Zachary Klaassen: Hi. My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. Delighted to be joined on UroToday by Dr. Amar Kishan and Dr. Jeremie Calais, who are both at UCLA. Today, we're going to be talking about the LUNAR trial, which was presented here at ASTRO 2025 and actually just recently published in the Journal of Clinical Oncology. So gentlemen, thanks very much for joining us on UroToday to discuss the LUNAR trial.

Amar Kishan: Thanks so much for the invitation.

Jeremie Calais: Pleasure to be here as always.

Zachary Klaassen: Always good having you guys on. And this is some great data. I'm excited to talk to you about it. Before we get into the LUNAR trial, Amar, maybe just tell us a little bit about why we maybe need new therapeutics for oligometastatic hormone-sensitive prostate cancer. This has become a really hot topic with SBRT and just some more data and more therapeutics. Why are we interested in this disease space?

Amar Kishan: Sure. Great question. So essentially, we've had a lot of phase two randomized trials in this space that have shown that SBRT or MDT in general, metastasis-directed therapy in general does provide what I think is a clinically meaningful benefit in terms of progression-free survival or hormone therapy-free survival for these men with oligometastatic prostate cancer, which is broadly defined as one to five lesions. Some of the earlier trials were one to three. It's been a little bit extended in more recent trials.

But the issue is that very few patients would see durable disease control, so if you look at all of these trials pulled together, the three-year durable complete response is actually less than 20%, so probably potentially significantly less of that. And that's because although we have these advanced molecular imaging like PSMA PET, the sensitivity is somewhat limited and oftentimes what we are seeing is not the true extent of disease. And so the premise behind this study is that we wanted something that could address the micrometastatic disease that we cannot see on the PSMA PET, but we didn't want to achieve this with hormone therapy, because one obvious question is why don't you just add hormone therapy?

There was a recent study called the RADIOSA trial that looked at that, but as you know and anyone who treats prostate cancer knows, most men do not want to be on hormone therapy. And particularly in this relatively early disease setting, they're looking at potentially ways to delay and avoid that. So our hypothesis and Dr. Calais, Jeremie can get into some of the details on the trial design, but our hypothesis was that by adding radioligand therapy directed against PSMA, we would be able to address the micrometastatic disease and use the SBRT to address the macroscopic disease and thereby improve progression-free survival.

Zachary Klaassen: Yeah. No. It's a great background. And just to put on my bladder cancer hat for a minute, when we explain to patients why we do neoadjuvant therapy before cystectomy, it's exactly that reason. It's treating the disease that we can't see. We're treating the whole body. Come back and do the bladder here. It's treating the metastatic disease in prostate cancer, SBRT to the lesions that we can actually see. So I think you're right. I think that micrometastatic assessment and treating that and then targeting is exactly the way I looked at it when I was looking at your trial. So I'll address Jeremie for the trial design. Maybe go through the inclusion criteria, the intervention of this trial.

Jeremie Calais: We came up with one-year progression rates with SBRT. That's about 50% from historical data. Our hypothesis was that by adding two cycles, neoadjuvant of lutetium-PSMA therapy before SBRT could reduce the one-year progression-free survival rate to 30%. So to do that, which is a pretty big difference, we needed 45 patients into two groups. So the patients were straightforward inclusion criteria. Patient with recurrent hormone-sensitive prostate cancer as attested by testosterone with a level above 50 and no ADT within the prior six months.

They underwent a PSMA PET scan. If the PSMA PET scan showed one to five lesions, then they were eligible. They were randomized one-to-one either to the control group, standard SBRT to the one to five lesions versus the intervention group, which was the combination therapy arm. Two cycles of lutetium-PSMA therapy, neoadjuvant before SBRT. Each cycle was 6.8 gigabecquerel, eight weeks interval between the two. Then patient underwent another PSMA PET scan for restaging after lutetium-PSMA and for retreatment planning if needed. Then patient got the SBRT to the one to five lesions as initially described at the beginning. And then in both groups, patients were followed up with PSA every three months and more importantly and quite nicely, they had systematic PSMA PET scans including into the trial, so that's something that is quite novel in this trial.

