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Oliver Sartor: Hi, I'm Dr. Oliver Sartor here with you all today. It so happens that I'm here with Louise Emmett at the PCF Meeting 2024. Louise is known to virtually everybody who does theranostics. Or perhaps, if not known, they've been living under a rock. It's true. It's true. She is a professor at the University of New South Wales and the Director of Theranostics and Nuclear Medicine at St Vincent's. But most of all, she's just Dr. Emmett, well-known theranostician.

Louise Emmett: Thanks for having me.

Oliver Sartor: Okay, Louise, there are many, many things that we could talk about, and the thing, I think, I want to focus on initially is combinations. We're using the lutetium in the VISION trial along with standard of care. You've used the PSMA-617 lutetium in the ENZA-p trial with very provocative results. I want to hear, first of all, about combination with hormones, and then we're going to go on from there. So, hormonal therapy combinations in any context, let's hear it.

Louise Emmett: Maybe, I reckon, we should just go back a step because just lutetium-PSMA on its own without anything else, it works really well in about a third of men, but not brilliantly in about two-thirds of men. And I think what we're doing really is we're celebrating our successes, but we're not really pulling together with the other two-thirds. And I think it's really time that we do think about everyone that we treat with lutetium-PSMA, and to me, that's combinations.

I think Johann de Bono did really nice work when he showed that if you take a tumor deposit in the metastatic hormone-sensitive or the castration-resistant prostate cancer state, you don't get PSMA expression in every cell. So, us trying to target with only lutetium-PSMA or with actinium-PSMA is not going to capture everything, and we're going to have progression pretty soon in the majority of patients.

So, I think this idea of combinations is super nice, and I think a combination that's going to target a different clonal population to that of PSMA is nice. And as you know, the androgen receptor and the PSMA receptor, they talk a lot in the cell and they both have very active targeted treatments, so the androgen receptor pathway inhibitors for the androgen receptor and ADT, obviously, and lutetium or actinium-PSMA. So, I do think the combinations with hormones is logical. It makes a lot of sense. And in fact, you used it in VISION. The first time you really started that in VISION, what, 52% of patients had second or third-line ARPI.

ENZA-p is really following along on that, except instead of using second or third-line ARPI with the lutetium-PSMA, it's first line in the mCRPC space. And we have published that now, the interim analysis, with the primary endpoint of PSA progression-free survival was good. It was 7.8 months compared to 13 months with the combination for PSA PFS. So, I think we're definitely heading down that path very nicely. I think it's a logical combination, and I think we've got our first solid we should be doing it. The question is, how do we do it?

Oliver Sartor: Let me back up for a second, and a little criticism and a little commentary. So, you showed in the interim analysis some data that was quite nice on PSA. In fact, it is outstanding on PSA, but yet, we never had a drug approval on PSA. We need to get that overall survival. When might we anticipate hearing something about overall survival, which will be a thumbs up or thumbs down for this concept in my mind.

Louise Emmett: So, I think in terms of criticism, it's not criticism. It's a phase II, not a phase III. So, not looking for a regulatory approval, looking more for a signal. And so, I think that a PSA PFS was reasonable and was strong. And the depth of response, I think the stunning bit was that the 90% response rate with using the combination of enzalutamide and lutetium-PSMA-617 was 80%.

Oliver Sartor: Fabulous.

Louise Emmett: That's amazing, right?

Oliver Sartor: Yeah.

Louise Emmett: So, we have cut for overall survival. We cut on July and we do have those results. And we will be presenting those, hopefully, at ASCO GU.

Oliver Sartor: Oh, that'll be fairly soon. That's wonderful.

Louise Emmett: Pretty soon. Pretty soon.

Oliver Sartor: Okay. All right, call out, ASCO GU.

Louise Emmett: ASCO GU.

Oliver Sartor: All right. Moving a little bit more toward the criticism because we're here to have a discussion that other people want to hear. I can't just say, "Louise, you're great." Although I believe Louise is great, but that was in that first-line population. And I wonder a little bit about how many of those patients are really prevalent in the major centers. It's going down. Would this approach potentially work even in the second line of the ARPI setting, do you think?

