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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the United States. I'm so pleased to be interviewing today, Dr. Alan Dal Pra, who's an Associate Professor and an Associate Director of Clinical Research in the Department of Radiation Oncology at the University of Miami Miller School of Medicine in Florida. Thank you so much for being here today to talk with me about an abstract that you presented at ASCO 2021.

Dr. Alan Dal Pra: Thank you, Alicia. It's a pleasure to be here discussing our work.

Alicia Morgans: Wonderful. So you presented some analyses of the DECIPHER genomic classifier within the SAKK 09/10 phase three randomized trial that was really looking at dose escalation of Salvage radiotherapy in patients after radical prostatectomy. Can you tell us a little bit about the study and then we'll get into what you did in terms of the DECIPHER assessment?

Dr. Alan Dal Pra: Sure. I'll give a little bit of background on the SAKK 09/10. This was a phase 3 randomized trial testing radiotherapy dose escalation for patients with biochemical recurrence after prostatectomy. So the lead PI of this study is Pirus Ghadjar from Germany. He tried to report the primary endpoints last year, and the paper is about to be published soon. Basically, patients with biochemical progression were randomized in Switzerland, Germany, and Belgium. So 64 versus 70 Gy to the prostate bed, 350 patients. Importantly, these patients did not receive ADT or pelvic elective, pelvic radiotherapy. So after a median follow-up of 6.2 years, there was no difference in terms of freedom from biochemical progression in the 64 versus 70 Gy arms and six-year freedom from biochemical progression rates were 62 and 61% in both arms.
There was no difference in clinical progression-free survival time to Parma three and overall survival.
In terms of overall toxicity, there was more late grade 2 toxicity or high in GI toxicity, 70 Gy arm, which interestingly did not translate into differences in quality of life. So I think the main message from the trial, the main trial is that the conventional dose to the prostate bed is sufficient. We don't need to increase those of radiation in the salvage setting, if there is no evidence of microscopic recurrence. So, but I don't want to be the spoiler here. People would need to read the paper when it's published, hopefully in a few weeks.

Alicia Morgans: Well, very important message though. And I'm sure that we all will make sure that we review those findings. But your group specifically looked at the genomic classifier DECIPHER and analyzed specimen within this trial to really understand this freedom from biochemical relapse and some other progression endpoints that are disease-related. Can you tell us a little bit about that?

Dr. Alan Dal Pra: Sure. So, in regard to our ancillary study, we know that prostate cancer is highly heterogeneous and although many patients can be salvaged and cure death, there's postoperative radiant radiotherapy. Some will develop a disease progression die of the disease. So there is a clear need for better tools for risk stratification beyond a Gleason score PSA and in clinical stage. So since inception, there have been several number of studies, basically mostly retrospectively in nature, that have consistently shown DECIPHER prognostic value, independent of clinical pathologic factors. So recently we published a review by Dan Spratt showing the evolving evidence for multiple studies, prospective registers, and few randomized trials. In fact, validation from prospective studies, mainly the post-op setting are still very rare. So recently also the group from Felix Feng reported Decipher validation in 9601. But perhaps we can talk about that later, but although our results basically corroborate 9601, there are a few important differences between our cohort and 9601.
So we sought to value the genomic classifier in the more contemporary randomized clinical trial. Basically, this was a pre-specified analysis, the trial endpoint had not been assessed, when we developed these ancillary study and radiotherapy samples. RP samples were sent for the revealed, and then we classify low, intermediate, and high GCs. So low, less than 0.45, intermediate 0.45 to six, and higher than six, high GC. And the primary endpoint for our study was time from, to freedom from biochemical progression. This is the primary endpoint of the main trial. So we decided to stick with the primary endpoint of the main trial. We also assessed time to clinical progression, free survival received salvage hormonal therapy, and overall survival. As well, some exploratory endpoints like rapid biochemical progression, time to active progression, and descend metastasis. So in terms of the results of this study, basically we saw that out of 233 patients with translation available 226 best quality control were included.
So this is very important because a 97% passing rate on translation studies was pretty important. So that kind of shows that this is our contemporary cohort with high-quality samples. So, did you see score is a continuous variable that was independently associated with freedom from biochemical progression, with a hazard ratio of 1.12. And when we classified high versus low intermediate, you have a ratio of 2.1 for freedom from biochemical progression with our confidence interval of 1.3 to 3.3. So patients with high GC, he had five-year freedom from biochemical progression of 45% versus 71% in patients with low intermediate GC. So what strikes me is looking at the results and when we compare high versus low intermediate, is that the curves split very early, most of the events occur around six months from randomization, which in my opinion represents systemic disease. And exactly those patients that clearly need intensification, whereas six months or even longer, perhaps longer duration of ABG.

Alicia Morgans: And that's what I think so important and interesting about this. So this genomic classifier was able to identify patients within this entire clinically selected cohort that would have a higher versus lower risk of relapse. Really, as you said, to give us the opportunity to potentially study groups that have this higher risk and potentially intensify our systemic therapies as an example of something we might be able to do. And then in the lower risk populations, perhaps we'd feel even more comfortable watching these patients. Again, this is, I think, added benefit on top of clinical characteristics that can be used or were used to include patients in this study. What are your thoughts? How, how does this complement perhaps the clinical characteristics that help us to predict the risk of relapse for these patients?

Dr. Alan Dal Pra: I fully agree. I think it's a very important tool and it has been shown in multiple studies and now we have prospective data and there's other studies validating it as well. So I think the evidence is pretty strong. It's becoming even stronger, that it is a very helpful tool. When we also look, there are other endpoints splitting between high versus low intermediate, the risk, although because biochemical control, of course, can always be decreased the size. But we saw association with critical progression-free survival, use of hormonal therapy down the road, which in my opinion, is something very important that affects quality of life, et cetera, and rapid biochemical failures, meaning PSA progressing within 18 months.
And also just on metastasis, although just the number of events for this metastasis was low, there was a very strong signal as well. We don't have enough follow-up, so only 6.2 years. Interestingly, we also assess some specific subgroups, particularly the breakdown of PSA. We were going to be presented with this data at ASTRO for this year but is very interesting because it also has a very important finding in terms of when you give radiation, showing the importance of early salvage. And perhaps those are the patients treated with early salvage, where DECIPHER has a very, very important role.

Alicia Morgans: Well, we certainly look forward to hearing more from your Astro presentation as well. And I want to congratulate you and the team. Like you said, it's actually phenomenal that you were able to pass quality control on such a large portion of samples in this phase three trial, really giving us a good understanding of how DECIPHER can be used to help restratify. What is your take-home message for the listeners as we wrap up?

Dr. Alan Dal Pra: Well, I think this is a very heterogeneous population and we tend to over-treat many of these patients and also under-treat many of them. So I think genomic classifier definitely is a helpful tool that not a tool in the [inaudible 00:09:36] for prostate cancer patients that can certainly help us personalize further the treatment for these patients.

Alicia Morgans: Wonderful, well, thank you so much for sharing your insights for doing this work, and congratulations to you and the team for such a successful investigation, really adding, I think, to our understanding for stratification in this very important patient population. We appreciate your time. Thank you so much.