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Nicholas Nickols: I'm Nick Nickols. I am a radiation oncologist from UCLA and the VA at West LA. And I am just thrilled to be here. And thank you so much to the organizers. Before I start, I just wanted to kind of zoom out a little bit and talk about the big picture. So we kind of all know this, but it's pretty obvious. Prostate cancer used to be one of the worst imaged cancers systemically. And then very quickly it has become arguably maybe the best imaged cancer systemically. And this is really a big deal and it's due to a lot of the work that people in this room have done. I mean, go back in time. You have a patient that had a planar bone scan, comes in, you see a couple of lesions and you don't know if they have metastatic prostate cancer or possibly they slipped on a banana peel and fell into the wall on their way in. The scary thing is they might've ended up getting the same treatment afterward anyway. So really important stuff.

So my talk is on incorporating PSMA PET into radiotherapy planning with an impact on definitive therapy. And I'm trying to advance slides, but... Here we go. So we'll talk about overall treatment management, optimization of target coverage, of focal dose escalations to areas of gross disease that you wouldn't have seen otherwise and we'll touch on metastasis-directed therapy. Where am I supposed to aim this? Ah. Here we go. So this is kind of a broad picture here. Without PSMA PET, often times you'd have a patient that has no evidence of metastasis, you may recommend... Oh. There you go. Thank you. Very good point. All right. So radiation or surgery, probably the wrong answer. If you had molecular PET imaging, you would see that there are metastases there and a revised plan would... Well, this is a good question. We're still trying to figure this out. Probably certainly escalated systemic therapy, maybe not metastasis-directed therapy, somatic sequencing, and hopefully strongly consider enrolling in a clinical trial.
So in terms of radiation oncology, what this enables us to do is really precision radiotherapy. We can escalate the dose to disease that we didn't necessarily see before and we can consider treating metastases, among other things.

So first we'll talk about optimization of target coverage. So going back in time maybe to 2018, 2020, it seems like a long time ago, but it really wasn't, lots and lots of people in and around radiation oncology were realizing PSMA PET is here and this is going to have a big deal. So a lot of people did very similar projects, many people that are here actually. We would take PSMA PET scans on patients that basically had high-risk prostate cancer and then without looking at the PSMA part, looking at the CT part, kind of delineate and make a plan for what we would have done and then kind of turn the light on and look at the PSMA PET part and see how well we did. Did we miss? Did we get the wrong stage? How did we do? And so overall it was about 9% or so upstage to M1 disease and changes in either the prostate or the lymph node radiation in maybe about 13 to 20%.

And we can classify the impact on treatment in a few ways. A major impact, that would kind of be like you got the wrong stage or you totally missed. That's obviously not good. Or minor impact could be, well, we would've hit it anyway, but we probably could have given a better dose. And so this was our work that we did early on, and we took patients that had unfavorable or high-risk prostate cancer, conventional imaging negative and then had undergone a PSMA PET. We did two. We did an approach and then tried to see if we had the PSMA to merge onto it how much of a difference that would make. A major impact in 16 to 37% depending on if you included pelvic nodes, which is this whole other debate, which I won't get into, and a minor impact potentially on 100% because all the patients had gross disease.

And so actually, there was a randomized trial for patients that were to undergo radiation, definitive radiation, for prostate cancer, high risk or unfavorable intermediate risk, run out of UCLA. And basically, they were randomized to proceed as planned or get a PSMA PET and have a PSMA PET guided radiation treatment plan. Now, the trial actually closed early due to the widespread adoption of PSMA PET in the use of staging of localized prostate cancer. So in a sense, PSMA PET was basically too successful for this trial to complete.

Also, there is a trial in Canada, multi-sites in Canada, basically the PATRON trial. So these are patients at high risk of having metastasis. This is a randomized trial. It's very large. They're randomizing patients to basically treatment plan based on conventional imaging, and then half of the patients will also get PSMA PET and the patients that get that will have an intensification of the radiation and surgery component of their treatment. So this is like tumor-directed intensification by anatomic treatments. And they estimate probably about 50% of the patients that go on to the PSMA arm will have some intensification. This is based on prior results from a phase two trial, the PSMA GRT trial. Failure-free survival is the primary endpoint. Excited to look forward to the results here.

Now, in terms of optimizing target coverage in radiation oncology, there are a lot of contouring guidelines. That means we delineate out the areas that we want to get the radiation as opposed to the areas we do not want to get the radiation. And the NRG recently updated their pelvic lymph node contouring guidelines. PSMA PET had a very large role in informing how they went about to do that. You can look at various. NRG isn't the only one out there. There are other groups that have made contouring guidelines. And now with molecular imaging in PSMA PET, we can kind of see maybe which ones might be good and less good. And so bottom line, probably we're still missing a lot. So molecular imaging adds quite a lot to it.

