Charles Ryan: Hello from PCF 2019. I'm joined by Dan Spratt, Associate Professor, Radiation Oncologist from the University of Michigan. You got a lot going on, my friend, and you really made a splash a couple of weeks ago presenting an update of the Shipley data from the RTOG studies, which was a really important study of high-dose bicalutamide in the setting of postoperative radiation. Tell us what you found.

Dan Spratt: Yeah, so this trial, for those not familiar with it, is a trial where men who've recurred after undergoing a radical prostatectomy received salvage radiation therapy with either a placebo or high-dose bicalutamide for two years. Overall, the study was published two years ago and showed a survival benefit for the addition of hormone therapy, bicalutamide. But we took a second look into it because nowadays we treat patients at lower PSAs. We call it early salvage radiation. Once it becomes detectable, the PSA, is when we'd start to recommend using salvage radiation.

But back when this trial was done in the 1990s and early 2000s, a lot of guys with PSAs of one, two, three, four, we would call that late salvage. They probably already had actually regional if not metastatic disease. So when we kind of dissect patients into this lower PSA or early salvage and those with high PSAs or late salvage, the guys at higher PSAs, again probably with metastatic disease, had a huge survival benefit. It was about a 25% improvement at 12 years. But the guys at low PSAs, a little more representative of today, all we saw was the morbidity, and so there's about a threefold increased risk of cardiac events, which translated into about a twofold increased risk in other cause mortality.

Charles Ryan: Okay.

Dan Spratt: It starts to ask some questions as to how should we be treating these guys with more favorable lower volume disease that maybe just have local disease in their pelvis after the surgery.

Charles Ryan: Right, right, so there's a bunch of questions.

Dan Spratt: Yeah.

Charles Ryan: One question is what is hormone therapy? Is high-dose bicalutamide actually hormone therapy? I would say that it is, but not really. I mean, it's not enough hormone therapy to be hormone therapy, and that it actually may induce a different set of toxicities-

Dan Spratt: Absolutely.

Charles Ryan: ... because testosterone levels go up and other things happen. We used to think it was completely safe, much safer than standard androgen deprivation therapy, but it may not be, and your data supports that.

Dan Spratt: I think unfortunately in this trial, they didn't look at using an LHRH agonist like a Lupron® or Firmagon® agonist or antagonist, but absolutely, so bicalutamide increases testosterone and increases estrogen, and so a lot of these guys got gynecomastia. When you're on an LHRH agonist or antagonist, you lower estrogen and testosterone, so it's less clear if this would have the same effects.

There are studies in localized, so they've not had surgery, where we give definitive radiation therapy and it's plus or minus long-term combined therapies, a dual blockade with, usually it's something like a bicalutamide and something like a leuprolide. They've shown increased risk of cardiac events with long-term use, but they have not shown it to this extent, so I do believe there is something at least partially unique to bicalutamide.

And it could also be the duration, right, in that a lot of people use six months of hormone therapy, and so this was two years at a high dose. This is not even really a dose we typically use with radiation therapy. It's usually just 50 milligrams, not 150 milligrams.

Charles Ryan: No, but we have apalutamide, enzalutamide-

Dan Spratt: Oh, absolutely.

Charles Ryan: ... darolutamide all coming down the pike-

Dan Spratt: Absolutely.

Charles Ryan: ... and there's a lot of trials going on which are asking the question can we replace castration with these approaches, and I think these data should be a little bit of a warning sign around that. I don't think people are using high-dose bicalutamide too much.

Dan Spratt: I hope-

Charles Ryan: I used to use it, but not much anymore.

Dan Spratt: You know, since presenting this, there are people I've found... You're 100% spot on. It's the vast minority use this, but there still are some people just given that you have less I would say typical hormone-related side effects, less hot flashes, less decrease in vitality, and so some people have been using this, but I think this data at least will shift away from that as these other trials... We have an ongoing national trial, the co-PI of using apalutamide as monotherapy, there's other trials using it as combined therapy, and it'll be very interesting to look because these are much more effective agents, and we're sometimes using them for shorter duration because they're more effective. So time will tell, but we may not see that side effect profile.

