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Alicia Morgans: Hi, I'm so excited to be here with Dr. Pedro Barata, who is joining us from the University Hospital Seidman Cancer Center in Case Western Reserve University where he serves as the Director of the GU Medical Oncology Research Program. Thank you so much for being here with me today, Dr. Barata.

Pedro Barata: Thank you. Dr. Morgans. It's always is a pleasure to be here.

Alicia Morgans: Wonderful. Well, today we're really going to dig into an important topic and concept, understanding the sequencing of radiopharmaceuticals in metastatic castration-resistant prostate cancer. I wonder if you could take it away?

Pedro Barata: Sure. Happy to do that. And believe it or not, I did put a few slides together just to help our conversation. I'm going to go through them relatively quickly, because I'm sure you have as always, fantastic questions and comments for us to discuss.

So we all know that radiopharmaceuticals as a group, the goal is to deliver radiation therapy to cancer cells. And we talk a lot about alpha particles and beta particles. We were very, very familiar in the past with alpha particles because of radium-223, which is a life prolonging therapy approved for men with advanced prostate cancer. And then we have beta particle. Recently we've got one agent called lutetium-PSMA radioligand here, that also have shown to improve overall survival. So there's a few differences between alphas and beta particles I think are relevant. In general, alphas have higher energy, they have shorter range, and they have a stronger killing effect, if you will. But nonetheless, we do have these alphas and betas available for patients with advanced CRPC.

Now, just reminder really quickly about the ALSYMPCA data, is a trial that was presented and published a decade ago or so. And just a reminder, we actually took patients back then with progressive castration-resistant prostate cancer with two or more bone mets, no visceral disease, the nodal involvement no more than three centimeter, had more than five PSA, and the goal was standard of care plus or minus radium-223. And those patients were symptomatic, despite regular use analogies or treatment with palliative radiation within the prior three months. And we all know the results. Basically, patients who received radium-223, either pre- or post-docetaxel actually lived longer, had a prolonged overall survival, compared with patients who did not receive it. And this is actually the first radiopharmaceutical agent to have shown a survival advantage in men with advanced prostate cancer. So very, very important data.

And then more recently of course, we have this beta particle lutetium-PSMA-617, the PSMA 617 is radioligand here. And in the VISION trial, again, designed a standard of care plus minus lutetium-PSMA. We know that it was able to improve outcomes, not only radiographic progression-free survival, but also overall survival. We see in this graph here, compare with standard of care alone. And just a reminder of this particular trial, this was designed for patients who were previously treated with one to two novel hormonal therapies, and one to two lines of taxane-based chemotherapy. So it was a little late in the game. So once these agents got approved, the question really is, how can we use them in the context of the current landscape for advanced disease? So that's one part.

And the other part that I think we need to be aware of is actually where we are going? And now, we just got a press release that basically confirm the positive results of the PSMAfore, which in essence, is taking the same compound of lutetium-PSMA, but in this setting for metastatic CRPC pre-docetaxel. So that's the difference, and is a positive trial for the endpoint of radiographic progression-free survival, and we'll see the data soon. But I think this is really important, as we think about how to sequence these therapies.

So as I said, optimization of these radioligand therapies and radiopharmaceuticals is really, really important knowing that they are a life prolonging therapy. So we do want to expose our patients to as many life prolonging therapies as possible. So just a reminder of for instance, we now start having a couple of studies looking at the question about what happens for patients who are exposed to radiopharmaceutical radium-223, and end up getting lutetium-PSMA, right? That's a real world question, because we're going to have more and more of those patients.

So here, we'll see data from the REASSURE study, this is published data by Oliver Sartor and colleagues. And basically, we have a relatively small cohort, 26 patients with mCRPC. But what's interesting here is, number one, patients got a median of six cycles of radium, which that's what you kind of shoot for. That should be our goal. And the median overall survival for patients who receive lutetium post radium-223 is really in line with what we've seen, and for example, in the VISION study. So it does suggest this piece of data, and of course, you have the time, the median time there on the right side of the screen. I really think this data kind of supports the idea that from the efficacy perspective that doesn't seem to be a compromise in the activity of lutetium for patients previously treated with radium-223, but also from the safety perspective, there were no new safety signals identified here, which was reassuring.

