And so, here we go, Louise. So number one, let's talk about the space, hormone-sensitive, castrate-resistant. How do you view today the PSMA lutetium fitting into the broad space of prostate cancer?
Louise Emmett: First of all, it's a great honor to be talking to you and at the APCCC, it was just a wonderful conference. So we have this space with lutetium PSMA which is changing so rapidly. In fact, you've been involved in that with the PSMAddition, which has taken lutetium PSMA, put it in the hormone-sensitive space, and come out with a positive trial for rPFS, pending, I believe, for OS. And so, I think that really upends what we're doing. We have VISION, funded and treatment available in the post-docetaxel space. We have PSMAfore positive as a trial and available pre-chemotherapy in mCRPC, and now a positive trial with mHSPC.
So where are we going to fit it? I think for a while, it's going to remain in the mCRPC space, but I feel quite strongly it's probably going to move to the mHSPC space, and I do think it fits very nicely there if we get the adaptive dosing right. I think that's something we really have to work on. And then, the mCRPC space is going to become alpha, possibly Auger, possibly Terbium, other things that are currently in trial at the moment. What do you think?
Oliver Sartor: Well, I think the field is changing so rapidly that the only thing we can bank on is change itself. We've got new isotopes, we've got new ligands, we have new doses, new schedules, we have new combinations. When I think about the space, actually, I think about evolution and progress. So come back tomorrow and we'll talk about something else.
Louise Emmett: That's a problem, isn't it? What are we going to talk about? And so, I think it's a very exciting time for the field. But what I'm most excited about is that we have an opportunity to really see how good we can be with radionuclide therapy with all the things that you've just mentioned, and I think we really need to work on that. We have a base level in terms of the overall survival with VISION, rPFS with the other trials, but how much further, how much better can we get? And I think we can get a lot better with radionuclide therapy in prostate cancer, and I'm really excited about where we're going.
Oliver Sartor: I think so too. Listen, let me just ask you, STAMPEDE2, I think it's quite interesting. This is, by the way, the dose and schedule that's very different than was used in VISION, PSMAddition, PSMAfore. Here, they're basically doubling up, giving twice the amount of lutetium, and the half time. So tell us a little bit more about STAMPEDE2 and what you think.
Louise Emmett: First of all, what I'd say about STAMPEDE2, the thing that I find exciting about STAMPEDE2 is it's an ARPI-lutetium combination trial. All the patients are not just on lutetium, I think it's very important to remember that, like with PSMAddition, it's ADT plus ARPI plus lutetium PSMA in the hormone-sensitive space. What STAMPEDE2 have done is they're giving, instead of giving 7.4 gigs every six weeks, they're actually giving day one/day seven 7.4 gigs, and then day one/day seven six weeks later, and then day one/day seven six weeks after that. I think that's interesting in terms of we haven't ever really shown, apart from Scott Tagawa's work, that we can dose intensify safely and that we get deeper responses. But I think that's very, very likely that we will get deeper responses, more effective responses if we're using higher doses, and I think using them early and upfront is super important.
STAMPEDE2 does that, but it's doing it, in my opinion, very aggressively in the hormone-sensitive space, where you may not still have a target, and I think we need to use our biomarkers more. There's not a lot of biomarker-adaptive dosing in the STAMPEDE-P trial design. They don't stop treatment. They keep going even if there's nothing left. I'm not sure that that is useful. I think we've published in the metastatic castrate-resistant space that you can actually stop treatment, or treatment pause in these patients, and actually get really prolonged responses before you start again, and that reduces toxicity. So I'm a little bit worried about STAMPEDE-P in terms of inducing more toxicity right upfront, more xerostomia, potentially more kidney toxicity. And I understand the rationale, but I think if you're going to be very intense upfront, you also need to be able to pull back.
