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Alicia Morgans: Hi, I'm so excited to be here today with Professor Dan Spratt, who is joining me from Case Western Reserve University and the Seidman Cancer Center, as well as joining me recently in Lugano for APCCC 2024.

Thank you so much for being here with me today, Dan.

Daniel Spratt: Thanks so much for having me.

Alicia Morgans: Wonderful. So Dan, in Lugano you gave several wonderful talks, but one of those talks was on thinking through biochemical recurrence and how we consider salvage radiation and systemic therapy for use in combination with that, and trying to understand and help us understand how long, how much, how intense or not. So can you share a little bit about your talk?

Daniel Spratt: Absolutely. So really at a high level, what we were talking about is for patients who experience a biochemical recurrence after surgery. The big question we often have to ask ourselves is do we give these men hormone therapy and there's various durations and intensities of hormone therapy and there's really four big randomized trials shown here that I discussed about that help inform which men should receive hormone therapy. And the punchline here, and there's a lot of nuance we went through, is that men with lower PSAs on average, not using any biomarkers, which I'll discuss, which probably further help personalize this treatment decision, probably seemed to not derive a measurable overall survival benefit in an unselected group. But really as the PSA rises, the risk of having metastatic disease goes up and that's where we're seeing some of these survival gains. But I think that the punchline here is that not all patients who have a BCR should be treated the same, many do not need hormone therapy, some men do, and some need intensified treatment.

And so we went through all of these trials, and these are all the overall survival curves. All these trials have long-term follow-up. And really outside of, and I'll show this in a moment, the highest PSAs that were enrolled in the RTOG 9601 trial, not shown here, it's really hard to appreciate some meaningful separations of these curves. And the RADICALS HD trial, which is the newest of these trials, actually did, although it's underpowered, one of the cleanest randomizations to help inform duration of radiation alone with short-term or long-term. But similarly, when you compare none versus two years, the metastasis-free survival hazard ratio, again small sample size, is basically one.

So how do we personalize this decision? And so I think one of the easiest ways for clinicians, we discussed, is that pre-radiation, salvage radiation PSA. And so I'm showing from that trial the RTOG 9601 randomized trial by PSA bucket, kind of here by bin, the incidence of just a metastasis or death, and you can clearly see that if you're giving late salvage radiation therapy there's much worse outcomes including much worse survival outcomes. And this probably parallels the success of salvage radiation from retrospective studies where you can see in the blue here at higher PSAs the success of rendering a patient disease-free at 10 years, most men are going to be recurring at these high PSAs who have been given salvage radiation. And this parallels actually now what we're seeing with PSMA PET Imaging where we are detecting some of these men having nodal or distant mets.

So really these high PSA men, unsurprisingly, that are having this big benefit from ADT, probably have metastatic disease. And this was most cleanly shown in that RTOG 9601 trial. Well, really those men here on the left with PSAs over 1.5 have a 25% absolute improvement in survival. But again, at the lower PSA it's really, kind of what I showed on the prior slide, we're really struggling to see that benefit. And PSA has shown some consistent trends here where, this is again from that 9601 trial, you see the PSA here going up and up and up. You see the benefit increasing in survival and increasing in distant metastasis as that PSA goes higher. And this has a statistically significant interaction effect, meaning PSA actually was a predictive, not just prognostic biomarker.

And we see similar trends in the other trials that were done, GETUG-16, which is plus or minus six months, there's greater relative and absolute benefit in the PSAs over 0.5. In the SPORT trial, similarly, again, they used a cut point of one. So a little, it's not exactly identical, but similar trends. And even in the RADICALS 0 vs 6 months, they actually included adjuvant patients as well as salvage and there's almost a significant interaction where the adjuvant patients really didn't seem to derive a benefit.

But the RADICALS trial also had this six vs. 24 months randomization. And I would say that I am drawing an arrow here, but it's hard to believe that's very convincing, although those with low PSAs, which is 880 patients, really it crosses one. It actually looks pretty similar to what we showed in 9601, that at these middle PSA groups, it's to the left of one, and that's exactly what we saw here. But it's really these high PSA patients that have this huge survival benefit from ADT.

A more recent trial done by Dr. Paul Nguyen, which was intensifying rather than prolonging ADT called Formula-509, was randomizing salvage radiation with six months of ADT with or without Abiraterone and Apalutamide. And you can appreciate, again, that there was no benefit of this intensification with lower PSAs, but higher PSAs hazard ratio of 0.3. And again, the interaction was almost significant here.

New to the camp here is some biomarkers that I think have shown promise where you see in the background, this is using the 22-gene genomic classifier, also called DECIPHER, in one of these trials, 9601, it re-stratifies prostate cancer-specific mortality. And when you look in this call-out box, this is the absolute improvement in metastasis from adding two years of hormone therapy, which really shows no benefit in the lower 22-gene genomic classifier group. In another randomized trial that did not use any hormone therapy, done out of Europe, you can see here that again the higher GC score patients had a much greater incidence of needing to receive subsequent salvage hormone therapy whereas the lower score patients really did not.

And the newest to the group, a big collaborative study we did that's being presented for the first time, is using two of the trials I discussed, RTOG-9601 and 0534, to use this MMAI multimodal AI technology to create a new biomarker in this BCR setting post-prostatectomy. And one of the highlights of this work is that not only is this new model highly prognostic, you can see in these two randomized trials that the benefit of hormone therapy here, if you have MMAI high in this model, there's a pretty profound benefit of adding hormone therapy, but in the MMAI low patients, there's absolutely no improvement in outcomes.