Of course, keep in mind, this is a small retrospective experience, but nonetheless this goes in line with other observational studies that we know, like the REASSURE or the WARMTH, that basically suggesting that patients who getting lutetium post radium-223, are actually doing well from the safety and efficacy perspective.
Now because it's a more recent study presented, I just would like to highlight quickly the RALU study. So radium lutetium study if you will, here's the design. This is the retrospective study, or data was collected retrospectively. And I really think what's interesting about this particular study is number one, the objective was to investigate again safety and effectivity of different or two radioligands of lutetium-PSMA.

We took 617 as well as lutetium-PSMA I&T, those the two radioligands, in patients who were previously treated with radium-223. Again, this is more recent data. And here's the baseline characteristics of that study. It's really what we would expect. We have about 85% of patients getting lutetium-PSMA, and then with 617, and then around 48 patients with PSMA I&T. And what's interesting here is, all patients got radium. There's a fairly high number of life prolonging therapies previously. So that means this was a little bit late in the game. We actually have over half of the patient population who have received four or more life prolonging therapies. A good number of patients with liver mets. And really, also patients were really exposed to taxane-based chemo. So we're really talking about patients who are exposed to different lines of therapy later in the game, and the goal is to see what happened here.

And as we can see in this next slide, we're basically looking at overall survival by the PSMA ligand. So 617 or I&T. And really, whether you look at the data from one perspective of the other regarding the first dose of lutetium or the first dose of radium, the overall survival, the median overall survival for these population, is actually, seems to be in line, or looks in line, with what one would expect, knowing all the therapies available today. And actually, what we've seen with lutetium-PSMA data, based on VISION for example, as well as for example, TheraP. So again, I really think this data from the efficacy perspective is very concordant to what we've seen. And it doesn't seem thus far, it does not seem to harm, the exposure to radium-223 does not seem to impact negatively the activity of lutetium by the contrary, because now we're able to actually offer two life prolonging therapies and sequencing down, if you will.

And finally, a word about safety for these particular two groups of patients. And if I get your attention to the bottom side of this table, you'll see that the number of folks, most of the adverse events that we've seen with therapy were mild or non-significant. And the number of significant adverse events here, grade threes and fours if you will, were really in line with what we would expect, way less than 30%. Which is really speaks about how safe actually, radiopharmaceuticals have been for men with advanced prostate cancer. And of course, when we think about all the options out there, of course, the safety profile of the therapies that we use is important. And for these particular agents, we're talking about dry mouth, some nausea, some fatigue. And that's for the most part we're thinking about that. Sometimes there's some hematologic alterations that we can see, and that's how, that helps us monitor these patients in clinical practice.

So it's kind of in as a conclusion before we let you take it and maybe have some questions, Alicia, is really, when you look at the schema that's adapted from Dr Share, and we focus on the right side of the schema, we now can see that really we have of course radium-223 approved. It's approved for men, again symptomatic mCRPC, you can do a pre- or post-docetaxel, and then you have the lutetium-617, again post chemotherapy for now. But there's the chance that actually, lutetium-PSMA 617 becomes available before first-line of taxane-based chemotherapy.

So right now, the data that we have, in my opinion, does support the sequence of radium-223, followed by lutetium-617, based the data that are presented, it is possible that in the future, if we move lutetium-617 earlier in the course of the disease, it is possible we'll start getting some reports about the other way around. Right? About patients who received previous lutetium-PSMA-617, end up getting radium-223 on an alpha particle here later for their disease. So maybe I would stop here, and get it to the point where we can actually discuss a little bit more the granularity of these data.

Alicia Morgans: So thank you so much. That was so helpful. And I think just really nice to go through some of the data with a different lens. And as we're really thinking about this landscape evolving, I think there are so many ways that we need to think about this, and really dig in. And when I think about my clinical practice, and data that's so meaningful and important today, I always think about these real world studies, and if they actually reflect the patients that I see in practice, and if that data is going to be meaningful. So the REASSURE study, this is a bit of a real world type of a study, shows some safety, some interesting alkaline phosphatase declines, and how that might be associated with response and to outcome, and really I think, pretty thought provoking. But does this feel like a population that is really informing your practice? What do you think?

