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Daniel Spratt: Hi, everyone. Thanks so much for being here and thanks so much to UroToday for sponsoring this session. I have two wonderful guests that are experts in the field of urologic and prostate cancer oncology. We have Dr. Ashley Ross, and also we have Dr. Allen Dal Pra, and I am Dan Spratt. And tonight's topic is on personalizing hormone therapy with postoperative radiation therapy, and to get this panel's thoughts on the role of Decipher in this setting.

So what are the big questions in this setting? After a man undergoes prostatectomy, one of the biggest questions is when do we initiate treatment? Is it at an undetectable PSA with adverse pathology or as the PSA rises and at what level? The next is, who will progress to next line therapy after postoperative radiation therapy, which are the men that are likely to fail radiation therapy by themselves?

And finally, who are the men that may benefit or be spared concurrent hormone therapy with salvage radiation or postoperative radiation therapy? So like in all of oncology, and we do this I think a little bit better in intact prostate cancer, the goal is to personalize therapy based upon life expectancy, tumor aggressiveness, and treatment sensitivity.  In the postoperative setting, we often are talking about which men should undergo observation, adjuvant radiation therapy, salvage radiation, when to add hormone therapy, or when to maybe omit radiation therapy altogether and just do hormone therapy. And tonight's talk is really focused mainly on patients that we think should receive salvage radiation therapy.

So in this setting postoperatively, we are mainly using clinical variables, surgical pathology, and the Gleason score margin status, but there is still a need for stratification in personalizing therapy. This is really where the Decipher test was originally developed and designed, to potentially improve treatment decision-making and prognosticate outcomes. While there are about 40 studies, most of them retrospective, we now have multiple prospective and actually post-talk analyses of randomized trials that we will be presenting tonight as well as some really important data from a study by Dr. Ross, as well as you see here, the SAKK randomized trial that Dr. Dal Pra will present. Each of these studies was very different as they will get into. Dr. Ross's study looked at really the importance of both Decipher as well as the postoperative PSA. The SAKK trial is a randomized trial as you see here, randomizing patients to either a lower dose or a higher dose of salvage radiation or post-operative radiation. And then RTOG 9601, is a randomized trial of salvage radiation therapy alone with, or without two years of bicalutamide.

And this is the study that is really derived from Dr. Ross's work, really showing the very important prognostic aspect of pre salvage radiation therapy PSA. So after a man undergoes surgery, as you can tell here that man with a very low PSA has a very low rate of developing metastatic disease five years later, and this sort of exponentially climbs as the PSA goes up.  But underlying this data, which is really something that I think many people do. to realize is that Dr. Ross has shown that Decipher can further stratify this prognostic ability of PSA. And so that high decipher patients, even with potentially low PSA's and this is 0.2 to 0.5, have a very high chance of developing metastatic disease. And so I think you will sort of be seeing this theme throughout the talk tonight about the importance of PSA and the Decipher testing to personalize therapy.

And so I am now going to pass it over to Dr. Alan Dal Pra, who is going to talk about his results of the SAKK trial and how they profile Decipher in this trial.

Alan Dal Pra: Thank you very much, Dan. So this is the SAKK trial is a phase three randomized trial off those, his colleagues are salvage radiotherapy after radical prostatectomy, 350 patients were randomized to the 64 grade or 70 grade to the prostate bed only. Patients who had a PT 28, 3B disease margins were negative or positive. We thought pelvic lymph nodes, had to have a biochemical progression after radical prostatectomy and a median PSA of this cohort was 0.3, basically an early salvage cohort. Radiotherapy was done to the prostate bed, with only no elective treatment to the pelvic lymph nodes. Patients were treated from 2011 to 2014 and the median follow-up for these studies, six years, and importantly, no patients received hormonal therapy. So these are the main results for the stride, a higher radiation dose of 70 grade to the prostate bed does not improve outcomes. There was no difference in the freedom from biochemical progression, which was the primary endpoint of this study, clinical progression-free survival, hormonal therapy-free survival, and/or overall survival.

So we performed by validation of the Decipher genomic classier in this cohort. And for that, we had a pre-specified statistical plan that was developed to assess the impact of the genomic classifier on the clinical outcomes. So radiotherapy samples were separately reviewed for the highest grade tumor and those passing quality control were run on the Decipher platform. So the primary endpoint for this ancillary study was time to freedom from biochemical progression. The secondary endpoints were clinical progression-free survival and receipt of salvage hormonal therapy. As exploratory endpoints, we had rapid biochemical progression, distant metastases, and metastasis-free survival.

So this is the [inaudible] diagram. 350 patients were allocated to treatment. However, we were able to retrieve 233 samples out of these samples. We had an impressively high-quality control passing rate of more than 97%. So out of this, we had 226 unique samples that were analyzed.  The randomization into two arms resulted in an approximately one-to-one split with very similar Decipher risks in each arm.

So next we have the cohort characteristics, and the cohorts were well balanced. The cohort was basically composed of Gleason seven tumors, 15% of Gleason eight in both arms. So here you see the cumulative incidence plot for the primary endpoint, freedom from progression, and the secondary endpoint, critical progression-free survival, and time to hormonal therapy. We see that the Decipher is a strong prognostic biomarker, not only for the primary endpoint but also for clinical progression and use of hormonal therapy. There is a substantial separation, as you can see here between the Decipher high and the Decipher low-intermediate risk groups. So similarly you can see here that Decipher high has greater than twofold, increased risk of biochemical progression in both the UVA and the MVA for the primary endpoint.

In fact, Decipher is a strong prognostic biomarker for all endpoints, including the exploratory ones, rapid biochemical failure, freedom from distant metastases, and metastasis-free survival with the effect size and/or risk reduction greater than two for all six endpoints. For the primary endpoint, for instance, the five-year freedom from biochemical progression Decipher high is 45% versus 71% in the Decipher low- intermediate.

So in conclusion, this study represents the first contemporary randomized clinical trial in patients treated with early salvage radiotherapy without hormonal therapy that has validated the prognostic utility of the Decipher genomic classifier. SAKK 09/10 confirms the Decipher prognostic ability that was seen in the NRG/RTOG 9601, I believe that we will be talking a little bit more about this study later.  And independent of standard clinicopathologic variables and radiotherapy dose, those patients with a high Decipher were more than twice as likely compared to low-intermediate Decipher to experience biochemical and clinical progression and use of salvage hormone therapy.

Daniel Spratt: All right. Thank you, Dr. Dal Pra, that was exciting data. Thanks so much for your work to generate that and to share that with us.