Amar Kishan: Thank you very much, Dr. Ballas, for that introduction and for the invitation to present my work here today. I'll be giving a brief presentation on the primary endpoint analysis of the Phase II LUNAR trial. So as we know, metastasis-directed therapy has emerged as a tool for prolonging progression-free survival or PFS in men with oligometastatic recurrent prostate cancer with stereotactic body radiotherapy, or SBRT, presenting itself as a highly effective modality with low treatment-associated toxicity on the basis of multiple Phase II randomized trials. We also know that highly sensitive prostate-specific membrane antigen, PSMA, PET/CT has allowed the optimal identification of patients for metastasis-directed SBRT. Unfortunately, however, progression ultimately still occurs in a majority of patients, underscoring the existence of occult microscopic disease in this population. Now, PSMA-based radioligand therapy, or RLT, agents that combine Lutetium 177 with ligands to PSMA have offered improved PFS in men with advanced prostate cancer.
These drugs were first studied in late-stage post-chemotherapy metastatic castration-resistant disease and now have promising data even in de novo metastatic hormone-sensitive disease. Thus far, the observed impact of PSMA-based radioligand therapy has been on macroscopic disease. The hypothesis that we investigated in the LUNAR trial was specifically whether adding PSMA-based radioligand therapy with 177 Lu-PNT2002 to metastasis-directed SBRT in men with oligo-recurrent metastatic prostate cancer will prolong PFS by acting on occult micrometastatic disease. You can see here the randomization schema is a straightforward one-to-one randomization. We enrolled men with one to five lesions outside the prostate or prostate bed on PSMA PET. On the control arm, patients received SBRT to all sites of disease. On the experimental arm, patients received two cycles of neoadjuvant 177 Lu-PNT2002 at a dose of 6.8 gigabecquerels, given in two cycles eight weeks apart. About four to six weeks later, we got an interval PSMA PET/CT and then we followed that with SBRT to all sites of disease.
Notably, on the experimental arm, we could adjust the dose and volume targeted by SBRT based on any potential response that was seen on that interval PET scan. As you can see, we had two stratification factors. One was staged on PSMA based PET imaging and the second was a number of lesions. Additionally, we did pre-specify translational blood draws at baseline and 90 days post-SBRT in both arms. Now, the primary outcome of the trial was progression-free survival, which was defined as a time from randomization until a composite outcome defined by PSMA PET/CT-based progression, salvage hormone therapy or death. Specifically PSMA PET-based progression was defined as either a new lesion on PSMA PET or local progression on PSMA PET. Local progression here would be an increase in SUV max of greater than 30% or an increase in the diameter of target lesions of 20% or more.
Follow up PSMA PET/CT was obtained one year post-SBRT in all patients or at time of PSA-based trigger, which depended on the PSA at enrollment. For patients who had a PSA of less than 0.5 at enrollment, an increase of 0.2 nanograms per milliliter or more would trigger a PSMA PET. And for patients who had a PSA greater than or equal to 0.5 in enrollment, a more than or equal to 50% increase in PSA over the post-SBRT nadir would trigger a PSMA PET. Now this is very important because we wanted to capture what we felt would be the real world follow-up of these patients. In many studies, PSMA PET defined disease does not constitute progression, but we felt in the real world, patients that are in this patient population that receive treatment and start to experience a rising PSA will very likely get a PSMA PET in practice. And with the FDA approval of that scan, with various agents now being approved, we felt that would be widespread practice and we wanted to mimic the real world.
Now as you can see on the left, on the consort diagram, we screened 100 patients from September 2022 to November 2023. We ultimately enrolled 92 patients who are then randomized. 45 patients were randomized to the interventional arm and 47 patients were randomized to the SBRT alone arm. Five patients immediately withdrew consent, so we ended up with 42 patients receiving SBRT and 45 patients receiving the investigational agent. On the right side, you can see a table with a treatment and clinical parameters of these patients. I've boxed in red what are probably the most salient features to highlight. The first is PSA at randomization. 1.2 in the SBRT arm and 1.1 in the neoadjuvant therapy arm. In terms of patients having an exposure to prior courses of MDT, this was fairly common, 38% in the SBRT arm and 28.9% in the investigational arm.
And in terms of stage by conventional imaging, most of these patients did have N0M0 disease on conventional imaging, about 69% in the SBRT arm and 75.6% in the investigational arm. But a minority of patients, about 20% in each arm, had M1b disease on conventional imaging. In terms of the types of patients being enrolled, again, I just want to hammer down that these are patients with low volume, oligorecurrent disease. You can see a typical pace on the right there. These are small lesions. If we look at the stage by PSMA, majority of these patients did have M1b disease, about 62% in either arm and the remainder had M1 or M1a or M1 disease. And in terms of lesion count, it's about an even split in patients who had one lesion versus two to three lesions, a minority of patients about 16% across both arms, had four to five lesions.
