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Rana McKay: Hello, my name is Rana McKay, and I'm a GU Medical Oncologist at the University of California in San Diego. It is my absolute honor to have Dr. Leslie Ballas here with us today, who is a professor of radiation oncology at Cedars-Sinai. Today, we're going to be discussing an educational series highlighting the state-of-the-art interdisciplinary management of prostate cancer. And today's topic is really focused on high-risk, localized prostate cancer, really with the lens of a radiation oncologist's perspective. So, Leslie, it's absolutely wonderful to have you here with us.

Leslie Ballas: Thanks, Rana. I really appreciate it. So, thank you again for inviting me to be part of this interdisciplinary management for patients with prostate cancer. I'm going to be talking about what we understand about high-risk prostate cancer in 2024 and giving a radiation oncology perspective. I think when we talk about high-risk prostate cancer in 2024, we need to figure out who is a high-risk prostate cancer patient, highlighting the use of PSMA PET. I want to talk about shared decision-making for these patients and touch on whether all high-risk prostate cancer is the same. As you can see from this figure here from the pro-PSMA study, PSMA PET scan has a 27% greater accuracy than that of conventional imaging. This reflected a lower sensitivity and specificity for conventional imaging compared to PSMA PET CT. And so in 2024, our high-risk patients should ideally be staged with PSMA PET. The question then becomes, should we be acting on what we find on PSMA?

The EMPIRE-1 study was a randomized trial to see if treating PSMA-detected disease in the post-prostatectomy setting improved freedom from event-free survival. And again, this is a different setting, but it is one such trial that looks at whether or not it's important to act on what's found from PSMA. And what they found was that the three-year event-free survival was 63% in the conventional imaging group versus 75.5% in the PET-CT arm. And so there was a statistically significant difference in using PET to direct post-prostatectomy radiotherapy. However, PET-CT is not perfect. And so when we think about using PET-CT to direct radiotherapy, we have to remember that there are other clinical variables that are still extremely important to use. And one such study that shows us this, I think, pretty well, is the POP-RT study. Dr. Murthy and his colleagues showed that when using radiotherapy for high-risk disease, there is a benefit in including the whole pelvis versus the prostate only in terms of biochemical failure-free survival and disease-free survival at five years.

These were patients who were thought to be node-negative, and importantly, 80% of them were staged with PSMA PET, indicating that while PSMA PET is great imaging and helps us stage patients, it can't alone decide how we treat patients and what our radiotherapy field size should be. When we look at the options for high-risk prostate cancer, there is a choice for patients, a choice in their care. Patients can get radiotherapy plus ADT or radiotherapy plus ADT, and perhaps an ARSI in the very high-risk patients, or prostatectomy with pelvic lymph node dissection. And this brings me to the next point that I wanted to discuss, which was that shared decision-making in the treatment of these patients is essential. The AUA/ASTRO Guidelines from 2022 indicated the components of shared decision-making for clinically localized prostate cancer treatment. And I think that both radiation oncologists and surgeons who are meeting patients upfront do a really good job in shared decision-making.

But as we use more surgery and/or radiation in the high-risk patient population, it's important to remember this. We know that the selection of a management strategy for clinically localized prostate cancer is a preference-sensitive decision and is often based on the patient's interpretation of the balance between the risks and benefits of each treatment. We know that randomized controlled trials of shared decision-making versus just routine care have demonstrated that patients who use shared decision-making are more knowledgeable, have more reasonable expectations, and so, therefore, just get another plug for that, whether it's in a multidisciplinary clinic or whether it is done in separate clinics, but to engage our patients.

I think the next question that comes up at this time is, "Is all high-risk disease the same?" We know that in the intermediate-risk prostate cancer population, there is a distinct difference in outcomes between favorable and unfavorable intermediate-risk disease. Does that same favorable-unfavorable dichotomy exist in high-risk patients? Work from the Dana-Farber group has shown that, in fact, there is a difference in prostate cancer-specific mortality in patients who have a sort of favorable high-risk picture versus this other high-risk picture, which you can see from the Kaplan-Meier curves on both the one on the left, which is from their own institutional database of 3,500-plus patients, and confirmed on the right when used in a 14,000 or 13,000 patient series from the SEER database.

And so that then brings up the question that if not all high-risk patients are the same, should we be using androgen receptor signaling inhibitors or other medications to distinguish high-risk patients from very high-risk disease? The current NCCN guidelines say that there is a difference between high and very high-risk. And when you look at data from the STAMPEDE trial that evaluated the standard of care versus the standard of care plus abiraterone acetate and prednisolone with or without enzalutamide in the Attard study, which combined two STAMPEDE platform studies, they found that there was a benefit to combination therapy when the patients had at least two of the very high-risk features. And so I think that then says to us as practitioners, "Okay, well, if we're going to be giving hormone therapy with radiation, how can we distinguish high versus very high?" Are these clinical guidelines, digital rectal exam, or MRI plus Gleason grade group and PSA, are they sensitive enough for determining what patient treatment is best? And so that brings me to the use of Decipher, a genomic test to help discriminate high-risk disease.