And something that I spoke about at APCCC wasn't STAMPEDE-P, but it was about this idea of dose intensifying upfront and then pulling back so you can have treatment pauses of the lutetium PSMA while you have the other ongoing treatment, ADT and the ARPI. So to me, treating with the target, then pulling back, allowing the low expression disease to actually be treated with the ADT and the ARPI, and then starting again once you have a target that's starting to grow is a very logical way to be using radionuclide therapy.
Oliver Sartor: Now, Louise, you've been a pioneer in adaptive dosing, but that may not be familiar to many of our listeners. Could you explain adaptive dosing, perhaps as you did in the ENZA-p trial, just to get the concept out there?
Louise Emmett: Yep. So what adaptive dosing, it's really taking radionuclide therapy and using the unique combination of imaging plus PSA response to guide how you're going to treat the patient. If you have a patient who's had two doses of lutetium PSMA and they've had a marked treatment response, 90% reduction in volume, 90% reduction in PSA, or reduction at all sites of disease, then what you do is you continue the underlying treatment, and I prefer patients to be on ADT and ARPI, but you pause the lutetium PSMA treatment until first confirmed PSA rise. This is what I would call adaptive dosing. So treating with the target, stopping when the target disappears, and then treating with the target again.
One of the things we found with the ENZA-p trial is that PSMA expression has different sensitivities. If you have low PSMA expression disease and you're just on an ARPI, we know that your PSA-90% response to enzalutamide is 47%. If you have very bright PSMA-avid disease and you're just on enzalutamide, your PSA-90% response is just 20%, so about half. So we can actually look at these scans and get information about sensitivities for different treatments, and we can use that information to better personalize. And it's something that we've been doing with lutetium PSMA using the SPECT images or the PET images and the PSA in combination.
Oliver Sartor: Louise, one of the things that really impressed me is that you're looking at biomarkers, not just for the lutetium, but for the ARPIs, like enzalutamide, and you made some fundamental discoveries by looking at the distinctions between those with low and higher PSMA PET imaging at baseline. But also, you recently published an important manuscript on the change in PSMA shortly after the lutetium and what that means for prognosis. Now, I wonder if you could take that for the enzalutamide-treated patients, and then briefly discuss what happens when you use the combination of enzalutamide and lutetium?
Louise Emmett: Yeah. So one of the lovely things about the ENZA-p trial was this translational work that we embedded into it. And we did a very, I'd say, an unusual thing in that we did two PSMA PET scans in the patients. So ENZA-p was enzalutamide versus enzalutamide plus lutetium PSMA. But in all 160 patients, we didn't actually start the lutetium PSMA for the first 15 days. So we did a baseline PSMA PET scan when the patients came on trial. Patients went onto the ARPI, the enzalutamide, for 15 days, we did a repeat PSMA PET, and depending on what arm they were on, after that, they got the lutetium PSMA.
That was really because we know from preclinical science that you get this upregulation of PSMA expression if you block the androgen receptor. And so, the question was, how often does that happen? Turns out it happens a lot. 68% of the patients who were on the ENZA-p trial had upregulation of their PSMA receptor in that first 15 days of enzalutamide. And if you were on the enzalutamide alone and you had upregulation of your PSMA receptor, you had a six-month progression-free survival. If you had a reduction, no upregulation of your receptor, you had a 13-month progression-free survival. So I think that's super interesting. We have a lever that we can use to identify patients who would benefit from combination and who would perhaps benefit from intensification from enzalutamide to enzalutamide plus lutetium PSMA, and we're developing this idea that we can actually predict which patients will do better with what and when.
Oliver Sartor: I think it's absolutely fascinating that a nuclear medicine physician is providing insights into hormonal responsiveness for castrate-resistant disease. So hats off to you, Louise.
Louise Emmett: Actually, I'm going to interrupt you there, because the nuclear medicine physicians provide the insight because we're looking at the images. And these images, we've been underestimating their value beyond selection for lutetium PSMA. They are valuable for selection of other treatments as well, and we need to be looking at them both as upfront screening biomarkers and response biomarkers with PSMA PET, in my opinion.