Now, if we look at our primary endpoint of progression-free survival, we find that median PFS increased significantly from 7.4 months with SBRT alone to 17.6 months with Lutetium plus SBRT. This was a highly significant difference, as you can see with the separation of the curves with a hazard rates of 0.37. Importantly, 98% of progression events, 64 of the 65 that we saw, were driven by new lesions. There was only one patient who actually happened to be on the experimental arm that had a rising PSA without any lesions found on PSMA PET that ultimately decided to undergo hormone therapy after a mutual discussion with the physician. On a per-lesion basis, lesional control was very, very high. So only two out of 91 lesions, about 2% on the SBRT arm, exhibited infield progression. And on the experimental arm, zero of 96 lesions showed infield progression. So again, just to underscore the point that the majority of progression events were indeed new lesions out of field failure on PSMA PET in terms of our key secondary endpoint, which was hormone therapy free survival, we also saw a benefit.
So median hormone therapy free survival increased from 14.1 months to 24.3 months. Again, highly statistically significant, with a hazard ratio of 0.4. And when we look at these patients, 46 of the 47 who started hormone therapy had new lesions on PSMA PET. The one exception is the patient I mentioned before who was on the experimental arm that simply had a rising PSA. Repeat metastasis-directed therapy without hormone therapy was delivered in 17 patients. It's always important to consider toxicity when we're intensifying treatments. So we looked, obviously, at toxicity prospectively in these patients as well. Specifically I'm showing hematologic toxicities, hepatic toxicity, renal toxicity, fatigue, dry mouth, dry eyes and nausea. And as you can see, there was no statistically significant difference between any of these toxicities between the two arms, suggesting there's no significant increase in toxicity with 177 Lu-PNT2002. So overall, we found that adding two cycles of 177 Lu-PNT2002 to SBRT significantly improved PFS in men with oligorecurrent prostate cancer, presumably by action against occult metastatic disease without an increase in toxicity.
And again, importantly, the majority of progression events that we saw were new lesions on PSMA PET. And I'll just mention this here, yes, PFS here was defined based on PSMA PET/CT, which may not carry the same prognostic impact of progression on conventional imaging, but for the reasons I elucidated earlier, we felt would be highly pragmatic and indicate what happens in the real world. In terms of some translational assays, we did see that increased TCR abundance was prognostic and a biomarker based on germline variants in genes largely related to immune response and DNA repair was identified and found to be highly prognostic as well. Finally, we do want to acknowledge that although patients on the experimental arm did have a significantly delayed time to progression, both in terms of progression-free survival and hormone therapy-free survival, ultimately a majority of patients, even on the experimental arm, still experienced progression, about a 64% rate of progression ultimately even on the experimental arm.
This suggests that there may be further optimization of the strategy, maybe increasing the dose of the radioligand therapy or using an alternate thing like an alpha emitter, potentially, but these could be things explored in future trials. I'd like to thank all my co-authors. You can see pictured here the 19 other authors on the abstract and some other authors on the eventual paper are listed as well. Of course, predominantly I want to highlight the contributions of Dr. Jeremie Calais, who is my co-PI in nuclear medicine for this trial. And of course I'd like to thank all the patients who enrolled on this trial and finally UCLA Jonsson Comprehensive Cancer Center for allowing me to run this trial and Lantheus, which did provide funding for the trial as well as the agent that we studied, 177 Lu-PNT2002.
Leslie Ballas: Thank you so much. So your last point in your conclusions brings up a couple of questions in my mind. How did you decide that two cycles of Lutetium were the right number when you first designed this trial?
Amar Kishan: Yeah, that's a great question. And as you know, this is essentially the first completed trial in this space. So there was a little bit of we are making a hypothesis of what we think would be reasonable. In metastatic castration-resistant disease, people have studied more cycles, four cycles or more of this agent. Our feeling was that this patient population is very early in the disease course. We want to minimize any potential toxicity of giving two much of a radioligand therapy so early, so we landed on two cycles. Would more cycles be more beneficial? Possibly. Could you get the same benefit with one cycle? Possibly. We don't know. And the similar thing goes for the sequencing, which I'm sure you would ask as well, why did we do it neoadjuvantly as opposed to adjuvantly? And part of the reason was we thought it would be useful to have that interval PSMA PET/CT because again, when we did this, we didn't know how patients would respond.
It ended up being that we needed to change the radiation plan in very few patients and the response to just the neoadjuvant therapy alone wasn't a huge response, but we didn't know that initially and maybe it would've offered the ability to really reduce the dose or volume size of the SBRT. The other thing that, I know you didn't ask this, but I'll just throw this in anyway. We did see the results of the RAVENS trial, which was recently published in the JCO, and that showed that the adjuvant use of four cycles of radium did not improve any outcomes and may have actually been counterproductive in terms of blunting any potential immune response that the SBRT may have initiated. And we feel that in this approach, we don't run that risk because the radioligand therapy, which didn't have too much hematologic toxicity to begin with. There was some, but it was not very marked, whatever that may have been came before we incited any immune response with the SBRT. So that might be preferable, but again, we don't know. Maybe doing adjuvant radioligand therapy would've been just fine.
