Alicia Morgans: Hi, I'm so excited to be at ASCO 2022 with Dr. Michael Morris of Memorial Sloan Kettering. Thank you so much for being here.

Michael Morris: Thanks for having me.

Alicia Morgans: Wonderful. Well, I wanted to talk with you about one of the more pressing issues in metastatic castration resistant, prostate cancer treatment.

Alicia Morgans: The sequencing of therapies, particularly thinking about prior exposure to other radiopharmaceuticals is really critical as we're now thinking about incorporating other radiopharmaceuticals into our treatment paradigm.

How do you think about this in the context of radium, which we've been using for years as a safe and effective drug?

Michael Morris: Very different drugs. In many respects, the targets are very different and one is an alpha, whereas Lutetium is a beta.

I think with many different drugs in the prostate cancer armamentarium when you have multiple members of the same family, it comes down to the individual tox profile of each drug and how they each... Has a mechanism of action that may be similar, but not quite identical. Those decisions come into play. I think as monotherapy, for example, radium, historically speaking has a very low hematologic toxicity profile in the low single digits in terms of high grade tox.

Whereas with Lutetium, you have higher rates of high grade toxicity of platelets around 8% of high grade and anemia around 13%.

It depends on the frailty of the patient, what the dominant site of the patient's disease is because if you have primarily visceral or nodal or other soft tissue disease, obviously radium isn't going to target that component, Lutetium might be more favorable.

It's those subtleties that allow us to make those distinctions and whether that's in radiopharmaceuticals or AR inhibitors or which chemotherapy you're going to start with, whether it be doce or will it be cabazi. You have to marry the patient with the right drug selection and that is in essence of the art of medicine.

Alicia Morgans: You know, I think I agree with that completely. I think from my perspective, I'm always trying to think about how to get every line I can possibly get into patients because I think as you mentioned, there are distinct mechanisms of action. Even when we're talking about two chemotherapies or two radiopharmaceuticals, some of them being more distinct than others, but these are different drugs and they may be used sometimes in sequence to try to have different effects. There has been some data looking at patients getting Lutetium after radium. In fact, in the VISION trial patients could have had exposure to radium. Is that true?

Michael Morris: Yeah. And patients could have had radium, as long as that last dose of radium was given at least six months prior to receiving Lutetium and they could certainly have gone and crossed over at the end of VISION and received radium afterwards as well. What we don't have as breakouts of breakout data of specifically how those patients did depending on one sequence for versus another. And it wasn't a huge number of patients either way. There is an abstracted ASCO this year that's been of a single center, 49 patient cohort of patients looking at real world data. Dr. Rahbar is the first author of that abstract. It's a small study, but I think that it, what it shows is that Lutetium, first of all, is feasible after radium. There may be a higher rate of anemia than it was seen in VISION in the sense that they found about a third of their patients at high grade anemia. Thrombocytopenia was slightly higher as well in the low teens percent, as opposed to around 8%, which was seen in the VISION trial.

Patients, about a third of the patients got six doses of Lutetium after, after radium. But I think one of the most important pieces of data is that the median survival in that cohort of patients who got Lutetium after radium, it was about 12.6 months, which is pretty close to what patients envision as a whole group received. So it looks like survival, it's about the same with treatment like it with anything. Second line therapy of a group of a class of drug can be more toxic than first line therapy. Although these toxicities were unsurprising and probably other than the anemia, not particularly startling. And so I think that it's good real world data. We'll probably have more as time goes on and that's more than 49 patients, but it's encouraging to see that it is a treatment option after radium.

Alicia Morgans: I would agree. I really thought it was important in that abstract, at least that it looked like the median number of cycles of radium that patients had received was about five. So they were, they were getting a substantial exposure to radium, and then there was about a nine month median duration of time between the end of radium and the initiation of Lutetium. So something to keep in mind. And as you said, in vision, of course, they had to wait at least six months. So, just from a safety perspective, this is not a directive of course, but this is the data that we have, giving a little time for that bone marrow to recover may be helpful, who knows.