So I think the summary was that hormone therapy does not have a clear survival benefit in unselected patients when you give them early salvage radiation. And I think this is informative because it's very different from localized prostate cancer where the benefit is very consistent. And we may realize that one of the mechanisms that hormone therapy improves radiation outcomes is it radiosensitizes things. But when you don't have a gross or bulky tumor, like you do in the definitive setting, maybe it's of less benefit, and this is consistent with dose escalation studies where they're all positive in the localized setting and both of the ones that have been done in the post-operative setting have been negative.

And I think the three biomarkers, we can call them, they help us personalize treatment beyond just patient factors themselves. Patients with higher PSAs, higher 22-gene GC scores, and higher, which this new model we showed, post-RP MMAI scores. Interestingly, some of these have already been shown to correlate with PSMA-PET positive nodal or distant disease and that may be the mechanism of why these patients benefit more or less from hormone therapy.

So, really appreciate the opportunity to tell you about the presentation at APCCC.

Alicia Morgans: Thank you so much, Dan. That was great. And I think as we all try to think through how we consider salvage radiation, systemic therapy, you definitely put a lot of things in perspective. One of the questions that comes into my clinic sometimes, particularly when patients are being referred from outside, "My PSA is now 3. Should I get salvage radiation?" And I know this isn't directly necessarily addressed in your talk, but you did talk about the higher PSAs and if you have a negative PSMA-PET, should we still do salvage radiation in those patients? What do you think? And maybe they're metastatic at that point, as you discussed. What are your thoughts there?

Daniel Spratt: Yeah, it's really interesting and it's a challenging situation that at the APCCC, when you talk to a lot of the people from Europe, they almost never see these patients with PSAs over 0.5 whereas in the US for unclear reasons, we often are seeing these late salvage patients that, maybe to your point, missed this window of cure with salvage radiation. I think I look often at the time interval from surgery to this PSA. Sometimes it's 20 years and it's probably very indolent, maybe they don't even need any treatment versus if this is something in the first few years with a rapid doubling time, similar to what we're now seeing in this high-risk BCR setting where it's a very rapid doubling time, high PSAs, it's unclear. Most of those patients will have something seen on PSMA-PET, but it really is an open question, will salvage radiation therapy with high PSA, high doubling time, especially if the PET is positive for metastatic disease, provide a benefit, unclear. And I think you do have to take that person-by-person or individual-by-individual.

I think old studies used and that's why RTOG-9601 made the cutoff of enrollment only PSAs up to 4 because back in the '80s and early '90s that patients with PSAs over 4, pretty much, a hundred percent were recurring after salvage radiation. So it's probably somewhere in that ballpark. But again, I'm sure you've seen as well these PSAs that are 2, 3 and you see just a local recurrence and maybe those are the ones that benefit.

Alicia Morgans: Yeah, I do think that PSMA-PET imaging has changed that decision-making process, but it is still something that once in a while I just think I'm not sure what the right answer is here, but we're going to talk it through and we'll come up with a plan. So thank you for that.

So you presented some really nice information from the Formula-509 trial, thinking about intensified therapy and where do we go from here and that study ultimately was negative overall, but I think it was so thought-provoking, so I appreciate you presenting it. Where does that kind of work go next? Are we continuing to study this intensified approach and is this something that you think we might be able to use in the future to help really consolidate our effectiveness?

Daniel Spratt: Yeah, I think that both in this post-operative setting as well as actually in the intact setting, I think that there's a lot of interest and promise in these smaller phase two trials of intensified hormone therapy. And is that an opportunity, given most of these men rapidly recover testosterone within about six months? When we compare that to the two-year duration of just normal ADT, some of these men, depending on the study, 40% may never recover testosterone and it takes years too. And so I think it's definitely whether this needs to be a non-inferiority trial to say can we get similar tumor control rates, but potentially improved quality of life. I think there's a lot of interest from patients as well as providers. There's a small study that's being led by, I think, it's Dr. Karen Hoffman, I think it's called Prost-IQ or Prostate-IQ, that's trying to use that MMAI model I showed and compare the intensified versus just ADT in that setting. But yes, I think a lot more work needs to be done in this to focus on the quality of life side to patients, assuming we can achieve similar tumor control.

Alicia Morgans: Great. So as we wrap up, where was there consensus, where was there a lack of consensus and what are your thoughts, just summarizing this topic for the audience?

Daniel Spratt: Yeah, I think it's reaching consensus. It really depends how you view the questions, in the sense if you get nitty-gritty in terms of do you use six months, do you use 24 months, I think you start to lose consensus pretty rapidly. I think if you say are there patients who benefit from hormone therapy with salvage radiation, I think there is consensus. I think there's also consensus of individualizing that and we probably don't have beyond PSA without using commercial biomarkers. We don't seem to have a great sense, is it T-stage, the margin status, the Gleason Score. They don't seem as clear-cut to say who should have it, who shouldn't. But I think that, again, I think there's consensus we need personalized treatment. Some men may need longer-term hormone therapy, some men need hormone therapy and some men don't. Exactly who, I don't think we have consensus. More work to be done.

Alicia Morgans: Great. Well, thank you so much for catching us up at the conference for 2024. I really look forward to talking with you over time and maybe by 2026, we'll have some more answers in this area. Thank you so much for your time.

Daniel Spratt: Thanks so much.