Pedro Barata: Yeah, that's a fantastic question, and I kind of feel the same way. Of course, we always want to see ideally level one data to support our decisions, but we all know that the patients we see in clinical practice are not quite trial patients. Some are, and we're able to enroll them in trials, and others, just we use the data we have available from the clinical trials. But more important than that, I think it's really important to confirm the signals we see in the trial setting, as well as to perhaps change them in the real-world data sets. So the REASSURE study, knowing that is a relatively small study, it is also one of the first, so it has that merit, right? Because of course, yes, we have a little bit over 20 patients or so with mCRPC, but it's also true that lutetium-PSMA did not become available that long ago.

So it will take us time to actually generate larger data sets, and perhaps confirm some of the findings that we got in REASSURE in larger and longer follow-up data sets. But with that said, I think it's one of the first studies to number one, confirm what we thought, is actually safe to do it. And I think that's what we see in that study. Number two, is actually feasible, and it does remind me a lot because we tend to have as you, you've been around for a long time, and you know that there's a lot of excitement about all this great excitement on novel therapies, and we tend to forget the therapies that made, that we offer to patients that help them. And radium is one, and we all know that ideal patient for radium-223 tends to be one with fewer bone mets, but relatively low PSA below 30. That's what some data again becomes, from some of the data out there.

And also, we should aim for five or six cycles of radium-223, and we know those tend to be the patients and perhaps African Americans as well, and they tend to be the patients who benefit the most. So when we look at the data from REASSURE the patient population is there, the median number of cycles for radium was actually six. And then the safety profile, as far as hematologic events, was actually very similar to what we would expect, and actually what I see in clinic, is including patients who have received prior taxane-based chemo like docetaxel. And then when you look at the outcomes, overall survival, thinking that over two years in this setting, which we're really talking about mCRPC after exposed to, for example NHTs, or about over a year for patients who receive lutetium, just counting the time that you're getting lutetium, I really think these are the outcomes that we're seeing in the best real world, and really honestly, clinical trial data we have out there.

I mean, this data is not that different really from the Phase III trial from VISION, for example. So that suggests to me that of course, we need larger data set to confirm those things, but the fact we're not identifying worrisome safety signals from one end, one other end is, or from the other perspective is, we are seeing the activity is real, and we are helping those patients. It's really a question about how can we optimize delivering life prolonging therapies to the patients we see, including not just lutetium-PSMA radiopharmaceutical, but also radium-223. So that's how I see trials like REASSURE playing an important role, I think, as we think about what to do in clinical practice.

Alicia Morgans: I think to some of those points that you made, there's definitely data that, and these are again from expanded access programs. There was a really interesting one that the European expanded access that demonstrated that patients did better, certainly if they had more cycles of radium for sure. And also, if they went into treatment without terribly uncontrolled pain. And I think that's really interesting, that those patients who are clinically better, are going to do better with most treatments that we give them. And the earlier we use these treatments, the better the patients have actually, at completing the number of cycles that we're aiming for.

And so, I always think about all of these options as being different things on a menu, and I really hope that we can get every item on that menu to the patient, because I do think that there's data that these can all be, as you said, life prolonging therapies. And importantly, when it comes to radium, I'm always thinking about the survival benefit, and whether that patient's going to be reasonable, in terms of the distribution of disease, not having visceral disease, or high burden lymph node disease. But I'm not necessarily saying, oh, this patient must have terrible pain. Now from your perspective, are you thinking about getting this drug to patients who are clinically well without severe pain, or are they symptomatic potentially, from their prostate cancer, in other ways beyond pain? How are you thinking about that patient selection piece?

Pedro Barata: Yeah. No, that's a fantastic question, right, because the eligibility criteria for all did require symptoms despite having pain with analgesics, and/or a palliative radiation within three months. So if I think of who is the patient, what I think is be the ideal candidate for that, I certainly use radium-223 in patients who are not actively in pain. Maybe some of them got palliative radiation therapy in the last three months, but not necessarily, to be honest with you, I really think about making sure that I don't have disease outside the bone, or the lymph nodes are not bulky nodal involvement. The other perspective that I like to think is, I like to think that, where is the sweet spot for it? Where can I buy six months of time, for me to offer radium-223 without being in trouble? And most of the times I come up with the answer that is usually pre-docetaxel when you develop CRPC, I think that's in the sweet spot.

