Michael Hofman: Thank you, Oliver. Always a pleasure to be with you and on UroToday.
Oliver Sartor: Well, you just gave a beautiful talk on some of the limitations of the PSMA lutetium therapies and theranostics and some of the ways that those limitations might be overcome. So I wonder if you might initially talk about some of the limitations that we see in this beautiful approach exemplified by PSMA-617 lutetium and what we might do to address it. So the first part is the limitation. The second part is how are we going to move forward?
Michael Hofman: Yeah. Thanks, Oliver. We've been doing lutetium PSMA down at Melbourne at Peter Mac for well over 10 years now, so we start to get a feel for what it's good at and what it's not so good at. And I think all these therapies go from hype and then reality hits a little bit. And I think we're entering a little bit of the reality phase of implementation of lutetium PSMA where 10 years ago we saw these incredible pictures, incredible responses on PSMA PET scans. But in clinical practice, maybe not everyone responds as well as we would like.
Now we're starting to see some of the limitations. And what strikes me is when we did the therapy study directly comparing lutetium PSMA-617 to cabazitaxel, the PSA responses were double with lutetium compared to cabazitaxel. And so was the PSA progression-free survival. But then when we looked at radiographic PFS, although still superior for lutetium compared to cabazitaxel, it was less. And then for overall survival, it was actually similar. And this was not a result I was expecting because when I saw a PSA-50 response rate of 66 compared to 37%, such a large difference, I was pretty confident that despite it being a small phase two trial, that we would show a survival benefit, but we did not.
And the way I've encapsulated this, and I think you have experience with this with the ALSYMPCA trial, when you have a tumor-targeted therapy, one, it results in tumor shrinkage and you see that PSA drops quickly. And if you look at the CT by resist, the tumors shrink. And again, in therapy, 49% objective response rate by CT resist with lutetium compared to only half that around 24% with cabazitaxel. So lutetium PSMA is really effective at targeting tumors and shrinking them. But I think it's less effective at stopping the formation of the new metastases that are always coming.
And when you think about new metastases coming that aren't targeted, well, that contributes to the endpoint of radiographic PFS, and overall survival's probably a combination of both those phenomenons, tumor shrinkage and preventing new metastases forming. Another thing worth mentioning is when you shrink tumors, you also improve quality of life a lot because often these patients have advanced bone disease pain or fatigue from such a large burden of tumor and lutetium without having many side effects is very effective at improving quality of life.
But when I deep dive on the therapy data, I think that cabazitaxel may be a little bit more effective at stopping new metastases landing. And that's why we see that delay in radiographic PFS and a similar OS, but we don't see as much PSA drop. This is maybe like radium-223 where you don't get much PSA drops, but clearly it's very active because maybe it's working on not directly on the tumor, but working on the tumor microenvironment, working at that bone cortex interface where new metastases are forming.
So tumor-targeted therapies will shrink PSA, but you also need to prevent the new metastases forming. And that's potentially a limitation of radioligand therapy that at least I'm beginning to note.
Oliver Sartor: Well, it's interesting. And one of the things we've always seen about the taxanes, they seem to punch above their weight on survival as compared to the expectations from the PSA declines. They're not so great at PSA declines, but the survival always seemed to be a little better.
I'm just curious, and this gets your thoughts, I had thought that perhaps the PSMA expressing cells, which are the most likely to be killed, are also the cells that are most likely to be expressing lots of PSA, that PSA is heterogeneous just as PSMA is heterogeneous. And I was thinking that some of the cells that were low in PSMA, they might be a little more FDG-avid for instance, are less PSA productive. So what I was thinking is we were going to kill those cells that make a lot of PSA, but the less differentiated cells, which are the killer cells are not as inhibited as well by lutetium as they would by the taxane. Whereas the taxane seem to be the opposite. They seem to hit those cells that are going to kill you more so than those cells that make a lot of PSA.
I'm just curious, what do you think of that concept?
Michael Hofman: I think that's quite rational. I think there's a lot we don't understand about, particularly conventional therapies. For lutetium, we kind of understand it because it's very mechanistic. We can visualize it. We know exactly how it works because we've made it. Taxane chemotherapy we're actually less certain how they work. I think they have a lot of off-tumor target effects. I think clearly they are effective at shrinking tumors, but not as effective as lutetium PSMA.
But I actually think part of the way taxanes work is another mechanism is affecting the tumor microenvironment. You see your blood counts drop, you develop neutropenia, on FDG-PET, you see diffuse marrow uptake, you're effectively poisoning the bone marrow throughout the body and prostate cancer loves growing in the bone marrow. So when you poison the bone marrow with a taxane, which is not a nice thing because you don't feel well, it doesn't make you feel good, it creates toxicity. But off-target benefit of that is the new prostate cancer metastases, they don't like growing there because it's not like a fertile soil. So I see some off-target mechanisms that aren't fully understood, but may improve progression, radiographic PFS overall survival.
