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Angela Jia: Hi, everyone. My name is Angela Jia. I'm a radiation oncologist. I treat genitourinary cancers at university hospitals and Case Western Reserve University. Today I have the distinct pleasure of chatting with Dr. Phuoc Tran. Hi, Dr. Tran.

Phuoc Tran: Hi, Dr. Jia. The pleasure is all mine. Thank you.

Angela Jia: And today, we're going to be discussing Decipher score as a predictor of response to treatment intensification in the RTOG 0534 SPPORT trial, which is a phase III randomized post prostatectomy salvage radiotherapy trial. Dr. Tran, can you share with us what this trial was about and how Decipher was used?

Phuoc Tran: Sure. First, I'd like to just state that I'm presenting this on behalf of Dr. Alan Pollack in a number of not only NRG investigators but staff, and I have the pleasure of being the person to not only present at GO ASCO but also to the audience here.

So as you mentioned, NRG/RTOG 0534 was a pivotal trial examining the space of biochemically recurrent prostate cancer after radical prostatectomy. It's a really common situation, as you know. Upwards of 50% of men experience this PSA rise or have persistent PSA.

We know, based on other studies, that early prostate bed radiation is an established standard of care. Unfortunately, long-term control is not optimal. It's about 60% or 70%. So 0534, the SPPORT trial, examined two key clinical questions.

As you mentioned, it's a three-arm trial with post prostate bed or prostate fossa radiation being the control arm, and then two forms of intensification were added. The first was the addition of a short course of androgen deprivation therapy, and then the third arm was the additional potential benefit of adding pelvic lymph node irradiation to this combination.

That trial, which was led by Dr. Alan Pollack, reported out a few years ago and showed incremental benefits—namely improvement in freedom from progression—but it was at a cost of increased toxicity. This space, as many people know, is highly heterogeneous, the patients that compose it.

We have done work in the NRG translational committee group to try to increase precision medicine approaches in localized prostate cancer. So we've done a lot of work with the Veracyte company and their transcriptome-based, 22-gene classifier, known as the Decipher genomic classifier (GC). And we know from that prior work that the GC is highly prognostic for metastasis in localized prostate cancer.

We were not able to see a metastasis benefit signal or MET-free survival signal in SPPORT, probably due to the low number of events that haven't matured yet and the heterogeneous population. So we hypothesized that the Decipher GC could independently not only be prognostic, perhaps predict these two forms of intensification.

So we took the available samples from that NRG trial. The original trial enrolled about 1,700 patients. We were able to get about 1,000 samples and profiled them all and got about 700—a little over 700 samples. We were able to obtain Decipher genomic classifier scores.

It was evenly distributed—approximately evenly distributed in each arm. So arm 1, which was the prostate bed radiation arm, had about 215 patients. Arm 2, which was the addition of short-term androgen deprivation therapy, was about 247 patient samples, and the last arm that included also the pelvic lymph node radiation had 247.

All the arms with this particular cohort had really well-balanced key factors, covariates. And first, the finding was on multivariable analysis: the Decipher genomic classifier was independently prognostic for freedom from progression, and that was statistically significant, with a hazard ratio of 1.10 and a statistically significant p-value.

It was borderline independently prognostic for metastasis-free survival with a hazard ratio of 1.08, with the genomic classifier being evaluated as a continuous variable, and the p-value trended towards significance at 0.08.

We then wanted to look at whether the genomic classifier could perhaps be predictive in one of the two types of intensification, the short-term androgen deprivation therapy or the addition of pelvic lymph node irradiation.

We did not see any significant interactions between the genomic classifier and the addition of short-term androgen deprivation in this cohort, but interestingly, what we found was that, when we looked at the addition of pelvic lymph node irradiation in arm 3 and compared it with the other two arms, we did notice that not only was freedom from progression improved in the high genomic classifier score cohort for freedom from progression but also, perhaps, predictive for metastasis-free survival.

So for freedom from progression, we had a p interaction value of 0.04—so significant, and suggesting that high genomic classifier could be predictive of benefit for freedom from progression. Metastasis-free survival was trending towards a significant result at a p interaction value of 0.06, so just missing that cutoff.

So in summary, what did we show? We showed that we confirm in a modern phase III randomized trial that outcomes following post-prostate bed radiation are heterogeneous, but that transcriptome-based genomic signatures such as the Veracyte Decipher GC can absolutely help risk-stratify patients and improve decision making, perhaps even direct treatment intensification, such as in this case, pelvic lymph node irradiation.

Angela Jia: Dr. Tran, thank you so much for that wonderful summary. What do you currently use Decipher for or what prostate patients do you currently obtain Decipher in?

Phuoc Tran: At the University of Maryland, through our initiatives in precision radiation oncology, we essentially obtain Decipher genomic classifier scores on every localized prostate cancer patient that comes through the door. As you know, it's NCCN recommended in the latest guidelines for prostate cancer, with high-level evidence for localized prostate cancer, not only in the definitive setting but the post-operative setting.

So long answer to your short question, we order it on essentially everyone because we believe it's really another critical, independently prognostic factor to help us risk-stratify patients not only in the definitive setting but in—and again, for the context of this discussion—in the post-operative setting.

Angela Jia: Thank you for sharing that. And how do you see this data from this analysis translating into the clinic?

Phuoc Tran: Well, the exciting prospect of working with a CAP clear-certified test such as Veracyte's Decipher genomic classifier is that it's already out in clinical use, and so this data—and the score—is obviously available. How we utilize it in the various clinical contexts is obviously a question that arises quite often, and it can be very complicated.

I would say, for this particular use, this particular context where we have data suggesting that a high genomic classifier may be predictive for pelvic lymph node irradiation use in the post-operative setting, the data is promising. I don't advocate right now that everyone go out and use it to determine whether patients get pelvic lymph node irradiation in the post-operative setting. I think it requires more validation from other data sets and ideally, prospective validation in a randomized study—integral biomarker design study.

However, as I told you, at least in my practice, we order a Veracyte genomic classifier from Decipher on every localized cancer patient because we know it provides really impressive, independently prognostic, risk-stratifying power. So I don't think it's unreasonable to use it as a factor as you would in the clinical context of a post-operative patient.

So do they have, for instance, seminal vesicle invasion? Sure. Margin positivity, Gleason score, some of these other tried-and-true clinical pathologic factors that we use, and integrate that into your decision-making.

Angela Jia: Thank you so much.

Phuoc Tran: My pleasure.