Now we know we don't combine it with abiraterone, but we do know thus far, actually the combination with enzalutamide seems to be safe. And actually that data, the PEACE III data that we haven't read out the final analysis, but we have seen data already from it showing that it's also safe. So I have done that in my practice. I've done radium-223 as monotherapy, but I've certainly done it combined with example, enzalutamide as per PEACE III data that we are aware. But the more important piece is, when I do radium-223, I always remind myself of the importance of bone health and bone modifying agents, and whether it's denosumab or zoledronic acid, I really want to make sure the patient is well protected, in addition to calcium vitamin D, and I want to make sure the patient is protected from that perspective.

So as I said, I like to think African Americans, I do practice, as you know, I practice in Louisiana, I practice now in Ohio, we do have a higher rate of African Americans with advanced prostate cancer, for which data radium-223, is really, really, really compelling. The difference in that trial, [inaudible] is really outstanding, to be honest with you. So African American is definitely something I take into consideration.

The PSA, I try to follow PSA around 30 less or so. Ideally, less than 10 bone mets, not necessarily symptomatic patient in my book. And if I have disease, exostosis disease, I tend to do it more combined with an anti-androgen such as enzalutamide, based the data provided. When I don't have exostosis disease, I feel very comfortable doing, and shoot for five to six cycles already radium-223. And I feel comfortable doing that, knowing that having the conversation with the patient, that perhaps PSA is not helpful, [inaudible], not helpful all the time. And also I do scan the patient, make sure he's not in trouble, but we know it does not impact time to disease in the scan. So we're really shooting for survival.

Alicia Morgans: So thank you for that. And I think it's so interesting when we're thinking about again, sequencing, and the way that the treatment landscape for metastatic hormone-sensitive disease is shifting. Some patients getting triplets, some patients not getting an AR targeted agent, an ADT, some patients still getting ADT alone, which is frustrating, because we know we can do better in that setting. But how does that affect your treatment choice, when you are thinking about using a radiopharmaceutical, given all of the options that are now available to us in the metastatic hormone-sensitive setting?

Pedro Barata: Right. That's a fantastic question, because when I mentioned docetaxel, in my mind, I'm thinking the old school way of thinking CRPC. And now, we move docetaxel, whether for CHAARTED, STAMPEDE, ADT, doce, or as you said, triple therapy for high volume disease. So you can definitely have docetaxel being offered normal safety space. I think it will depend when you progress to CRPC, right? In general, to be fair, for you to be getting these days docetaxel with abe or darolutamide and ADT, you likely have high volume disease. So you can only get that one or two ways. Either you have more than four lesions in the bone, went outside the pelvis and spine, and/or visceral disease. Probably based on the data what we know, radium is not a good option for patients with visceral disease, right? Because the way, based on the mechanism of action, or at least as monotherapy.

But it is true that the other piece of the high volume disease component is actually given you by more than four lesions in the bone. So if you were to progress to CRPC, you actually have data with radium-223 post-docetaxel, and that's actually ALSYMPCA, they included half of the patients pre- and post-docetaxel. It's a different setting, because it was in the mCRPC setting. But also remember, those patients were not completely exposed to the same level of NHTs as we do now have, because the landscape changed tremendously from the last decade now.

So I would say, to answer your question, I really think it's reasonable to consider radium-223 for patients who got a triple than normal safety space, assuming that probably we're talking more about those patients who have disseminated bone marrows, or at least more than four bone mets. And now, they are in the CRPC setting and you are asking about what to do. And maybe, because now you have some real-world sequencing data, you can do that, and then you'll do lutetium, right? The question is, for patients who might be getting lutetium right away, can you do radium-223 afterwards? And you change from a beta particle to a alpha particle. And I do believe we need more data. I don't think if we have data showing that's actually safe and a good idea to do, that's another opportunity for us to consider that agent, as we're trying to exhaust or use all life prolonging therapies available to us when we're managing these patients. But there's a little bit lack of data on that last part.