The PSMA PET scans were done at 12 months, at 24 months and at each PSA rise. The main primary endpoint was the progression-free survival defined as time from randomization to PSMA PET-based progression. Basically, a new lesion or the initiation of salvage hormonal therapy or death. Well, at the end, there was no death event that was observed, so it was either new lesion on PSMA PET scan or a salvage hormonal therapy initiation, basically. For secondary endpoints, we had some toxicity assessment, hormonal therapy-free survival and we'll report, in a separate study, dosimetry as well.

Zachary Klaassen: I just want to ask you guys, I know we've seen six cycles in VISION and PSMAfore, how did you decide on the two cycles for this trial?

Jeremie Calais: Yeah. So VISION is in a much more advanced patient population, so the toxicity concern are different than in a very early disease stage patient population such as here. They have probably a life expectancy of close to 20 years, I would say. But the exposure to the number of cycles does matter a lot in terms of toxicity. So that's one thing. For example, if you take PSMA-DC trial, which is the Novartis trial done pretty much in the same patient population, they choose to do SBRT plus four cycles of lutetium-PSMA therapy in the adjuvant setting, so after SBRT. You should look at PSMAddition, which is a little bit later in the disease stage trajectory, but still hormone-sensitive metastatic.

Of course, these patients will have a higher volume of disease. They got up to six cycles and people are a bit concerned about giving six cycles upfront in a role like that to these patients. So our approach was really to initiate something. I think lutetium-PSMA therapy in this range of dosing we're doing, everybody deserves at least two cycles to retrigger some effect. Most of the effects that you get from lutetium-PSMA therapy, both in the very advanced stage setting or early, you observe it when the patients are responding during the first two cycles, so that's when the disease is responding the most. Then it would trigger something. And so it's this compromise between toxicity, adding something, but not too much, followed by the control SBRT. But of course, one could have discussed four cycles, three cycles. There is some empiricism in that, of course.

Zachary Klaassen: Sure. That's a great explanation, Jeremie. Amar, maybe just walk our listeners through the key results presented at ASTRO and then published in JCO.

Amar Kishan: Sure. Absolutely. And one other thing just to hammer home for everyone is that this was a very early disease setting as Jeremie was discussing. So the median PSA was 1.2 in the control arm and 1.1 in the experimental arm. And we did get conventional imaging as well for these patients. There were some that did have M1b disease on conventional imaging. About 20%. But 69% on the control arm and 76% on the experimental arm had N0M0 disease on conventional imaging, so a very early disease state. As expected, almost 100% of patients did have PSMA avidity. This was an inclusion criteria and the vast majority of patients had what would be called VISION-positive disease on PSMA PET, so even in this very early disease stage, these were high uptake lesions.

And in terms of the response, what we observed following the addition of the two neoadjuvant cycles, just on follow-up, median six months or so after receiving it before SBRT, is that 19% of patients in the experimental arm had no evidence of visible disease on PSMA PET while in the control arm everyone still had visible disease. And so it was showing that even with just these two cycles, you were able to get durable complete responses in some patients. And when we look at the progression-free survival at the 24-month median follow-up of the trial that now has been published, the median PFS in the control arm was 11.8 months. Quite short if you think about it. This is why most patients with oligometastatic prostate cancer, even today, are offered hormone therapy on a regular basis and not offered this kind of concept of only SBRT or metastasis-directed therapy to avoid hormone therapy. But in the intervention arm, the median was 23.6 months. The hazard ratio was 0.44 and this was statistically significant.

So we were able to really effectively double the progression-free survival from 12 months to two years. Hormone therapy-free survival was also significantly improved here, so that was actually extended from 14.1 months to 24.3 months, so the hazard ratio was 0.4. So we were buying patients two years off hormone therapy on median. And I think for this patient population, that's critical. Patients want to avoid hormone therapy if they can and all the toxicity that that comes with. I think that's a very meaningful endpoint in early oligometastatic prostate cancer.

