Neal Shore: Okay. So welcome back everyone. We had a fantastic first session. We're looking forward to this second session and it's my great pleasure to co-chair with Professor Zapatero. We have a fabulous panel looking at the issues around BCR. Some of the things will be a little bit of a carryover from the first session. The importance of the controversy of adjuvant versus salvage, systemic therapy combinations, and then biomarkers, and especially classifiers, and as well as with imaging. All of this, an ongoing field of incredible excitement and change. So with that ...

Almudena Zapatero: Hello. Good morning. Welcome again. It's my pleasure to introduce to the next speaker, first speaker Kosj Yamoah from Moffitt Cancer Center to the podium to speak about who needs salvage radiotherapy, and who needs adjuvant radiotherapy in 2022. Whenever you want.

Kosj Yamoah: I want to thank the organizers for having me have at this talk and I am looking forward to an amazing session because there's a lot of things to discuss today. Next slide, here are my disclosures.

So I'll just go over a few definitions, which I think everyone in this audience is very much aware of, but it's been important just to set a stage, since we're going to be talking about a lot of these things. So adjuvant radiotherapy really is when we administer RT to postop patients who are high risk of recurrence because of adverse pathologic features prior to evidence of disease. And salvage would be when you administer radiation to the postop bed and surrounding tissues in the context of PSA recurrence. And we define biochemical recurrence in a post-surgical setting, when you have a detectable PSA of greater on 0.2 with a secondary confirmation of that, the AUA definition of post RT will be if you have PSA plus two nanograms per mil. And NCCN defines a similar way, typically given one year postop after side effects have stabilized, with no evidence or recurrence for adjuvant. And for salvage, like I described, or when you have a single PSA greater than 0.5.

So there has been a lot of both prospective retrospective data looking at this subject, and it's brought us to a meta-analysis, three different meta-analysis by the way, over the last decade, summarizing the importance of adjuvant radiation. And what you recognize here and looking at the end points of BCR that indeed adjuvant radiotherapy in the context of these features we described improves biochemical recurrence, improves metastatic free survival. So metastatic free survival, metastatic endpoints, however has no observable benefit for overall survival and can actually add more GIG toxicities.

So the take home point from the last decade and a half of adjuvant radiotherapy is indeed, does immediate post operative RT improve outcomes for patients with high risk features? Yes, it benefits patients with positive surgical margins, EPE, extra prosthetic extension, seminal vesicle invasion, as compared to surveillance. So is early salvage RT superior to adjuvant RT? In this context we will say is postop RT better before the recurrence sets in or after the recurrence is detected at its earliest standpoint? Those are the two questions we're going to look at. And when we look at one of the studies that was not a randomized study, was really a propensity score matched cohort analysis involving 10 academic institutions across the US, here the defined adjuvant RT, if PSA was less than 0.1, undetectable, and early salvage is when it's 0.1 through 0.5 with a 5.6 medium follow up.

As you can see from the curves here, it appears that adjuvant radiotherapy was better for biochemical failure as compared to early salvage. Also, the P values at least were significant for distant metastasis and overall survival. However, that's not the end of the story. Like I said, this [inaudible 00:04:25] study is called match cohort.

There are three trials that were going on and around the same time that was evaluating the timing for salvage radiotherapy, the radicals, GETUG and RAVES. And real quick, I don't expect you to read all that, but this was really looking at patients that had at least one risk factor. Some of what we went on, we reviewed earlier towards the end of this morning's session, pT3/4, Gleason seven through eight margins, and then a little bit of higher post pre-operative PSA. And biochemical recurrence or biochemical progression with PSA had to be a PSA greater than 0.1. And this was the radiation schedules below.

And the results show that five year progression free survival, biochemical progression free survival was similar between adjuvant versus early salvage. And that in fact also the freedom from hormonal therapy use was similar. Yet you paid a higher price for it. Urinary incontinence, grade three to four urethra strictures. So the conclusion of this study was, does not support routine use of adjuvant RT after RP, and yet you buy yourself more toxicity.

Similar study with the RAVES was a non inferiority randomized trial. And again, you can see the curves on the right hand side, pretty much no difference. So in conclusion, salvage RT did not meet trial specified criteria for non inferiority. And so it supports the use of Savage RT and because there's similar biochemical control and you spare around half of patients from pelvic RT, which is associated with a lower GU toxicity.

And so when you put all these things together, the artistic meta-analysis was really looking at these three trials I've gone over. One thing that I wanted to highlight here is that the trigger for early salvage radiotherapy was all PSA based. But then when you look at the data, even though it was clear that there was really, out of the 270 events that it showed, there was no evidence that events free survivor was improved with adjuvant radiotherapy versus early salvage, arguing in favor of early Savage. So until more data emerges, it looks like early salvage seemed to be the winner. Although I have to say, there's a slight tilt past the left side of the one line, which is really what we look at on this meta analysis.

So is it true that adjuvant radiotherapy is truly dead? And I know that we talked earlier on about some instances where adjuvant radiotherapy can be considered. And I would like us to focus on a few things here. So who needs early salvage radiotherapy and who needs adjuvant? I think the answer lies with a non PSA based genomic stratification. And they're we're going to hear a little bit more about it, but I just wanted to give you a little flavor of how that's going to be important. Where we initially looked at 22 gene classifiers, that gives you a combined genomic classifier score, and it was used to predict risk of metastasis in men with high risk of recurrence, EPE, SVI margins and biochemical recurrence. And when you looked at patients that had a lower genomic classifier score, they didn't benefit from adjuvant versus salvage.

So those patients you can safely monitor until they really hit their pre-specified salvage endpoints before you trigger radiation use, but the patients that did have a little bit of a higher genomic risk of recurrence, five year metastatic disease, seem to benefit when you look at that yellow line from adjuvant radiotherapy, giving it earlier versus salvage.

Now there was another was still not randomized, but a paper that really very nicely looked at how the genomic classifier can augment the role of pathologic features in identifying the optimal candidates for adjuvant radiotherapy. And I think this is where we need to really hone in the field a little more that as you can see, the four clinical genomic features came out, and PSA wasn't one of those. It was pT3B and T4, Gleason grades eight or higher. Gleason sum, sorry, pathologic sum grade eight or higher, lymph node invasion, which we talked about extensively this morning, how adjuvant radiotherapy can benefit those patients and obviously decipher. And if you stratified by a number of risk factors, you can see the patients that had three to four risk factors indeed had a much higher clinical recurrence than any of the other groups.

And when you bend those risk factors into less than two or greater than two, those that had less than two of those risk factors, there was no benefit with adjuvant radiotherapy versus salvage. However, if you had a few of those higher risk features, two or more, you clearly saw a superiority in adjuvant radiotherapy. And so I think that the way of the future is not to base adjuvant solely on PSA, but really start looking at some of the factors, including aggressive pathology. We talked about here, there's a nice nomogram that tries to put it together. I think those patients that need early salvage are who need adjuvant radiation, it's in this slide, if they have pathology T3 or 4, Gleason sums higher or lymph node invasion with a [inaudible 00:09:54] score, those patients, we should consider adjuvant radiotherapy. So with this, I'm going to stop here and acknowledge APCCC for having us. And then we can here the next speaker and we can have some questions later. Thank you.