Louise Emmett: Actually, I think that's being done. So, the reason for ENZA-p being put in the mCRPC space setting was it was a proof-of-concept trial. What we really wanted to see was, do you get this interaction in the cell without the androgen receptor turning off? So, if we put it in hormone-sensitive space, which, of course, you've done with PSMAddition in a much, much larger trial of ARPI plus ADT plus lutetium-PSMA six doses, six-weekly in metastatic hormone-sensitive prostate cancer, the risk in a small phase II was we could actually get the receptor turning off with the ARPI and we may get a negative trial.

So, we put it in mCRPC space, first-line pre-chemotherapy, to prevent that from happening, to look at proof of principle. But I totally agree, using ENZA-p, translating that to the clinical space is difficult because, in a sense, it doesn't exist anymore. It's a little bit like PEACE-3, right? PEACE-3 is a great combination trial as well, enzalutamide first line plus radium in the early mCRPC space in patients with non or minimally symptomatic bone metastases and bone-only disease. So, it's interesting, ENZA-p and PEACE-3 are both in the same space and it's a space that's evaporating. People are getting first-line ARPI.

So, I guess it's very compelling, the combination, but how do we use it? And I think we need to think about second-line ARPI. Should we be using it in all patients who are getting lutetium in the mCRPC space? Should we be looking at AR degraders in that space, in patients who've already had ARPI? And should we be looking, well, of course, you're already looking with PSMAddition, but can we take some of the learnings from ENZA-p and do something like adaptive dosing in the hormone-sensitive space to adjust for this variation in receptor that you're going to get?

Oliver Sartor: Awesome. Very provocative. So, thinking about the near-term future, imagine ENZA-p is outstandingly positive and you want to extrapolate that learning, what trial would you do next to be able to take advantage of this combination to make a really big impact? What would you do? And just hearing you think is fun because the way you think about this is important.

Louise Emmett: I think that it's really well-tolerated, lutetium-PSMA. It's effective, right? It's more effective than chemotherapy. And we know that we've got a very effective treatment with ARPI in the hormone-sensitive space, but not in everyone. So, I think it would really fit taking this and fitting it into the metastatic hormone-sensitive space. But of course, being very careful about how you try and target those cells as they become androgen-resistant. So, in order to do that, what we would need to do is have this adaptive dosing where you try starting dosing. You stop when you don't have the target anymore. You restart when you do have the target. And that way, we can try and really stretch the period of time at which even men with fairly high-risk disease have disease control with low-volume disease in the hormone-sensitive space. That would be perfect, I think.

Oliver Sartor: That'd be fine.

Louise Emmett: Non-toxic, really well-tolerated, and hopefully effective in combination.

Oliver Sartor: I didn't mention the adaptive dosing because I didn't want to go down that path, but you're raising a really good point. And the bottom line is taking advantage of the sensitivity that would occur between the lutetium and the hormonal therapy is a really important one. Now, let's move on just because I'm curious to hear how you think about other combinations. And you can take whatever combination you like. Maybe PARP inhibitors, maybe IOs, or maybe something different. What's your pleasure?

Louise Emmett: There are so many interesting trials around that are happening. I do think that the PARP inhibition is an interesting concept, this idea of taking lutetium or actinium-PSMA and then working on how you actually translate a single-strand DNA break into more durable double-strand DNA breaking and cell death. Whether it should be a PARP inhibitor, because PARP inhibitors themselves have a bit of toxicity, and things like ATRs also have toxicity. So, I think we've got quite a lot of work to do to figure out what is the least toxic radiation sensitizer that we can possibly use, and I think that's a nice combination.

I have to really point out and give a heads-up to Michael Hofman and the team at ProsTIC because they're doing a trial called LuCaP, which is lutetium-PSMA plus cabazitaxel, and that's in combination, putting the two together rather than doing them in sequence. Quite often if we have a patient with mCRPC, we'll give them lutetium-PSMA, they fail, and then we give them cabazitaxel. And we know that their chances of responding are not high.