Zachary Klaassen: Yeah. Just to highlight the take-home points, the PFS and HTFS, you essentially doubled them in both of the groups, which is just very impressive, I think. A few times you've hit on this, Amar, but contextualizing the LUNAR trial with PSMAddition, they were all over the internet last week. Everybody was talking about it. Some people are excited, some people were a little less excited just about the trial design. How do you contextualize? I know different stages. You just highlighted that. Are there any other ways we can help our audience understand the difference between these trials? And maybe I'll start with you, Amar.

Amar Kishan: Sure. Yeah. I think a key thing to understand is what did the control arm of PSMAddition receive, which was intensive doublet hormone therapy using an ARPI. That, as we know and have shown in a few studies in the metastatic hormone-sensitive setting, is highly effective, providing a clinically meaningful RPFS benefit, radiographic progression-free survival benefit. And so when you compare that to adding Lutetium on top, if there is a difference, it's a bit more of a marginal effect that you would see.

And even though there was a benefit, it was somewhat limited in terms of the actual effect size. And so I do think that in that more advanced setting, using radioligand therapy, especially with the extensive six cycles, particularly if it's delivered up front within a certain time frame, you are at risks of toxicity and the question is was it worth it? Was it truly worth it given that what else is on the table is something that was already incredibly effective and already significantly improved here, so that was actually extended from 14.1 months to 24.3 months, so the hazard ratio was 0.4. So we were buying patients two years off hormone therapy on median. And I think for this patient population, that's critical. Patients want to avoid hormone therapy if they can and all the toxicity that that comes with. I think that's a very meaningful endpoint in early oligometastatic prostate cancer. In the PSMAddition trial, these were patients with true metastatic disease based on conventional imaging and there certainly was an RPFS benefit, which is meaningful, because in that context on hormone therapy, radiographic progression implies development of castration resistance, so that's a meaningful endpoint.

But perhaps other things to think about would be did the patients need all of the six cycles that were delivered? Could there have been a response on ADT alone? Could the dosing have been adjusted? Because there were some toxicity seen at that study as opposed to LUNAR which obviously had less dose and a different agent. And another question just is maybe there's a way to leverage these things differently. Perhaps not all the patients need lifelong hormone therapy or doublet hormone therapy. Maybe there's a way to use this active agent to reduce the duration on intensive hormone therapy, analogous to what we did. Maybe not eliminating it entirely, but shortening the duration to give patients a break from the toxicity.

Zachary Klaassen: Sure. Jeremie, what are your thoughts?

Jeremie Calais: Yeah. So first, as a reminder, in the PSMAddition, it was doublet therapy, ADT plus ARPI versus triplet therapy. ADT, ARPI plus lutetium-PSMA therapy. And in that setting, we know that the doublet therapy is already quite effective, so that's why the RPFS difference, first of all, it was already significant, so there is something, but all the other endpoints and even the order of magnitude of difference was, for some, already disappointing, but just to remind that it was doublet therapy versus triplet, so it was already quite effective treatments. In LUNAR, the patient population is obviously at a much earlier disease stage.

The PET scans, you see tiny dots barely with uptake above the liver one, so they would not meet VISION criteria for example. We don't have these big black spots. They're VISION negative if you follow strictly the rules, but nevertheless, they still benefited from the treatment. And so that really gives some depth about the mechanism of action of the drug, depending on the disease stage. When you are in the very advanced patient population, when you have the differentiation processes, here, you really need to ensure you see PSMA expression on the PET scan, because you know the volume of disease is high, so you don't have these tiny dots that the level of expression will be low just as a matter of size and not matter of expression. Whereas in high volume advanced patients, you really want to have high PSMA expression visible, because these lesions are big. Now, this criteria, they don't translate here in the early disease stage population, because the lesions are mostly micrometastatic.