Oliver Sartor: I could not agree more. But it took a physician trained in nuclear medicine to teach the oncologists how to reduce hormones, so that's why I want to give you the hats off.
Louise Emmett: Thank you.
Oliver Sartor: Now, we don't have forever to talk today. I'm sorry about that. But I want to talk about something very innovative that you've been pursuing on dose and schedule for patients with advanced disease. And I wonder if you could talk a little bit more about your innovative use of dose and schedule in trials that are now underway and a bit immature? But what you're doing, I think, has ramifications beyond your own work. So Louise, let's hear about this dose and schedule modification that you're playing around with now in early trials.
Louise Emmett: I think it's a little bit like STAMPEDE P, and I'm going to push back on you, Oliver, and say, actually, this is happening with a few trials around the world, and we're doing it all a slightly different way, which I think is very useful in terms of ultimately deciding how we should dose intensify, how we should pull back with lutetium PSMA.
The six doses six-weekly really originated because we were worried about kidney dose, and also because we took the treatment from neuroendocrine cancers, which are very different cancers to prostate cancer. And so, what we need to do is we need to say, "Are we using the right dose schedule? Can we use it better? And do we get deeper and longer responses just using lutetium, not going to alpha, not going for Terbium, by intensifying dose schedule?"
So what we did, and if you talk to the biologists, the radiobiologists particularly, they will tell you that you're done and dusted within three days with the DNA damage in the cancer cell if you give a dose of lutetium. The other six weeks, you're really not doing anything. It's that first few days that's very important, and we know that the first dose is also very important. So if we double down on that information and we do first dose, we intensify the first dose, and we try and treat within the time window of DNA damage, do we actually get better responses for our patients and longer responses for our patients?
So that's the trial I'm doing at the moment. We're doing a day one, day three, and day 15 dosing of 8.5 gigabecquerels of a novel PSMA peptide, 597, which has got low salivary and kidney activity. And we're really trying to see if we dose within the window of DNA repair, if we dose at a time when DNA damage may actually cause upregulation of the PSMA receptor, do we get deeper responses and longer responses? Just using the same, so six doses over 30 weeks, but changing the dose schedule so you're giving more upfront. And to randomize the trial, we're comparing it to standard six doses six-weekly. So who knows? We've got to finish the trial and see if it's actually going to work.
Oliver Sartor: Well, I love your innovation, and I look forward to learning more. Louise, we do need to wrap up, but I wonder if you might have any other final comments for our audience today? We've covered a lot. We've talked about the different spaces. We talked about the ARPIs, we talked about predictive biomarkers, we talked about dose and schedule. Anything else you'd like to leave for our listeners before we exit?
Louise Emmett: Look, there's one other trial I'd like to discuss, and that is the PR-21 trial. It's a super interesting trial that came out comparing early mCRPC post-ARPI pre-docetaxel, and they compared docetaxel to lutetium PSMA, finding that if you had docetaxel followed by lutetium PSMA, patients had a longer overall survival than lutetium PSMA followed by docetaxel. But to me, I've been having a look at that trial and I've discussed it at the APCCC, it's very interesting. Those patients had very, very aggressive disease. The overall survival pre-docetaxel was 14 and 18 months, so very low overall survival with very high primary treatment resistance.
So what I want to say is we're not finished with lutetium PSMA. It's not necessarily better or worse than docetaxel. We have a lot more trials that we need to do, where we use it in combination, where we use it with a better scheduling, where we use it in an earlier space. And I'd say jury out in terms of how we should be optimally using lutetium PSMA and how it's going to compare to other treatments in the future.
Oliver Sartor: Well, let's put it this way, Louise, if we come back in a couple of weeks, we'll probably have a different discussion because we'll have so many new things to talk about. Always a pleasure to have you on UroToday. Thank you so much for participating, and thank you for all the work that you do across the broad spectrum of prostate cancer.
Louise Emmett: Thanks so much, Oliver. It was such a pleasure.