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Christopher Wee, MD, a medical oncologist from the Genitourinary Medical Oncology Program at Taussig Cancer Institute joins the Cancer Advances podcast to talk about therapies for metastatic prostate cancer. Listen as Dr. Wee discusses Lutetium-PSMA and the clinical trials that showed patients had better response rates and fewer toxicities when they got lutetium on top of their care.

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FDA Approved: Lutetium-PSMA for Metastatic Prostate Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic Podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a medical oncologist here at Cleveland Clinic, overseeing our Taussig Phase One and sarcoma programs. Today I'm happy to be joined by Dr. Christopher Wee, a member of the Genitourinary Medical Oncology Program at Taussig Cancer Institute. Christopher is here today to talk to us about treatment of prostate cancer with Lutetium PSMA, a new therapy from management of this disease. So, welcome, Christopher.

Christopher Wee, MD: Thank you for having me on here.

Dale Shepard, MD, PhD: Absolutely. So maybe start off, what's your role here at Cleveland Clinic? What do you do here?

Christopher Wee, MD: Yeah, so I'm a medical oncologist, so I treat people with medicines for genitourinary malignancies. So that includes kidney, bladder, prostate, testicle, et cetera. I don't do surgery, I don't do any radiation. So anything that's medicine, that you either take by mouth or IV is what we do.

Dale Shepard, MD, PhD: Okay, excellent. So we're going to talk about metastatic prostate cancer today. Maybe just as an overview, because we have a lot of different people might be listening. What are the kind of categories of treatments we have right now?

Christopher Wee, MD: Well, so we have a lot of treatments for metastatic prostate cancer and the overall survival is continuing to improve. The mainstay of treatment for decades has been hormone therapy, androgen deprivation, and that's achieved by either most commonly a GnRH agonist such as leuprolide, an antagonist, such as Degarelix, or Relugolix, or bilateral orchiectomy. But what we found in the past decade is that if we combined androgen deprivation with a second agent, whether it's chemotherapy or one of these novel hormonal agents, such as an androgen biosynthesis inhibitor or androgen receptor blocker, people live longer and do better than if they went on androgen deprivation alone. And so, that's currently the standard of care when someone comes in with newly diagnosed metastatic prostate cancer, is androgen deprivation plus a novel hormonal agent, that's a pill, or androgen deprivation, plus chemo, plus pill.

Dale Shepard, MD, PhD: And so, a lot of our most recent therapies have really pushed to earlier treatment. So instead of advanced metastatic disease, before people even have metastatic disease. And so, there is a new drug that's now going to be available for that advanced setting. Is that that correct?

Christopher Wee, MD: That is correct. And so, those first therapies that we just talked about, whether it's one of those novel hormonal agents plus androgen deprivation, that usually works well for some time, but unfortunately, it generally stops working. And at that point, we consider other therapies such as taxane-based chemotherapy, most commonly docetaxel. If there's a mutation in homologous recombination repair, we can consider a class of drugs called PARP inhibitors. There are a couple of other different treatments, but once we get past one or two treatments, the options become more and more limited. So, Lutetium PSMA offers an option, and is currently FDA approved for people who have prostate cancer, that has had progression on antigen receptor or a novel hormonal agent, as well as a taxane-based chemotherapy. And if you have metastatic castrate resistant prostate cancer and have had progression on both of those, this is a potential option.

Dale Shepard, MD, PhD: So, people are more familiar with hormonal therapies, of course, chemotherapies. The taxane therapies. This is neither. What exactly is this?

Christopher Wee, MD: I think, it's a radioligand is the fancy word. So prostate specific membrane antigen or PSMA, is very often expressed on prostate cancer cells. So there's a diagnostic component where they use a PSMA PET scan, where they use a radio-labeled isotope that basically lights up all the PSMA AVID cells. If the cancer does express PSMA, which the majority of men with metastatic prostate cancer do, then we can target that same target, the PSMA, but instead use lutetium to be, radiation to specifically those cells. And it also, therefore it's more directed therapy with, be able to minimize the side effects and toxicity to surrounding cells.

Dale Shepard, MD, PhD: So, can you tell us a little bit about the data that has led to this being?

Christopher Wee, MD: So there are a couple trials. One is called the Vision Trial, and this took men that have had prior novel hormonal therapy plus androgen deprivation, and they've also had chemotherapy with the taxane. And men were randomized to standard of care, or standard of care plus Lutetium PSMA. So the standard of care could have been an agent such as enzalutamide or abiraterone, one of those other novel hormone agents that a patient has not had yet. And when we compared those two groups, men had better response rates as well as they lived longer when they got lutetium on top of the standard of care.