Dr. Nguyen at Dana-Farber looked at taking biopsies of patients with prostate cancer and seeing if the genomic analysis known as the Decipher score, when dichotomized into sort of a high and then intermediate-low, could distinguish incidents of prostate cancer-specific mortality. And what they found was that indeed the Decipher high patients were doing worse in terms of their prostate cancer-specific mortality over time. If you compare this to CAPRA and NCCN in terms of their ability to discriminate patients, and this is all comers, they are not quite as good as the Decipher test. So that brings us to a current NRG clinical trial that is looking at the personalization of radiation for high-risk disease, which is where I think all of these features have brought us. One, they're using PSMA-PET as part of the staging. Two, they use the Decipher score to either intensify or de-intensify therapy based on risk stratification.

And within the highest-risk group, they are adding apalutamide in order to try to see if that ARSI does in fact provide better prostate cancer survival. And so this trial is open. I've enjoyed enrolling patients in it. I think it really encapsulates where radiation and personalized treatment for high-risk prostate cancer is today. Additionally, the NRG just recently opened another compendium study, which looks at, "How should we be giving that radiation? Should it be our standard hypofractionated radiation, 20 treatments or 28 treatments to the prostate, seminal vesicles, and pelvic lymph nodes, or is there room to use stereotactic body radiotherapy (SBRT)?" Can we shorten the course of radiation for these patients? And while we know that SBRT has similar oncologic outcomes to hypofractionated radiotherapy in the low- and intermediate-risk prostate cancer population, we don't know if that holds true in the high-risk population.

And the reason that it's slightly different is because of what we talked about earlier, that we're going to be treating pelvic lymph nodes in this population. And so, we want to make sure that one, the toxicity is acceptable, which studies have already shown that it looks to be, but also that it does produce similar outcomes. And so both NRG GU009 and 013 are really at the forefront of what is prostate and what's under the umbrella of prostate radiation in 2024. So, in summary, I think we have a better understanding of where disease is located. We know and use shared decision-making with our patients, and we are hopefully able to discriminate treatment for high-risk patients since, really, they are not all the same. And that's all I really wanted to show you in these slides. So, thank you so very much.

Rana McKay: Well, thank you so much for that amazing overview. I think it's really important for us to look at things through the lens of different specialists across the board. And I think PSMA PET has been such a disruptive modality in the treatment of prostate cancer, and we've unleashed this new technology, and the technology is absolutely changing management, but we haven't tested whether that change in management impacts outcomes. So I love your thoughts on that. And as you highlighted in your presentation.

Leslie Ballas: Yeah. And I think that, if I'm not mistaken, Cynthia Menard, who is a radiation oncologist in Montreal, is also looking at a PSMA-based change in treatment in higher-risk patients. She has a trial that is almost done accruing, if it's not done accruing. And so we'll have to wait for those results. But I couldn't agree more, Rana, that it is something that we are changing in the way that we treat patients without the full data yet to say that it's worth making the change.

Rana McKay: And it's absolutely impacting the conduct of our clinical trials because we look at these localized studies, and historically, MFS by conventional imaging has been utilized as an endpoint surrogate for OS from the ICECaP initiatives. And now patients are going to get PSMA PET scans, they're going to have stage migration, they're going to undergo interventions for those. And it's almost disrupted our endpoints that we've been using because they were all based on conventional imaging.

Leslie Ballas: Yeah, actually, I mean, we didn't even talk about this, but the use of SBRT for oligometastatic disease in prostate cancer is another one of those areas where we are drastically changing treatment based on PSMA PET, and yet there's a current clinical trial that's looking at the use of SBRT plus or minus hormone therapy in this patient population. And because we are so uncertain about how to use PSMA and how to follow patients with it, the endpoint has to be a radiologic classic, conventional radiologic endpoint still.

Rana McKay: Yeah, no, absolutely. And I think the other piece that you touched on is just we've historically lumped these high-risk individuals based on clinical parameters like classic NCCN criteria, but this group is so heterogeneous. We've got people that are not destined to recur, they're going to do just fine with minimal therapy, and there are individuals that need escalated therapy. So there's been a lot, I know, that's been done in trying to tease out the outcomes of those individuals, certainly Decipher. And the other marker that's assay that's been looked at as sort of pathology tools, the MMAI sort of path tool to predict individuals that are at high risk. So, I love the NRG-009 study that's integrating Decipher, but also thinking about all the other tests that are coming out at this time.

Leslie Ballas: I know, I think, as the technology is advancing, and like you said, the use of MMAI and pathology to predict outcomes is so exciting to think about the idea that you could use biopsy material and sort of know how someone's going to do because it's predictive and prognostic. But I always worry, and this is always a question in clinical trials, is 009 is such a smart trial, and it's using Decipher, and then by the time it matures, is everyone going to be using MMAI and not Decipher? And then we're sort of stuck with the chicken and the egg, and we've got to start all over with 009, but with AI.

Rana McKay: Yeah, yeah. No, I hear you. I mean, the good thing is, I think integrating path AI is simple. It's digitalized images from H&E slides, and in the context of a great over 200-patient trial conceivably, that could provide some validation. But it's been fantastic chatting with you, Leslie, kind of going through where we are in the field, things to look forward to in the future, and it really is exciting that we're moving the needle, not just in the way that we deliver radiation therapy, but also in how we stage our patients, the extent of disease that gets treated, and then the integration of systemic therapy. So, thank you so much.

Leslie Ballas: Thank you for inviting me. This was so much fun. I loved it.