Charles Ryan: But if we were to go back in time and take all these patients enrolling on this trial with the PSAs of two and three and do a PSMA PET, we're going to probably see metastatic disease as you pointed out in a vast majority of them.

Dan Spratt: 100%.

Charles Ryan: So one of the things that this data seems to suggest is that early hormone therapy in the form of AR blockade with bicalutamide confers a survival benefit, and we're in subset territory here-

Dan Spratt: Sure.

Charles Ryan: ... so it's problematic, but it is another sort of point that early hormone therapy may be beneficial. So what does it tell us about radiation?

Dan Spratt: Yeah, so I think there has never been a trial that in patients who have recurred that's randomized to plus or minus salvage radiation. I think the closest we'll get is data that just shows the superior outcomes when we deliver radiation earlier than later, and given data like with the PSMA PET scans, most of the recurrences at low PSAs appear to be local or local and regional, and so the majority of patients... Some of the new trials just presented at ESMO, the RADICALS and RAVES trials, the vast majority of patients have no evidence of metastatic disease 10 years later when you give early salvage radiation. So I think there's definitely a role with low PSAs.

I think the question becomes, to your point, at high PSAs, when we really think they have metastatic disease, what is the benefit of radiation? And it almost gets into this debate people have in low volume metastatic disease-

Charles Ryan: Metastatic disease.

Dan Spratt: ... can there be a benefit of sort of cytoreduction, so to speak, and so I think... There's trials ongoing looking at low volume metastatic disease. I think that there's definitely with newer next-generation hormone therapy agents, it's something that probably does need to be asked, and I don't know what PSA cut point or if you-

Charles Ryan: Well, radiating the prostate bed in the setting of oligometastatic disease is not the same thing as radiating the primary-

Dan Spratt: Correct.

Charles Ryan: ... as the data should point out, and biologically those are distinct entities, so that remains a question that we'll have to answer. One of the things I wanted to take away from your data is as I'm facing patients, and I do frequently who are postop with a rising PSA, is there an inflection point you think where radiation should be given less consideration, right? You've pointed out, I think appropriately, that the lower the PSA the better, because the lower the volume of the disease and the greater the benefit of the radiation. Where's the cutoff?

Dan Spratt: Yeah. So I looked back to the 1980s, and when they used to... Now we talk about PSA cut points of early versus late at PSAs like 0.5?

Charles Ryan: Yeah.

Dan Spratt: Back then it was PSAs of four, like the '80s-

Charles Ryan: Yeah, 4.0.

Dan Spratt: 4.0.

Charles Ryan: Yeah.

Dan Spratt: And they showed that if your PSA was over four, it was essentially 100% percent of men recurred within like three or five years. And we see patients, I see routinely patients whose PSAs are over four that we're doing more and more surgery in patients with high-risk disease, and so we're seeing persistently elevated PSAs. I don't know what that magic cut point is, but I think as new studies, especially with PSMA PET, when you start to see substantial extrapelvic disease, it's something that we probably need more studies to help interrogate what did the radiation therapy add. And it's heterogeneous, because you could have a lot of the PSA coming from a regional, local, and it could be widely metastatic as we're seeing with these new PET imaging.

So yeah, I really start to question when PSAs are, I would say for right now over four, but I'd give a lot of thought and I would say systemic therapy is critical. Going back to this 9601 data, how often can you see a 25% survival benefit in anything? The hormone therapy is probably driving that outcome, and so I think that patients really just need to understand the importance of it.

Charles Ryan: Very good. Great. Well, congratulations on all your work and you're bringing... I love bringing new insights to maturing data because that's what's so important because we face these dilemmas with our patients every day about how to do these things, and to have 25-year-old data is very valuable, so thank you for doing that work and always a pleasure chatting with you.

Dan Spratt: Thanks. Appreciate it.