And even if there is sufficient PSMA expression, which is the case in a hormone-sensitive prostate cancer stage. The differentiation processes. There were not a lot of prior systemic therapy exposure yet, so it's still very PSMA-positive disease. It's just too small to be seen. And so that's another level of consideration, but we don't see it on the PSMA PET scan, but we still treat it with a PSMA-targeted agent. So that's one thing. Then another thing I think is clearly how we define response and how we can tailor a little bit at the number of cycles, maybe the treatment intervals. For sure in PSMAddition, the main concern was to give six cycles in a row upfront like that and I think maybe some patients may benefit from that. If you still see some disease, if the PSA maybe is still high, you want to continue of course. But if everything disappeared, which happened quite frequently in these patients, you may want to pause and save potential toxicity for later and additional cycles for later.

Zachary Klaassen: Yeah. Absolutely. I appreciate you guys contextualizing that for our listeners. Before we wrap up, Amar, I wanted you to touch on some of the really cool translational work you also presented at ASTRO. So I think it's important maybe as a biomarker moving forward.

Amar Kishan: Sure. So there are two things that we wanted to look at as correlative objectives. One was this potential story of an immune response being helpful in these patients and so we did look at productive rearrangements in the T-cell receptor and we found that that was highly prognostic when measured 90 days after SBRT in both arms. The hazard ratio was 0.46. And I think this adds to some building evidence that maybe in the oligometastatic space, so obviously, prostate has been the most cold in terms of immune response in general, but perhaps by ablating all sites of disease, you are activating some kind of antitumor immune response that can be prognostic.

There are now several other studies that have also shown this. And then we also wanted to see if there are any germline biomarkers that might predict for an increased risk for progression, because to what we were discussing, maybe not everyone needs the intensification. Maybe there are some patients that may be controlled with just SBRT and not everyone progressed. And so we did look at microRNA-related binding element, single nucleotide polymorphisms. We call them areas of interest in our group. And we did find a biomarker based on 25 of these single nucleotide polymorphisms that was effective at separating patients in both the control arm and experimental arm into those at very high risk and very low risk progression. And so I think this just adds to enhance patient selection. Who are the people that are most likely to benefit from systemic intensification? And then those that need it, how might we may be able to harness things like the immune response to help our modalities be more effective?

Zachary Klaassen: No. Absolutely. Great. It was beautiful work. I think more to come on that for sure as we move forward and listen, just want to thank you guys both for joining us. Maybe a quick take home message from each of you just to wrap things up. I'll start with you, Jeremie.

Jeremie Calais: Yeah. I think this trial is especially exciting, because it showcased the full potential of PSMA-based theranostics. We know we leverage the PSMA PET sensitivity to better select patient for oligometastatic directed therapy and then we use a PSMA-targeted radioligand therapy agent to treat the microscopic disease. And also, I think it's a great collaboration between nuclear medicine and radiation oncology and that's a great example on how we can leverage therapy, imaging, radioligand therapy, image-guided radiation therapy. Yeah. And just kudos to my buddy and colleague, Amar. Such a pleasure to do these kinds of trials.

Zachary Klaassen: Yeah. Well said. Amar, you have the final word.

Amar Kishan: Well, I echo Jeremie's sentiments and it's always a pleasure to work with him and his team. I think, again, this does underscore the potential benefit we can have for patients using these drugs that have been verified to be active in more advanced settings. Moving them earlier, it's just an idea that we need to test. Testing in a rigorous clinical trial, we're able to see a clear benefit for patients. I think the PFS benefit and particularly the hormone therapy-free survival benefit is really meaningful to patients.

Zachary Klaassen: Absolutely. Thank you again for joining us. The JCO publication just released online, so invite our listeners to check that out as well. We'll link it to the discussion. Thank you both for joining us on UroToday.

Jeremie Calais: Thank you.

Amar Kishan: Thanks.