Oliver Sartor: Interesting. But let's get to the second half of the question. So what are we going to do about it, Michael? How are we going to make this important new therapy even better? And I know you have some really good ideas that you presented in Lugano. I'd love to hear more about those.
Michael Hofman: Yeah. So I think the next phase is going to be much like the rest of oncology combining lutetium PSMA with other treatments. And we have some phase-three data for this because in the VISION trial, you could combine with an androgen receptor pathway inhibitor, but it really wasn't the goal of the study, but we can combine with a whole variety of things. And this has been a focus of our Australian research over the last few years.
So what I did is I went through the various combination therapies and maybe the advantages and disadvantage of them. So they can be combinations with ARPIs, they can be radiosensitizers, which could be a PARP inhibitor, could be combining with cabazitaxel rather than doing it sequentially. Immunotherapy is obviously another combination. We can combine with multiple radionuclides, maybe an alpha and a beta. We can combine with stereotactic radiotherapy, particularly in the oligometastatic setting. Or if we move back right to the beginning, maybe we combine with surgery, our LuTectomy study where we give lutetium followed by a surgery.
So we deep dived on all those things and they're all really interesting. We've only got mainly phase one and two data on these, but I think we've got good data from that and we can pick some to move forward with. The most interesting of them and the most compelling to me is the ENZA-p data from our colleague, Louise in Sydney, where we took patients around Australia with a high risk of failure to enzalutamide monotherapy, and we randomized them to either enzalutamide alone or enzalutamide in combination with lutetium PSMA. Now this was not an RP crossover population like many of the big pharmaceutical trials. This was de novo enzalutamide, and there was a lot of imaging biomarker work built in the study.
And what we saw is that by day 15, in a proportion of patients, despite PSA coming down on our PET scans, the intensity of uptake on increased. So this was causing PSMA up-regulation. And then when we hit with two cycles or four cycles of lutetium PSMA-617, there was very good activity, so much so that in this phase two study, it was positive for overall survival in the second readout, which was published in Lancet Oncology.
So super interesting data, and I think that improvement in overall survival was in the range of slight 14 months, I think. It was not a small amount, but a large amount, and I think quite compelling data for that combination.
Oliver Sartor: I agree with you. I thought it was excellent. The other thing, and this just recently came out and one of the coauthors, is that up-regulation in the enzalutamide monotherapy arm was associated with a worse survival as compared to those with a downregulation. But when you gave the lutetium, you abrogated that decline in survival for those with the PSMA up-regulation. So I thought there's a very interesting interaction between the enzalutamide up and down and then adding the lutetium. And as you pointed out, it's a beautiful hazard ratio, 0.549, which is absolutely stupendously good for overall survival. It doesn't matter if it's a phase two or phase-three, that's outstanding.
Michael Hofman: Yeah. And that phenomenon you described is super interesting. And this is my hypothesis, if you have patients that are super sensitive to enzalutamide, you put them on enzalutamide in the castration-resistant setting and everything gets better. Your PSA goes down super sharply. Even within two weeks, you repeat the PSMA PET, everything's getting better. But the really nasty castration-resistant prostate cancer cells that are the ones that maybe have the most metastatic potential, the most aggressive, the ones that are going to kill you, they're the ones that have this phenomenon of PSMA up-regulation. And when you come in a few weeks later and hit them with lutetium PSMA, you're kind of eradicating the nastiest clones. And that's why I think we see a survival benefit in such a small study.
Oliver Sartor: Well, it certainly was successful, but let's talk a little bit about another study that came out of Peter Mac that I was very impressed with, and that's the LuPARP study. And when I saw the PSA declines, I thought they were good, but when I saw the overall survival, I thought it was amazingly good. And I wonder if you might touch on that a little bit for our readers.
Michael Hofman: Yeah. So this comes to the next theme, which is radiosensitizers, which are radiation on colleagues with external beam radiation have been doing for a very long time. They don't necessarily just give external beam on its own in a nasty head and neck tumor and they combine it with a radiosensitizer. So here we're not using the PARP inhibitor for patients with BRCA mutations, we're using it as a radiosensitizer. Cancer cells will heal themselves. We don't want that to occur. When we throw in a PARP inhibitor on top of the lutetium, we get more double-stranded DNA breaks, and we also impair the tumor's ability to repair itself from the radiation damage. We don't give the PARP inhibitor as a continuous dose. We give it as a pulse, which with each cycle of therapy, at least that's what we did in the LuPARP study.
We're actually very concerned that this would be a very toxic treatment. So we were very careful. And this was a study run with me and Shahneen Sandhu, and we dose escalated very, very cautiously over a number of years, and we got up to a full dose, I think day minus four to day plus 16. And as you allude to, the PSA-90 responses were really remarkable over 40% of patients having really, really deep PSA responses. I think this shows even in the phase one, two design that this is effective in, really, it's almost like it's a method to give a boost of radiation. Maybe you could give double the dose of lutetium, but that would cause side effects, and this is a way to really improve the efficacy of lutetium.
