Alicia Morgans: Hi, I'm delighted to be here at APCCC 2022, where I am talking with Dr. Brandon Mahal, who is Assistant Professor of Radiation Oncology at the University of Miami. Thank you so much for being here with me today.

Brandon Mahal: Thank you for having me.

Alicia Morgans: Wonderful. So, I wanted to dig into a little bit of the talk that you gave at APCCC about when we think about using salvage systemic therapy in the context of salvage radiation therapy for patients who have had a prior prostatectomy. Can you talk us through the conundrum a little bit and then we can figure out what's the answer to that pressing question?

Brandon Mahal: Yeah. I'm happy to share. So, the major conundrum is what type of ADT, should we be giving ADT, and for how long? And so far, to date, we have three randomized trials that seek to answer those questions. And then, we have at least six ongoing randomized trials. Right now, the data from the randomized trials suggests that ADT may provide a survival benefit in particular for men who have high PSAs after surgery. So these are individuals who have a PSA greater than 0.7 after surgery and who are going on to receive salvage radiation therapy. Those men, what we see, they have a significant survival benefit when they receive salvage ADT.

We also see in other studies where they're using more contemporary cohorts of patients where salvage radiation therapy is being delivered earlier, that there's actually a progression-free survival benefit, but no overall survival benefit yet to those studies. There's two randomized trials that show that six months of ADT provides a progression-free survival benefit in the salvage setting when the PSA is lower, meaning early salvage, however, there's no overall survival benefit. So, the conundrum is, do we believe the progression-free survival benefit? Should we be using that evidence to change our current practice? And if so, for who do we do that for? And are there patients who are even more at risk of aggressive disease, and should we be giving them even longer ADT or more aggressive forms of systemic therapy in ADT?

Alicia Morgans: Absolutely. So one of the issues that I face in my practice at least, is trying to apply the Shipley data that really suggests maybe two years of Bicalutamide in the salvage setting with salvage radiation therapy is going to be a helpful thing to improve survival. But two years of Bicalutamide, that's a drug I barely use, and so that's not what I actually do in practice. It's interesting through many conversations and, of course, time digesting that data. We commonly do six months of a GNRH agonist type approach or an antagonist, but that's not supported by the data. That's a major extrapolation. So, what do you do in your practice, and how do you think through that data and rectify what we're doing in practice with what the data says?

Brandon Mahal: Yeah. Exactly. So to your point, the Shipley data used 24 months of anti-androgen, specifically Casodex 150, which is not even approved in the US or Canada, and many other countries. And there was a survival benefit, but that cohort of patients in the Shipley study, 44% of those men had persistent PSAs after surgery. So a very high-risk cohort, and the medium PSA on the study was 0.6. Whereas, the newer studies, the more recent studies I should say, the GETUG-AFU 16 and the SPPORT RTOG-0534, the medium PSAs on those studies was 0.3 to 0.35, and they used LHRH agonists. The SPPORT study used in combination with an anti-androgen, the Bicalutamide 50, was allowable on that study. However, there's nowhere you'll find in the United States, in particular, anybody using Bicalutamide 150.

So, an extrapolation is being made, that's for sure. And I think it's because there was a survival benefit and that's not being ignored, but now there have been secondary analyses that have been performed. One by Dr. Dan Spratt, led by Dr. Dan Spratt, that looked at the pre-salvage radiation therapy PSA, and when those PSAs are lower on the Shipley study below 0.7, those men didn't have a survival benefit. And a lot of those men actually had an increased risk for all-cause mortality. So is that because it's 24 months of Casodex 150? Probably. And that's an extrapolation that's being made, so we don't use that.

But we are tending to use the regimen that shows a progression-free survival benefit. But those studies were done in men who it's difficult to show an overall survival benefit because these men are being treated with salvage therapy so early in their failure. And so the extrapolation right now is really counting on their to potentially be a metastases-free survival benefit in one of those studies. And the ongoing studies, actually, the standard of care arms tend to use a backbone of at least six months of ADT. So it's really been adopted as standard of care, and it's an extrapolation certainly from the Shipley study.

Alicia Morgans: Yeah. It's just so interesting to be, especially in a field like radiation oncology, where we are so dedicated to the data, but at the same time, as you said, it takes forever for these studies to mature. So what do you see coming in the future in terms of molecular characterization potentially of patients, and helping that potentially shape how we choose treatment or the duration of treatment versus clinical features that may inform that thought process?

Brandon Mahal: Yeah. Thank you for the question. And I think the answer's going to be, we're going to use both. Felix Feng published a really elegant study in Gem Oncology last year in 2021, using patients from the Shipley study, using over 350 patients looking at genomic classifiers and the benefit to ADT. So, we know for sure that genomic classifiers are prognostic for men who are receiving salvage therapy, but his study, though it was under power to detect a predictive benefit to the genomic classifier, what the study did suggest is that if you get a genomic study and that genomic study shows high-risk features or high-risk disease, those men are more likely to benefit from salvage ADT, in combination with the radiation therapy. For men with low genomic risk scores or more favorable genomic characteristics, those men are less likely to benefit from ADT.

And when you combine that with PSA, men who have low PSAs who are getting early salvage and a favorable genomic risk classifier, they actually do not benefit from ADT on that study. They tended to actually do worse with ADT. So I think what we're going to see down the pipeline is that studies, randomized trials are going to incorporate risk stratification by genomic classifiers and by pre-salvage PSA. And I think those are the two most important factors that we can probably use in practice today. Absolutely pre-salvage PSA is still going to be the main clinical factor that we pay attention to, but we're also starting to pay more attention to the genomic classifiers as we gather that information.

Alicia Morgans: It's really fascinating and so much work to be done, but I really do look forward to these prospective studies to really help confirm some of the work that's being done retrospectively within these energy studies that are so rich in the information that they provide. So, I really appreciate you taking the time to talk this through with us. It has truly been a pleasure. We will benefit from your expertise for a long time.

Brandon Mahal: Thank you. Thank you very much for having me.