want to manage this patient. And so one question to you, Dr. Spratt is if you went over sort of the GETUG data, and also looked at the timing of adjuvant versus early salvage radiation. Is there ever a consideration... and some of those trials looked at 0.1 as their threshold. Given this patient's characteristics, when would you like to see him to maybe think about post-prostatectomy radiotherapy? If you knew his Decipher was high, would you like to see him when his PSA, before it got even to 0.21? And would you have initiated radiation therapy in that setting? And what would you do in your practice about when you should get a Decipher classifier on these patients with adverse pathology?

Daniel Spratt: Yeah, it's a great question. I think some of the most provocative, and I think it'll be when, you know, fully published data from Dr. Dal Pra from SAKK is when you look... And that's an early salvage radiation cohort, that radiation alone. You look at their high Decipher, I mean it was through the roof. Patients are just rapidly recurring, progressing to hormone therapy. And that's not even at 10 years.

And so those patients clearly, early salvage radiation of PSA's even a 0.3 with radiation alone, is inadequate. It's clearly inadequate. So there are ways to combat that, yes. I think that, although the historical definition people like to say, and I say, this is an old definition of PSA of 0.2 is a biochemical failure. I think that is context-specific. And a guy who has, you know, whether it's adverse pathology and, or a high decipher score, if that PSA on ultra-sensitive is marching up, even if it gets to 0.06, 0.07, 0.08, 0.1.

To me, it's a balance at that point, of their functional recovery from surgery. Because you do want to make sure. And so my typical practice is that if they essentially have a very, very high chance of recurrence, I would start them often on hormone therapy to make sure we buy the time, depending on when their PSA was detectable, even if it's ultra-sensitive, to buy them until they are about six months or more out. They've had some functional recovery, and I think these patients, on the 9601 data, the hormone therapy improved to me, a meaningful degree of outcomes. And I think that should be the standard for these patients.

Ashley Ross: My last question to both of you, I think that we saw the evolved data. We saw that for me, and for all of you, that the data that we are presenting shows that genomics is really part of the general practice now, at least for myself. You guys are usually seeing the patients after they are referred to you by urologists. But if in the workflow, a lot of people are getting these tests pre-op as well, will you go by those pre-op Decipher values you ordered again, or are you going off of one Decipher score having a good enough concordance that you can use it all the way through?

Alan Dal Pra: I haven't had personally, scores before and after prostatectomy. So I don't have a lot of experience with that. I'm not sure if Dan has, or what we can put with that.

Daniel Spratt: Yes, often... And Ashley, I'd like to know about your practice. But often if it's in the intact setting, I order Decipher often for, let's say, an intermediate-risk patient to help guide hormonal therapy. While the urologist thinks there may be potential, some benefit, maybe if they want to consider a favorable intermediate for surveillance, they often are not ordering a Decipher, both for, let's say an unfavorable intermediate-risk because they sort of view it as I'm taking them to surgery, either way, and then we can get the Decipher after if we are going to order it. So I would say it's not common that I see sort of a pre-op and post-op test.

I think that the studies show that probably the prognostic accuracy is even superior post-op because you've got all the pathologic information, you really know the most aggressive tumor, even if it's not the biggest. So typically post-op, and now that I've been at multiple centers, I think that all of you on the call know that I think there is a variable understanding of all the evidence. And we see now, two randomized trials to sort of profile this.

And so I think sometimes it's just sort of a multi-disciplinary education, and that I think all of us want to learn how to give better-personalized care. But there's just so much data that I think urologists are working on, whether it's a surgical technique or they are managing numerous diseases, radiation oncology, and their techniques. And so I think it really has helped to sort of figure out that pathway. And so to me, the two settings where I think Decipher is where I prefer is actually guiding the hormone therapy, is for intermediate risk. And then post-op is where I think, it has for me, added the most value in my practice with patients.

Ashley Ross: And I do the same thing that you are saying, is that I'm usually now getting preoperative Decipher because when I'm counseling the gentlemen about what their initial treatment is going to be, I want to know if it's going to be surgery versus radiation or surgery versus radiation plus hormonal therapy. And I want to sort of know where we stand. And then going into postop, we already have their Decipher score. If I don't have it post-op, if I didn't get it pre because we knew we were going to surgery, then I'll send it then. Then I usually do not send it twice. So that's great. But I thought that was a great discussion. And I always learn something listening to both of you. So thank you for walking us through that.

Daniel Spratt: Thank you guys so much again. Thank you, Dr. Ross and Dr. Dal Pra. And thank you UroToday and thanks to everybody for listening.

Alan Dal Pra: Thank you very much.

Ashley Ross: Thank you.