So, if you've got someone who's not doing particularly well after two doses of lutetium-PSMA but has derived some benefit, to just add the cabazitaxel but not stop the lutetium, I think, is a really nice way of combining. Cabazitaxel is a taxane. It has some radiation sensitization capability as well, so we can value-add to the lutetium. And it will also be treating some of those clonal populations that are not going to be responding to lutetium. So, I think that's a really nice combination. But what's your favorite combination?

Oliver Sartor: Oh, I'm still trying to figure it out because I haven't seen enough data yet, so I'm an all-of-the-above kind. And I'm very intrigued with the idea of generating real data, even though we're probably going to have to do some phase Is in terms of getting the combination in a proper dosage. By the way, I actually do like the taxanes. I can remember the samarium-153 taxane combinations that were quite provocative. Another beta emitter, bone-targeted but still interesting combination effects. DNA repair inhibitors, I think DNA-PK could be interesting.

Louise Emmett: Do you know how toxic it is?

Oliver Sartor: I don't. And see, that's part of the problem, is I don't understand the activity outside the animal models. So, I'm still in the learning phase. And I am interested in the IO, and I'm not going to go down that path because I'm a bit of a skeptic. But on the other hand, do I want to see data? Absolutely, I want to see data.

Louise Emmett: I actually think IOs with radionuclide therapy is interesting for two reasons. I think when we have a DNA-damaged cell and we need it cleared away and you have an immune-suppressed tumor microenvironment, having some IO on board probably helps depth of response with lutetium or possibly even with actinium, we don't know. And then, obviously, the abscopal effect that you could potentially get as well. So, I haven't given up on that. I think it's interesting. There are quite a few trials that are happening. Shahneen Sandhu is doing a pretty brave trial with lutetium-PSMA plus ipi-nivo compared to lutetium alone. That's called Evolution and that's going to be reading out soon, but that was stopped early with some toxicity.

Oliver Sartor: I've got to say that's brave. The ipi-nivo is not a very tolerable combination even without the use of an isotope.

Louise Emmett: I think the real thing about the combinations that we choose is they have to be rational. They have to be well-tolerated. So, if you're going to have a significant toxicity, it's because they dramatically change outcome in patients. Not minor, major.

Oliver Sartor: I'm going to give you a provocative question. So, there's some people who've talked about the shorter-lived isotopes and I'll say maybe lead-212, for instance, who believe that the interaction with the immune system might be enhanced relative to a long-lived isotope like lutetium or actinium because you're not radiating the microenvironment. Presumably, you damage the cells and then these immune cells will pile in after you have that initial damage. But if you're radiating the cells with a long-lived isotope like lutetium, you might be radiating the cells that you actually want to execute the immune response. So, is there a rationale in your mind to think about lead-212 as being an optimal or maybe shorter-lived isotope in general as opposed to the long-lived isotope?

Louise Emmett: So, I'm going to ask you another question perhaps. So, there is an alpha trial. Scott Tagawa has been in a trial he presented at ASCO, which is actinium-J591 plus a second-line ARPI plus pembrolizumab, and that got really good responses in—

Oliver Sartor: Two patients.

Louise Emmett: Two patients, really good responses.

Oliver Sartor: Two patients.

Louise Emmett: They did six patients in each arm.

Oliver Sartor: Two of the patients had outstanding responses, absolutely.

Louise Emmett: Two out of six in the higher dose.

Oliver Sartor: Two out of six, that's correct.

Louise Emmett: In the higher dose, right?

Oliver Sartor: That's correct.

Louise Emmett: Outstanding responses, and that's just really thought-provoking. Why? One dose, second-line ARPI and pembro, none of those things together should give that kind of a response. So, what is happening? Is it the actinium? Is it the alpha that's doing better than lutetium? And then you've got Tom Hope and Rahul Aggarwal's trial, the single dose of lutetium-PSMA.

Oliver Sartor: One dose.

Louise Emmett: Plus two years of pembrolizumab. And really, they got good responses with that too. What was it? A 6.9-month radiographic progression-free survival and a 44% PSA 50% response rate. So, I think they're going on and they're doing a phase II in that trial. So, they're extending that and they're also making that an adaptive dose as well with more doses of the lutetium to see if they can get deeper responses. I think we'll know maybe in about 10 years which combinations we should have.