And then there have been approaches to develop contouring guidelines for para-aortic lymph nodes. We're not even really sure yet what the role of that will be in the treatment of patients, but it's here. Which begs another interesting question that probably was not thought about so much before. So we can target individual lymph nodes. That's true. We can also target lymph node regions. That's also true. What should we do? Should we target individual lesions or individual lesions plus the lymph node basin in there? And this trial is looking to answer that question. This is the PEACE V-STORM trial. It's in Ghent. And it is randomizing patients with molecular PET imaged pelvic lymph node metastases to basically metastasis-directed therapy versus that plus include sort of the whole pelvis there. So far, I don't think there's any primary endpoint data on this yet, but the toxicity looks pretty tolerable.

Okay. Now, we're going to talk about how we can use the primary lesion in the prostate to potentially improve prostate radiation. So this is actually MRI. So the FLAME trial was a randomized trial that actually looked at doing a higher focal boost inside the prostate to the dominant lesion as identified based on MRI. It worked. So there was a disease-free survival benefit for patients with localized high risk and there was no impact on safety and quality of life. So maybe we could do this with PET. And as you can see, the FLAME trial really caught fire and there have been a bunch of other trials as well looking at can we do it with SBRT dosing. Yes, once a week. How about two or three times a week? Yes. Can we do this with PSMA PET? Clearly, MRI is great for looking inside the prostate. PSMA PET can look inside and outside.

So one question that you have to look at is if you're going to try to use PET to identify lesions in the prostate, how well are we doing in comparison to MRI? Because we already know kind of works with MRI. And so this is a group from UCLA that looked at this, patients that had undergone PSMA PET and MP MRI and then surgery with the pathologic examination of the slides as the gold standard. Basically, bottom line summary, both imaging have similar accuracy for the detection of localization of prostate cancer foci, but the best thing would be to use both. Similarly, a group in Freiburg did similar work and kind of similar outcomes except also noted that the PSMA PET delineated lesions might be a little bit larger than they would be on MRI.

Now if we're going to talk about trying to do focal boosts within the prostate using PET identified lesions, how are you going to delineate them? How are you going to segment them? This is not that simple because the lesion could be bigger or smaller based on how you threshold, which is very challenging. So this was a project done at Hopkins to look at more optimizing how are you going to segment these lesions? They found out that manual segmentation probably overestimated and they had an adaptive segmentation algorithm that looked to be the best. People have also applied AI and deep learning to delineate lesions. So this is a collaboration that we have with Exini and Lantheus. This is promise software that actually can detect lesions automatically throughout the body and then as well as within the prostate, and then the segmentation of lesions is based also on an adaptive thresholding algorithm.

Others have also used AI to delineate lesions here as well. And now trials incorporating focal boosts within PET identified focal boosts have been done. So this was a group out of Freiburg and this was basically looking at feasibility. "Can we use PET boosts safely and get the dose higher?" And the answer was yes. They had an arm with fractionated radiation and an arm also with brachytherapy. And they basically merged the MRI and the PET volumes as their boost volumes. And that has led to a larger phase three trial. This is the HypoFocal-SBRT trial in Germany, Austria, Switzerland, and Cyprus. And we will see what the result is. We're anxiously awaiting.

So we were talking about using PET interlesions for boosting. So this is another approach here. So not only that, but also looking at the PET emission as basically a way to target and guide and follow and track what's going on in the prostate. So this is the reflexion technology. This is a project out of Peter MacCallum, which was a planning study feasibility. Could it be done? What percentage of prostate patients that were going to undergo radiation could it be applicable to? Probably about half. So I don't think they've actually done this yet, but probably will.

Now, what to do about metastatic disease? So we're catching. Sometimes the metastatic disease we call on bone scan actually isn't really metastatic disease, but probably a little bit more often the PSMA is catching metastatic disease. And the question is what to do about this? So this trial that we did at GLA. We kind of just finished it. So these were for veterans that had de novo prostate cancer with limited metastatic disease, one to five M1 metastases. And the majority, 90%, were staged with PSMA PET. And so the treatments were aggressive local therapy, RP or RT to the primary, SBRT to all the metastases, and then limited but intensified systemic therapy, eligard, apalutamide, and abiraterone, and then stopped systemic therapy and then waited until testosterone recovered and then waited another six months. And if they were free of any PSA progression, we considered that a success.

And this is a swimmer plot here, where the orange is when they're on active therapy, the green is off therapy, testosterone not recovered, and the blue is testosterone recovered, off therapy. And there's a lot of blue and green, which we're very excited about. So, so far, 20 of 24, which was actually all of them, have met the primary endpoint, and looking good. All right. But now there are also bigger trials ongoing. So this is the VA STARPORT trial. So it initially was just for recurrent patients, recently changed to de novo, also, best systemic therapy, plus or minus PET-directed, tumor-directed therapy or surgery. The vast majority of the patients are PSMA PET. So we will anxiously await the results of this trial. And then also the PRESTO trial, which allows PSMA or choline PET. And this is being done in France, similar systemic therapy, plus or minus metastasis-directed therapy. And we're looking forward to the results as well. And I think STAMPEDE2 was also doing something like this, but I couldn't find the details on it, so I didn't include it. And that's all I got.