The Future of Prostate Cancer Treatment: An In-Depth Look at Emerging Personalized Strategies "Presentation" - Daniel Spratt

November 15, 2023

Daniel Spratt discusses how radiation therapy is expanding its role in prostate cancer treatment through techniques like dose painting and as adjuvant therapy with systemic treatments. He presents research showing how AI and biomarkers can help personalize radiation and hormone therapy to avoid over-treatment. Dr. Spratt sees radiation therapy continuing to evolve with more convenient hypofractionated regimens and an increasing focus on oligometastatic disease.


Daniel Spratt, MD, Chair and Professor of Radiation Oncology, UH Cleveland Medical Center, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH

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Daniel Spratt: I did mention hormone therapy, a lot of guys, especially as we get into the higher grades, we give hormone therapy to. So what's coming very soon in this talk, there's a ton of work being done with this 22-gene classifier that I won't be talking about today. I'll be talking instead, and not to steal any thunder because I know there's a talk later, but this is work we just published on using AI, and this is in NCCN guidelines now and the new edition of NCCN guidelines should come out soon, to where using AI digital histopathology, it's called a multimodal AI model, can more personalize the use of artificial intelligence.

This just came out, for those who didn't see it, in June. And so this is a huge effort where we essentially trained using five phase III randomized trials and validated it in the largest randomized trial ever of radiation with or without hormone therapy, can we truly predict, not be prognostic like all the genome classifiers and all the other stuff that you probably have heard about, can you truly predict the way you can, like in breast cancer with ER positivity and giving endocrine therapy?

And so using this model, we estimate that for an intermediate-risk patient, that's just most of this trial, two-thirds of men that we right now today would give hormone therapy to do not benefit from hormone therapy. One-third would. To walk you through this, this is this RTOG randomized trial. No biomarker, no AI, nothing. This is why we add hormone therapy. Radiation alone is in red, you add hormone therapy, a short course of it, there is an improvement, 4% at 15 years reduction in distant mets. That's why NCCN says for unfavorable intermediate risk and/or higher, we add hormone therapy because of this trial.

But if you apply this AI model to this randomized trial, if you look in the middle, these are that one-third of patients that are model positive or biomarker positive. And you can see the hazard ratio 0.34, a massive relative reduction and a pretty sizable, about 10%, absolute reduction. And what men really want to hear is the two-thirds of men that right now you'd recommend hormone therapy to that are model score negative, there's not a lick of benefit. Or maybe if you want, there's no significant difference. It's 0.5% At 15 years. So this is pretty meaningful.

This is something that, Andy Armstrong, we worked on, it's not yet published, but it was presented. The same thing. Short-term hormones, you can usually get a guy through. It's not the end of the world. Long-term hormones, guys do not like for obvious reasons. So this can, in a pretty high risk population, again, this was trained and validated across multiple randomized trials, about a third of men with high-risk prostate cancer, you can have the exact same outcomes to giving them just short-term hormone therapy. And that's what you see on the left. These biomarker-negative patients, you can just give them short-term hormones. On the right, obviously giving long-term hormones provides a pretty profound benefit to them.

Radiation has expanded, and this is not just for prostate and there wasn't time to talk about all the stuff going on in kidney cancer. But across lung cancer, a variety of cancers, radiation is expanding from localized disease to node-positive disease to recurrent disease to oligometastatic to second line to third line, and I'm going to show you some of these randomized trials. Our clinics are packed.

Radiation to the primary in low-volume metastatic disease, I don't think is that controversial. In some countries it's not even debated. So pretty much every patient that has low-volume metastatic disease gets referred for radiation therapy. The question was at hand, from STAMPEDE, there was no ARPIs, there's no abi, enza, et cetera. Well, PEACE-1 was conducted. PEACE-1 is a four-arm trial and it's actually very small, when you take all four of those arms, and half the guys in the trial about had chemo. So it's really a triplet/quadruplet therapy trial. But in low-volume disease, as you see on the left, the primary endpoint for this radiation sub part of the trial was rPFS, radiographic progression-free survival. There's a significant benefit of adding the radiation even on top of ADT plus abi plus half the guys had chemo.

And then if you look in all men, and this is actually the interesting thing, I don't think anyone was surprised by this on the left, but on the right is that whether you're low or high volume, adding RT to the primary in the setting of abi and some had chemo improved freedom from castration-resistant prostate cancer. At the bottom is the same thing in all patients, freedom from serious GU side effects. Do you need to have a TURP, do you have obstruction, et cetera? We, in our practice now for younger men that have started doublet or triplet systemic therapy that have high-volume disease that are not rapidly progressing, usually give them four to 6 months that they're having a good response. We will talk to them about this data if they want to do treatment to the primary.

I won't talk about all the old data like STOMP and ORIOLE of radiating just a couple PSMA mets in the recurrent setting. What I'll instead talk to you about is in metastatic castrate-resistant prostate cancer, this is the ARTO trial just published in JCO, they took patients with oligometastatic castration-resistant disease. It's a small trial. This is not like a thousand patient trial. You can see here that progression-free survival, which is what it was powered for, was substantially improved by radiating these metastases.