Alicia Morgans: I love the way you put it, the sweet spot, the way that you think of it, or a window of opportunity is the way I think of it. And those windows can close if the disease progresses in a way where more lymph nodes are involved, or patients develop visceral disease. How does that affect your treatment choice? And then the other piece of this question is, do any supply chain issues, in terms of getting things like lutetium, affect your treatment choices today? Recognizing that that may not be a long-term issue, but certainly it affects the patients who are trying to get treated in our clinics now.

Pedro Barata: Right? No, you're absolutely right. And I do have experience from practicing in different countries. And so I know what it means to talk about one therapy that helps people, and not having access to that therapy. And I'm sure, as folks who are listening to this out there can understand, depending where they're practicing, that concept. So we do have an access issue currently. I hope that gets better over time, and I think you will. So how does that play into the equation? So that's one question. So I think it does impact how I practice, you don't have access to that. So you need to play with what you have access. And so I think it depends on where the patient are. We know in America, most patients will be getting novel hormonal therapy. We know that's the reality, and most patients will be treated like that. So that's almost your starting point. Whether you got a CYP17 inhibitor, whether you got an anti-androgen, that's usually the scenario.

And so upon progression, then really the question is, what do you do? Well, you can do chemotherapy. You can actually think about doing radium-223 before doing chemotherapy with docetaxel, for example. And that's one, assuming you don't have targetable alterations, that you'd be a good patient for target therapy like a PARP inhibitor. But that's, as we know, that's less common than the other scenarios. So in that situation, I think radium is actually a good opportunity for patients to get, and maybe that actually will buy you time for the point where you actually progressing on radium perhaps, you get docetaxel, and you get to the point that you might get lutetium. And if you still don't have lutetium available at that point, then you actually can use CARD data to make the case to use cabazitaxel, right? Instead of using the second oral agent, after you've used radium and docetaxel. That that's one strategy, that's one who to go about it, right?

Now, when you have patients progressing with hormone-sensitive disease to CRPC, getting NHTs, and most of our patients in academia are getting that, the question is, what you do? And I really think it depends what the volume of the disease is, and obviously, how symptomatic they are, and actually how quickly, or how long have they been on therapy for hormone-sensitive disease. So I actually would not be, I don't think it's unreasonable, definitely not unreasonable to consider radium-223 a part of progression as monotherapy. But in some situations, let's say, you have a patient with bone mets, but also with lymph node involvement, the question is, can you bring radium on board if you have the lymph nodes under control, and if you have new bone mets at time of progression to CRPC? That's another example where you can actually think radium-223 could be a reasonable approach.

Again, I think what we're trying to do is, we're squeezing the effect of all life prolonging therapies as much as we can, because the number of options is limited. And this is a marathon not a sprint. And so, the goal of the game is buying us time, until we get to deal with the next line of therapy.

So I do think, to summarize, I do think that radium is something that for, because things change, not a lot of us are thinking as much as before. I certainly bring that up in the discussions with my patients in clinical practice. And definitely, the access to novel radiopharmaceuticals is actually something that should make us think more about the radiopharmaceuticals we already have available. And by the way, that we don't have problems with access to radium-223, and I'm sure all of us have figured out how to get access to radium-223 these days. So that's definitely an advantage favoring radium-223 in the context of where we are today.

Alicia Morgans: Wonderful. So I really appreciate you sharing your expertise. We have discussed so many things, certainly some exciting data, and thank you for presenting that. Really understanding the sweet spot, where we might be able to fit this particular therapy, radium-223, among all of the other things that we have, and this changing landscape, which is including increasingly radiopharmaceuticals. And I would also like to just point out, and thank you for mentioning, bone health, which is of course something so important to patients with metastatic CRPC. They all qualify for bone health agent treatment. And it is important that we think about that, as we try to maintain, not just their lives, but really, ensure that they have function, that they really prevent those complications that can be so limiting.

So thank you so much for your time and your expertise. I appreciate it.

Pedro Barata: Thank you. It was a great conversation. Thanks for having me.