Michael Morris: Right. And, and we should say that in the label for Pluvicto, there's nothing about a treatment break. And in fact, it's completely agnostic to any issue with radium. So you're just left as a clinician with the data that we have, and that's the data from vision, but as more real world data comes into the arena of meetings like this and publications, we should have more information about this tolerability issue, the efficacy issue. I don't think that we should expect that if as we sequence therapies that later line therapy will be as well tolerated as early line therapy. And that we shouldn't see an increase in some toxicities that may be overlapping. We should expect patients who are further down the line to live less long than patients who are earlier down the line, and we should expect the tox profile to be somewhat worse. We would see that for example, with, Docetaxel. And Cabazitaxel second line chemotherapy comes on top of first line chemotherapy, but it is useful to know that, all of these are in the tool belt, one doesn't prevent another and the treatment effects and the benefits, at least at first blush look pretty good.

Alicia Morgans: Yeah. I would agree, here's one more question. We're obviously using chemotherapies radio pharmaceuticals, we're using AR directed therapies. Is there any reason to think that treatment with radium before Lutetium would give you a different effect in terms of side effects, than treatment with Cabazitaxel before Lutetium? These are both drugs that end up targeting the marrow. If you have disease there and they can have effects.

Michael Morris: Yeah. And ultimately it's really hard to know for either drugs singly, much less in series, what's going to lead to significant toxicity. Certainly with chemotherapy, preexisting neuropathy is concerning, and with radiopharmaceuticals preexisting marrow compromise would be concerning as well. And you might select one drug over another for a patient who is neuropathic on the basis of that. And just as you might select a patient who goes in with significantly compromised marrow to get one drug versus the other. I think that all of that, ultimately you don't get data for every question that you have in terms of practice, but you do have sort of some common sense and as well, we always select the best drug for the right patient based on what comorbidities they have and preexisting side effects that they have from their prior treatments. We have to do much the same here.

Alicia Morgans: I think that's a good message. So, at the end of the day, we have the opportunity to give another treatment to patients with prostate cancer. And it's probably a good thing for us to try to get in every option that we possibly can give that patient the opportunity to have all those different mechanisms of action. Do you have any final words for the listeners?

Michael Morris: No. I mean, I think that we should approach all of these issues with real apropos. That is right now, there's a lot of enthusiasm around the world of radioligand therapy, and that enthusiasm is well earned. It's a new drug. We should not think that radioligand therapy is going to replace, supplant, or displace any other therapy in the armamentarium. It's it is just another drug. It is not a miracle drug. There's still half the patients who don't respond to it. We have a lot of work to do to figure out what the right combination of patient factors, tumor factors, dosing factors, the right timing and the place of the disease. We have a lot of work to do in terms of how to optimize this therapy. I wouldn't think that it should be used as, and I think many patients are thinking like, maybe I can use Lutetium in substitution for ADT, in substitution, for salvage strategies and substitution for even primary definitive therapy. It's just a tool. And there's, there are many things we don't know about how to use it, but without the data, it shouldn't be thought of as, as replacing existing life belonging, if not curative, depending on where you're on the disease methods of treating a disease.

Alicia Morgans: So still a lot of work to do...

Michael Morris: Much work to do.

Alicia Morgans: A lot of work to do, but a lot of patients who can benefit from any and all of these treatments. And so I really appreciate you talking us through because the sequencing gets very confusing and it's nice to have a voice of reason as we try to sort it all out. Thank you.

Michael Morris: You know, I think that my parting message is vision was for the patient who really doesn't have too many treatment options left. And it is in that sense, a really significant therapy. There's just a lot of work to do. And a lot of questions to answer on a treatment that has promise, but it's really it's greatest potential has probably not yet been realized.

Alicia Morgans: Great. Well, thank you for your time and your expertise.

Michael Morris: Thank you.