Leslie Ballas: Fair. You have a very good relationship, obviously with Dr. Calais, and you have a very strong nuclear medicine program at UCLA, which allows for you to make sure that you can start SBRT within four weeks of completing the Lutetium treatment. How applicable do you think that that timeline is in the community or outside of a comprehensive cancer center?
Amar Kishan: Yeah, that's a great point. I think that, because at least in the workflow of this trial, right, patients are ultimately coming to a radiation oncology clinic to receive a consult about MDT and then they're being randomized and some patients are getting the neoadjuvant therapy, we already know the patients well. They know us, they're in the system, so to speak. So to get someone that you already are aware of set up for treatment should not take that long. So I don't envision there being any issues in replicating this approach in a broader sense. So just make sure that all members of the team are aware of the patient and the time, weeks, months in advance actually. If they're getting two cycles of this, then it's not something that sneaks up on you, so everything could be scheduled well in advance.
Leslie Ballas: And so I guess my next question is when I look at your trial and your trial results, it reminds me a little bit of the RADIOSA trial recently published, which looked at SBRT alone versus SBRT in combination with six months of ADT for metachronous oligo-recurrent hormone-sensitive prostate cancer. They had a slightly more favorable population, one to three bone or lymph node METs where 60% were lymph node only, and 70% were one oligomet. So it definitely seems like a more favorable population. They had a similar endpoint, and your point about the endpoint is a really important one, but they also had a clinical progression-free survival using PSMA PET or Choline PET. And their SBRT plus ADT median progression-free survival was 32 months compared to your 17 months. How do you put this, your data, in comparison with RADIOSA when you could either give them the two cycles of Lutetium or the six months of ADT and get improved results?
Amar Kishan: Yeah, no, that's a great point and a main question to answer. And so there's two answers to that. So the first would be whether it's surprising or not that adding hormone therapy, which suppresses testosterone production, therefore suppresses the production of PSA and delays any onset of disease, is actually killing microscopic disease or simply delaying that. In fact, not a conflict of interest. But myself and my colleague, Luca Valle, wrote the commentary on the RADIOSA trial that appeared alongside the publication, which was titled Delay or Destroy, which is alluding to this. It's not surprising, if you give someone six months of hormone therapy, you're going to improve their progression-free survival for that six months plus however long it takes for testosterone to recover, which we've actually also looked at, and on average is at least another six months to get to non-castrate testosterone, let alone a normal testosterone.
So we're building in a 12-month advantage. That would be just by default, even if the ADT didn't accomplish anything, you would be getting a 12-month lead in time. So that's one aspect, not to mention that not everyone recovers at the same rate, and it would be a lot longer potentially for everyone to have a recovery. So we need to look at something called the eugonadal progression-free survival. And eugonadal progression-free survival means the progression-free survival measured from the time of testosterone recovery or from time of normal testosterone. And in the RADIOSA trial, you could look at that because they did publish it. Eugonadal progression-free survival measuring time from recovery of testosterone in the experimental arm versus any time to progress in on the control arm, because those patients didn't get any ADT, was not significantly different.
In our trial, this is eugonadal progression-free survival because these men did not get hormone therapy or you could look at our hormone therapy free survival. On either approach, we significantly improved that. So I would argue that just on the science of it, it's not the same endpoint. We actually showed a benefit in eugonadal progression-free survival. We're not calling it that way because we didn't suppress anyone's testosterone, but we actually did change the natural history of the disease. Even if, ultimately, disease did emerge in 64% of these patients, whatever benefit we accomplished was without any ADT at all. The other thing I would say is more maybe tongue in cheek, but not necessarily. You treat many men with prostate cancer. How many patients have you ever seen that want to go on ADT?
Leslie Ballas: That was going to be my point, is that your toxicity looks quite a bit more tolerable to men than a six-month course of ADT.
Amar Kishan: Right. And because this is recurrent prostate cancer, many of these patients have had prior exposure to hormone therapy. They know what it is. They know how they feel on hormone therapy. These are patients that don't want to have hormone therapy, which I would argue is probably the vast majority of patients in this disease space.
Leslie Ballas: I agree. Well, this has been a treat for me. I really enjoyed getting to hear you present this data. It's really exciting. I can't wait to see next steps, LUNAR II or maybe the LUNAR landing. I don't know what you're going to call it. But the last final thing is, are you starting to use this in the clinic now that you have these results? Is this your new normal?
Amar Kishan: Yeah, that's a great question, first of all, and thank you for the kind words. I would love to be able to use this in clinic, but of course, currently this is not FDA approved. So if it becomes FDA approved, that would be a different story and absolutely, I would use it based on these results. Having treated the majority of the patients on this trial and seeing the benefit that it has, I would absolutely use it. Currently, because it's not available, we would have to only enroll on other trials that may be open or that may be opening,. Looking at this. But hopefully with results like this, this could be FDA approved.
Leslie Ballas: Well, congratulations, Dr. Kishan. Thank you so much, and we look forward to hearing from you again in the future.
Amar Kishan: Thank you again for the invitation.