And it works more on the tumor than on normal tissues. And the way that works is when we give the pulse, your lutetium PSMA circulates around the body and then it's taken up into the tumors. When we introduce the PARP inhibitor shortly after giving the lutetium, or around the time, we're going to get clearance from plasma pretty quickly and even clearance from parotid gland and radiosensitize maximally within the tumor, which is where the lutetium tends to stick. Now, so I'm very impressed with the LuPARP results as well. It's also worth saying that it was, at least to me, a surprisingly well-tolerated combination. Me as the nuclear medicine physician seeing these patients, I didn't see a visibly increased toxicity burden compared to lutetium monotherapy. So I think I would like to see this move forward to a phase-three trial.
Oliver Sartor: I was very impressed. And I know that there are a variety of additional combination trials.
Michael Hofman: Now, a cheaper way to do this is just to combine with cabazitaxel, which is the LuCAB trial we don't have results of yet, but the statistical lock for this trial has just occurred. So we hope to present it later this year, and it's a little bit PARP inhibitor inspired. We're using the taxane as a radiosensitizer, and we know that taxane are very good radiosensitizers. It's a lot cheaper than a PARP inhibitor. It also has potentially the added benefit that it will target the PSMA-negative cells, which is what you were alluding to earlier. And maybe what I was alluding to, some off-target effects from the taxane chemotherapies that may be not well understood, but favorable in prostate cancer with its marrow biology. These may be an added benefit as well.
So this was another Peter Mac run trial dose escalation. We went up to 20 milligrams per meter squared. We gave the cabazitaxel every three weeks. Every second cycle you gave concurrently a lutetium PSMA. Again, we gave the lutetium on day zero. The patients came back for their 24-hour SPECT CT, and then we hit them with the cabazitaxel so that when the cabazitaxel entered the system, the plasma clearance had occurred, the salivary gland washout was already occurring, so to hit it for the sweet spot for tumor sensitization.
Oliver Sartor: What was the dose on the cabazitaxel there?
Michael Hofman: 20 milligrams per meter squared. So the same dose as the TheraP study. So I think this is a super interesting combination. I know you've got therapy and we've got interesting data from Kim Chi about docetaxel followed by lutetium or lutetium followed by docetaxel. And it seems that for many men that are fit, they are going to see both a taxane and a lutetium. And Kim Chi's data would suggest that maybe you should give the lutetium after the taxane rather than before. We don't know, but I propose that maybe this is better done in combination. It could be a one plus one equals three because of the radiosensitization.
Oliver Sartor: And I'm sorry, correct me, you may have said it, maybe I missed it. Is it cabazitaxel Q6 weeks instead of the usual Q3 per FDA?
Michael Hofman: No, we gave it every three weeks.
Oliver Sartor: You did give it every three. So your going Q3?
Michael Hofman: Yes.
Oliver Sartor: So that's an FDA approved regimen.
Michael Hofman: So every second cycle, you came for a dose of lutetium.
Oliver Sartor: Okay. Okay. Wow. Okay. Well, I'm really looking forward to that. Michael, we're going to need to wrap up pretty soon to keep within our timelines, but I wonder if you might have a final word or final point you'd like to make to our audience, because I know they love to hear your thoughts. And just a little wrap up from your perspective, please.
Michael Hofman: Yeah, look, I think we've got all these options with lutetium PSMA. It's clearly a highly effective tumor-targeted therapy at both prolonged survival and improves quality of life. And the question is when to sequence it. One, how early to use it, which is the subject of other talks we've heard in this meeting, but in my talk really focused on rather than sequencing it, why don't we combine it? And what are the optimal combinations? I don't think we know to date, but the ENZA-p data with an improvement in OS to me is already compelling. So I think we need more data, but I think the future is actually to combine it. Since it is such a well-tolerated treatment, we can combine it with other treatments rather than just sequence it before or after.
Oliver Sartor: Yeah, no. And by the way, I completely agree that the path forward is going to be with combinations. We can maximize these monotherapies, but the end result for almost all the cancers we treat is that combination therapies are required to make the big difference.
And by the way, if we go all the way back to Vince DeVita and Hodgkin's disease, it was putting together the mechlorethamine, the Oncovin, the prednisone, procarbazine, putting them all together that resulted in the dramatic effects of cure for metastatic Hodgkin's. And that was a huge step forward for oncology. Anyway.
Well, listen, thank you for presenting at Lugano. Thank you for stimulating discussion. Thank you for being on UroToday. Always a pleasure to have you.
Michael Hofman: No, thank you so much. The pleasure is mine.