Then there's another trial called the TheraP, T-H-E-R-A-P Trial that was presented at this year's ASCO meeting. And what that did was, they randomized men who had, had progressive disease after docetaxel, and they randomized men to lutetium or cabazitaxel. And this is a stronger control arm, because cabazitaxel, we know has survival benefit over other therapies such as mitoxantrone after docetaxel. So in this randomized trial, men that had cabazitaxel or lutetium, they had this similar overall survival, but significantly fewer toxicities and better response rate than the cabazitaxel. So it suggests that this therapy can be more effective than cabazitaxel and less toxic.

Dale Shepard, MD, PhD: Stepping back to the Vision Trial, the standard of care. What are your thoughts like, as you approach a patient, you're thinking about giving this treatment. Do you think the control arm is standard of care, and a second hormonal therapy sort of lessens your enthusiasm in any way? Or how do you address that with patients?

Christopher Wee, MD: Certainly, that's a great question. So if we take a step back, when someone is newly diagnosed with metastatic prostate cancer, they're going to get androgen deprivation or they should get, plus a novel hormone therapy, plus/minus chemo. So we know that when men have prostate cancer that has had progression after one novel hormonal agent, whether it be abiraterone, enzalutamide, apalutamide, the chances that they will have a significant or meaningful clinical response to another agent with a similar mechanism is less. It can happen, but it's less likely to work. So in the Vision Trial, that is a limitation because that standard of care we know, is not that good in that setting, in the control arm. So we would expect that if people get lutetium, they will do better than the standard of care.

Dale Shepard, MD, PhD: And then I guess, if you combine the Vision Trial data with maybe not the best control arm, with the therapy trial against a standard therapy that has efficacy that gives you some additional confidence.

Christopher Wee, MD: Yeah. So what the way I take it is that we were not able to demonstrate survival benefit when lutetium was compared against the stronger control arm, cabazitaxel, in the TheraP Trial. However, it was better response and better tolerated, which are very meaningful endpoints. Just the overall survival benefit was not demonstrated. So the way I look at it is, is that Lutetium PSMA is an option that should be considered for men who have castrate resistant prostate cancer, who have had progression after docetaxel. But if Lutetium PSMA is not readily available because there may be some supply chain issues, or a center does not have access to this therapy, cabazitaxel still is a very effective drug and can be used first. And so, I don't think patients should feel that they're getting inferior treatment necessarily from a survival standpoint.

Dale Shepard, MD, PhD: And so, you mentioned things about access, we'll talk about in a second, and really just availability of the therapy. So you talked about prostate cancer cells having PSMA. Do all of them, and was that a requirement for getting treatment? Do you have to have the targets?

Christopher Wee, MD: Yes, you have to have that, because if we get a PET scan, so that's one of the criteria, and they're pretty broad for the label and the approval. But if cells are not expressing PSMA, this therapy is not beneficial. So you do need a PET scan prior. And so, that I do foresee is a rate limiting step in certain situations. Because if a patient were to develop a castrate resistant disease, and have had progression on a taxane, such as docetaxel, they would have to get a PET scan in a relatively quick timeframe to be able to become eligible for that. And then after that, submit the authorization and the manufacturer needs to provide this radioactive treatment in a relatively quick time, otherwise they could have progressive disease.

Dale Shepard, MD, PhD: Do you anticipate that patients, kind of quirky how patients sometimes think that, they'll get bone scans which have radioactivity, or they'll get other PET scans that have radioactivity, but sometimes when you talk about treating them with radioactivity, there's a little bit of a hesitancy. And do you ever anticipate that being sort of a challenge?

Christopher Wee, MD: That's a great question. Generally, at least right now, the patients in whom this is currently approved for have limited options left. And so they're more willing to accept particular toxicities. The second, I've been really impressed by how much the patients have been trying to learn about this themselves, and they like the idea as a targeted therapy that's more targeted toward their cancer. And that's appealing to a lot of men, and why we are actually testing it in an earlier line setting.

Dale Shepard, MD, PhD: So I guess when we think about, it's certainly an interesting drug to consider. It is a different category, it's a radioactive compound. The most recent radioactive compound we had for prostate cancer, radium, doesn't really have a lot of uptake. And so, it's no pun intended there. But what would you say to people who maybe had some experience or with radium, how's this different? How do you like this, compared to that as a treatment?

Christopher Wee, MD: Yeah, so radium is a good option, because it's well tolerated and can really help with bone metastases and bone pain. It doesn't help with soft tissue disease. So this has more broader activity than radium 223. I would consider this before radium. If a patient can tolerate Lutetium PSMA, for a couple reasons. One, Lutetium PSMA can actually have response, PSA response, you know can have radiographic response. The second is, one of the toxicities of radium is that it can be damaging to the bone marrow, which could preclude patients from Lutetium PSMA. Lutetium PSMA, although significantly better tolerated than chemotherapy, so it is something that we need to be mindful of. I would hate to preclude a patient from Lutetium PSMA due to hematologic parameters from a prior treatment.

Dale Shepard, MD, PhD: Makes sense. Tell me about clinical trials that you're interested in with lutetium.