Oliver Sartor: Oh, no, no, no.

Louise Emmett: Think we're going to do it sooner?

Oliver Sartor: No, less than 10. Less than 10.

Louise Emmett: Five.

Oliver Sartor: It's too much effort. Okay, so just think about a summary on this particular issue. We've covered hormonal sensitivity. We covered even taxane, which we took as an example of a radiation sensitizer. We took DNA repair inhibitors and we took—

Louise Emmett: IO.

Oliver Sartor: —PD-1 and CTLA-4 inhibitors. So, we have IO. So, that's four that we covered briefly. Are there others that we ought to be thinking about?

Louise Emmett: Actually, rather than others, what I think we need to figure out is what we use in what space. So, we've got intensification and then we have non-toxic. I think if you have metastatic castration-resistant prostate cancer, you've failed everything, you want to intensify your treatment. And I think that's where that lutetium plus cabazitaxel looks really good or an alpha plus cabazitaxel. You need to overcome that radiation resistance. And then we need non-toxic much earlier or potentially the abscopal effect, to identify the tumor to the immune system. So, that high-risk pre-definitive treatment, how are we going to use radionuclide therapy in that space? I mean, obviously, that's enticing for a lot of men that don't want to have hormones.

So, I don't know that I would think about too many other combinations at the moment, but rather think about what we use when.

Oliver Sartor: I'm going to hit you with one more combination.

Louise Emmett: Yeah, which one? Which one?

Oliver Sartor: It's the double isotope. Maybe we have an alpha-beta.

Louise Emmett: Oh, double isotope, yes.

Oliver Sartor: And maybe we're even talking about radium because it targets the bone and that's a little bit of a problem. Or maybe we talk about actinium, but we lower the dose of actinium to maybe spare some salivary glands a little bit. So, let me just ask you, double isotope, any of these you find provocative?

Louise Emmett: So, once again, ProsTIC is doing AlphaBet, which is the radium plus lutetium-PSMA combination treatment. So, I think we'll have the answer on that soon, and that is a rational combination. We have less good responses in bone than we do in soft tissue with lutetium. So, does adding radium really help? Though I have to say that I'm so impressed with PEACE-3, with enzalutamide plus radium, in terms of with a hazard ratio of 0.69, 7.5-month overall survival benefit. Is it going to be as good as that? I'm not sure. So, definitely, that combination.

And then using an alpha and lutetium, I have to admit, I'm sure there's rationale for that, but we get quite severe xerostomia even at low doses of actinium. So, alpha-PSMA, if you have a salivary gland targeting alpha, it causes toxicity at really low doses, and it's very idiosyncratic to the patient. So, you can give one patient quite a low dose of an alpha, get really severe side effects that are irreversible. So, in that patient, alternating is not going to be particularly helpful, I don't think. Because really, the reason to alternate is to reduce toxicity, correct? So, if you're not reducing toxicity because you're already getting it at low doses, not useful. But if we somehow managed to get an alpha that was non-targeting of the salivary glands, perhaps then I would change my mind. But at the moment, I can't see the use.

Oliver Sartor: Very enjoyable discussion, covering a lot of territory. In an interesting way, sort of taking the current data and extrapolating it. But just for our viewers, hormonal therapy, maybe double isotopes, maybe IOs, maybe DNA repair inhibitors.

Louise Emmett: Taxanes.

Oliver Sartor: Taxanes and other radiation sensitizers, which we didn't go to because we just don't have so much time, but this is very enjoyable. We'll have to have another discussion—

Louise Emmett: It's so nice.

Oliver Sartor: —fairly soon.

Louise Emmett: So nice talking with you. And the space is like watching a... It's just incredible, isn't it?

Oliver Sartor: Wonderful time for the field.

Louise Emmett: Yeah, it really is.

Oliver Sartor: Thank you, Louise. Thank you for being here.

Louise Emmett: Such a pleasure.