So effectively, you could think of that as if, let's say, first-line CRPC therapy, I'll just make it up, is enzalutamide or apalutamide, whatever you want to give, that you are staying on that therapy for a substantially longer period of time. OS, which I wouldn't expect, is whatever, you can pretend if that's a signal of survival benefit. But what I show is SABR-COMET, which included prostate cancer patients, but it's got lung cancer, a bunch of worse acting cancers. I think this is a lot more similar than what we're seeing in STOMP and ORIOLE, which those were trials that if you had, let's say, surgery, you recurred, you radiate a couple mets with no systemic therapy, we'll never see curves like this in those trials. But I think when you're in the advanced, these men do not have a long life expectancy, that there's a really profound impact in cytoreducing or getting rid of their their oligo-progressive clones that are resisting systemic therapy.

To put this concept out there for people, that I think there's more and more trials trying to ask this question is just for a moment that usually in tumor boards, if someone gets radiation and they recur, we say they failed radiation. Now, if it's a patient advocacy group, the patients get, "The patient didn't fail radiation, the treatment failed." And that's true. But the question I ask you is, if I were to give one cycle of docetaxel and the patient wasn't cured, did they fail chemo? Or we have patients, right, that you give full, full course chemo, maybe they progress later and you give chemo again. We even do that with ARPIs. With lutetium-PSMA, there's been published papers now of people giving up to 10 rounds of this stuff. We don't say they fail after one or two. And so the question is, why are we thinking of this as an isolated event of just treating, let's say, one met or two mets, and not doing cycles of therapy over time. To put it in perspective, lutetium-PSMA is like $45,000 a pop. It's about $10,000 plus or minus for a course of SBRT.

This is one of my patients who was heavily counseled to what the standard of care and what the standard of care is not. And we had multiple tumor boards, et cetera. He had, before I met him, surgery, he recurred. Had salvage radiation, he recurred. Went on hormone therapy, was on it for quite a while. This is his plotted PSA. They put him on abiraterone, PSA started going up. They put him on PROVENGE, PSA didn't really do anything, maybe went down a little.

Then was referred to see me. We had a long talk. This guy is about 80 years old, did not want to do chemotherapy, did not want to do other therapies at that time. So I radiated a lymph node and his PSA went back to near undetectable just on Lupron. About a year later, SBRT to a bone met, PSA went down just on Lupron. And then he actually wanted to be off Lupron. So he went completely off Lupron for a guy that's now multiple years out with mCRPC, and he had seven lung mets. Who's Dr. Spratt? He must be insane. Why is this guy not getting the kitchen sink thrown at him? We talked, the patient still refused. He's like, "I'm not doing anything more than Lupron." I said, "Okay, I will radiate each one of these lung mets." And this guy has, since then, so he's 6 years as you see here with mCRPC, he's almost 3 years out from radiating his lungs. He's on Lupron alone. He has, definitionally, metastatic hormone-sensitive prostate cancer. The PSA of 0.1. This is not standard of care. Please do not take that.

The point is, is the concept that, and they're way far ahead of us in non-small cell lung cancer. They have like three randomized trials showing survival benefits of radiating oligo progressive disease. This is coming and you can do this in different ways. You can use radionuclide therapy to cytoreduce, but I think this is something that's going to be spreading. We just need, obviously, this to be done, obviously, in a controlled way.

People will ask always, "What the heck's the role of proton therapy in prostate cancer?" I am the chairman of a center that has proton beam. I've treated under 5 patients with proton therapy and don't recommend it for any patient. I was telling someone earlier, I say, "It's a Samsung or an iPhone. The tumor control is the same. There's some theoretical benefits. I don't think there's anything worse. If you have Medicare, the cost is the same. If you don't have Medicare, you're going to pay a lot of money. So if you're fine paying a lot of money for a theoretical benefit, that's why some people buy a $1,500 iPhone and don't just get some cheap off-the-shelf thing that does the same thing." That's really up to the patient. No one should be saying proton beam therapy has been proven to be better. This is the only randomized trial that's been done. We participated in it, we'll wait for the results to come out.

Some centers, which I think this will be less relevant now, but I was super excited about this technology, this trial done by Amar Kishan at UCLA, it's called the MIRAGE trial. They use this MRI, and it's an MRI linear accelerator instead of just CT images. There's some criticisms to the trial, but end of the day, it showed probably the lowest side effects that we've ever seen before in any prostate cancer radiation trial because they, essentially, could give almost no margin, which we always give some error buffer because the MRI, there's no radiation, it can constantly image that prostate and turn the beam on and off if it moved. The company went bankrupt. Fired chapter 11, then chapter 7 went bankrupt, they're desperately trying to get service contracts, et cetera. I think there's some criticisms to the trial. But anyways, just so you hear.

In summary, I think radiation therapy continues to expand its role, especially if you start talking about the ultra-high-risk or node-positive and beyond. More and more of those patients. I think radiation therapy has become increasingly more convenient. That's one of the biggest downsides compared to whether brachytherapy or surgery. And so a lot of patients now, I would say a third of my patients, come from out of state or out of the US because they just stay for a week, week and a half. This dose painting concept I showed you, I think keep your eye out that I think we're going to, that's sort of the true breast conservation paradigm of giving a high dose to the tumor and a low dose to the gland. I think we'll see the results of that. And then biomarkers, I think men will love if they can safely avoid hormone therapy. With that, thank you guys, really appreciate the invitation. Don't know if there's time for questions. If there is, happy to take any.