Christopher Wee, MD: Oh, certainly. So we know that this is a very effective and good option for men with castrate resistant prostate cancer. Now, we're trying to start with the intensification in earlier line therapy. The idea that, you get your best shot at getting a meaningful response and prolonged response, if you intensify therapy up front. You don't want to save therapies for later lines, because you don't know what shape the patient will be in at that point.

So we've seen this in a number of ways. One, we've seen the move from androgen deprivation alone, to androgen deprivation plus one of these novel hormonal agents, apalutamide, abiraterone, enzalutamide. In the past year we've seen the argument some people have made for triplet therapy, both from PEACE1 and ARASENS demonstrating that ADT plus docetaxel, plus Darolutamide in ARASENS, was superior than ADT plus docetaxel.

So now currently, we're testing in a clinical trial here at Cleveland Clinic for men that have newly diagnosed metastatic hormone sensitive prostate cancer, that have PSMA avid disease on a PET scan. They can be randomized in a one-to-one fashion of standard of care. So ADT plus abiraterone, enzalutamide, or apalutamide, or standard of care plus lutetium. And so, this is very attractive because the control arm is standard of care. You're getting what you would have been recommended anyway. And furthermore, if you're randomized to the standard of care arm and you have progression of the disease, the protocol allows for crossover at that point to lutetium, which is currently not the option, because a patient would have to have progression on chemotherapy as the label currently stands.

Dale Shepard, MD, PhD: Excellent. So assuming that this trial shows success, what would sequencing look like to you? I mean, how would you like to fit this in? If you had the ability to use lutetium in any setting, what do you think would be the best sort of sequence for a patient that shows up with metastatic disease?

Christopher Wee, MD: That's great. I really would like to see the results of this trial, right? Because the median overall survival of men with prostate cancer can do well for years, sometimes many years with effective treatment. And we need to take a look at the patient's overall health. What the other non-prostate cancer mortality risks are? And so, you'll always try to balance not giving too much toxicity up front, but appropriately intensifying therapy.

So I don't know, I would want to see what this data would show, and this was going to take years to pan out, but currently I see it as it's currently labeled. I would consider it in the castrate resistant setting, after docetaxel. Whether or not to use cabazitaxel first I think, depends on a case by case basis. Based on availability of lutetium, patient preference or what prior toxicities they've had with taxane. So for example, if a patient has significant residual neuropathy from docetaxel, I'm going to be more likely to use lutetium than cabazitaxel as the next line of therapy at that point.

Dale Shepard, MD, PhD: And then, I guess really from a purely logistic standpoint, I know that as this has rolled out, there have been some supply issues and things, but outside of that, once this gets up and rolling, how likely do you think that this will be widely available? Is this going to be kind of specialized center therapy because of the complexity?

Christopher Wee, MD: I don't know. My hope is that it's not. And there are a number of centers I know in the state. I think there's going to be some pent-up demand initially, as a lot of patients who are waiting for this. My hope is that it is more widely available. They've been using lutetium with dotatate for neuroendocrine tumors, though that's a lot more rare of a tumor. So I don't know, necessarily, what the logistics are going to be because there are a lot of moving parts. You have to have specialists that are able to work with this nuclear medicine technology. And what we have here at Cleveland Clinic is a team based approach, that we work very closely with our folks in the imaging department, as well as our nuclear medicine specialists. And it works seamlessly, which makes it easy for us to deliver good care to our patients.

Dale Shepard, MD, PhD: And, that's primarily thinking about the treatment itself, but from a scan standpoint? Is that going to be, you think that'll be more widely available?

Christopher Wee, MD: I've seen it more widely available, but anecdotally speaking, patients have had to wait to get the PSMA PET scan at other facilities longer, versus usually we can hopefully get them in within one to two weeks here, because that is a rate limiting step.

Dale Shepard, MD, PhD: So, lutetium looks like it's going to be a promising therapy, that's going to sort of change the way that we manage metastatic prostate cancer. I guess while we have you for another couple of minutes, what else do you find exciting right now in the field of treating metastatic disease?

Christopher Wee, MD: So, I think a lot of things that we're looking at now, is survivorship issues right now. And we know that men are living longer and longer with metastatic prostate cancer. And as men live longer, then the risks of other comorbidities becoming an issue increases. For example, cardiac toxicity. And we know that androgen deprivation has been associated with an increased risk of cardiac toxicity. So trying to figure out ways to minimize side effects and long-term detriments to health is important. Now, there was one trial that showed that relugolix as a secondary endpoint had fewer major adverse cardiac events, compared to a GnRH agonist. We need to interpret that data in the context of everything, because we don't have strong prospective data that we've used this agent with other hormonal treatments that we like to use, but these are things we need to start considering when we're treating men, and as they're living longer.

Dale Shepard, MD, PhD: Very good. Well, you've given us some great insights today. Appreciate you being with us.

Christopher Wee, MD: Thank you.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. You'll find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget, you can access real time updates from Cleveland Clinic's Cancer Center experts on our consult QD website, at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.

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