Pre-Taxane Lutetium in Prostate Cancer: Changing the Treatment Algorithm

Podcast Transcript

Dale Shepard, MD, PhD:

Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Christopher Wee, a Genitourinary Medical Oncologist here at Cleveland Clinic. He was previously a guest on this podcast to discuss use of lutetium PSMA for metastatic prostate cancer, and that episode is still available for you to listen to. He's here today to discuss new indications for lutetium in this disease. So, welcome back.

Christopher Wee, MD:

Thank you for having me.

Dale Shepard, MD, PhD:

Absolutely. So tell us a little bit again about what you do here at Cleveland Clinic.

Christopher Wee, MD:

So I'm a genitourinary medical oncologist. I treat patients with medicines or systemic therapy for all types of genitourinary cancers. I would say prostate cancer's probably the majority of what I do just based on how common it is.

Dale Shepard, MD, PhD:

Makes sense. Well, we're going to talk about prostate cancer. We're going to talk about lutetium, talk about where that's fitting into the world now. But as we talk about lutetium, we start this discussion, a lot of different people, different backgrounds listening in, what exactly is lutetium, and how does it fit in the landscape currently?

Christopher Wee, MD:

The simplest way to think of this is it is a molecular missile per se. There's the PSMA targeting ligand that is the guidance system and lutetium-177, which is a beta-emitting radionuclide that acts as the warhead. So PSMA, or prostate-specific membrane antigen, is a protein that's over-expressed on most prostate cancers. So when you administer this intravenously, this ligand hones in on these PSMA expressing cells and lutetium-177 delivers the beta particle radiation that induces DNA double-strand breaks in the cancer cell and in its surrounding microenvironment.

Dale Shepard, MD, PhD:

So as a radioisotope, radionuclide, a little bit different than what we think about with chemo or targeted therapies. I'm just going to have a throwback question. So we had radium as a treatment that could be used in prostate cancer. How do we think about radium versus lutetium in terms of a treatment?

Christopher Wee, MD:

Radium is an alpha emitting, and it works very well for bone metastases. So it only works in bone metastases, because that's where it's uptake. So it does not target any soft tissue metastases, whether it's in a lymph node or a visceral metastasis. So although radium can be a very effective treatment and we still use it, lutetium PSMA has broader activity in different disease sites anatomically.

Dale Shepard, MD, PhD:

Because of that targeting-

Christopher Wee, MD:

Correct.

Dale Shepard, MD, PhD:

... specifically to PSMA, whereas radium is essentially like calcium and goes to the bone?

Christopher Wee, MD:

Correct. It's only in the bone.

Dale Shepard, MD, PhD:

Okay, fair enough. So last time we talked about lutetium, we talked about its use sort of as a treatment for metastatic disease treatment after chemo. What has changed?

Christopher Wee, MD:

So initially, just to take a step back, this was initially approved a few years back in the post-chemotherapy, post-taxane setting. So patients had to have had previous taxane-based chemotherapy, most often docetaxel. In the past year or so, it has now been approved in the pre-taxane setting. So if someone were to have metastatic castrate-resistant prostate cancer before they receive, let's say, docetaxel, they could now be eligible to get lutetium PSMA. And that's primarily from the PSMAfore data.

They took patients with castrate-resistant prostate cancer who have metastatic disease, but have not yet received a taxane. And they were randomized to either lutetium PSMA or an androgen receptor pathway inhibitor switch assuming that they got an androgen receptor pathway inhibitor in the hormone-sensitive setting, which is the standard of care. And what they found were improved outcomes, the improved progression-free survival, it's better tolerability. The important caveat, overall survival was not statistically different, though there's a lot of crossover, and it's hard to interpret in this setting whether or not there's going to be a benefit there.

Dale Shepard, MD, PhD:

Because there's a significant number of people crossed over?

Christopher Wee, MD:

Correct.

Dale Shepard, MD, PhD:

We're going to talk about sequencing. And part of that is when you think about the trial, other trials like CHAARTED and things would suggest that going from a hormone receptor inhibitor to another hormone receptor inhibitor, probably not a great idea, and that was the control arm. Does that give pause to the benefit of this drug?

Christopher Wee, MD:

You do have to definitely take that into account. We know that if you're to use an androgen receptor pathway inhibitor after prior failure of another androgen receptor pathway inhibitor, the chance you're going to get meaningful benefit is low. But there are patients who want to, A, avoid chemotherapy, or whose disease is not progressing that rapidly in whom chemotherapy is not necessarily necessary at this time, this can offer an alternative.

So I think the key point is that this is not supposed to replace chemotherapy. It's an additional option instead of chemotherapy in this setting. Because if someone already had an ARPI in the hormone sensitive setting, prior to the availability of lutetium PSMA, oftentimes assuming they don't have a BRCA or another HR mutation, oftentimes taxane-based chemotherapy was the next option. This offers another option.

Dale Shepard, MD, PhD:

When we think about some of our historic radionuclide therapies, some things have been in development, there's concern about marrow toxicity. And so of course, chemotherapy, you worry about marrow reserve. How does that work with lutetium? Is there concern about whether you give it an ability to get chemotherapy afterward?

Christopher Wee, MD:

Absolutely. All of these treatments, actually a lot of them, do have some sort of effect in the marrow, whether it's chemotherapy, whether it's a PARP inhibitor, whether it's radium, whether it's lutetium. And so, this really is something that we have to consider in the back of our mind. I'm generally not of the philosophy of "saving a treatment," because you can't predict what's going to happen in the future. You want to use the best treatment at the time, but it's something to consider.

Interestingly, the Canadian Cancer Trials Group, CCTG PR.21, they released an abstract form at ESMO last year, the European Society of Medical Oncology. And they had about 200 patients in a trial they randomized to docetaxel or lutetium in first-line castrate-resistant prostate cancer. Interestingly, the progression-free survival appeared similar between the two arms. Lutetium was better tolerated, but there was an overall survival benefit and then this was a secondary endpoint in the chemotherapy arm.

And one of the hypotheses are, more patients appeared to cross over if they got chemo first to lutetium than vice versa, lutetium then chemotherapy. So this is an evolving science. I don't think we can make any... It hasn't been published in manuscript form yet. I don't think we can make any broad conclusions. But certainly, ability to give further treatments is something to keep in mind, though that generally isn't my top consideration when choosing a treatment. I want to give what's most effective.

Dale Shepard, MD, PhD:

We'll talk about biomarker kinds of things in a couple minutes, but just sort of gut feel things that we routinely look at. What are the factors you're currently looking at? What's a patient look like? What's a profile of someone that you would go to chemo or one that you would go to lutetium?

Christopher Wee, MD:

Great question. So one, is the patient healthy enough to get chemotherapy? Generally speaking, there's not a right answer. These are a number of different considerations. If a patient's performance status is more compromised, then chemotherapy may not be a good option. On the other hand, you do have to consider some other radiation safety effects with lutetium that you do not need to consider with chemotherapy. For example, if a patient is unable to take care of themself, if the patient is incontinent and cannot clean up urine and needs help with that, that is not a good situation to give lutetium, because that will potentially expose caregivers to radiation. So I really like to have a patient be able to do their basic ADLs, bathe, eat, dress by themselves before considering either of these. Though that being said, the bar is a little bit higher to be able to generally get chemotherapy than it is to give lutetium.

The second is how aggressive is their disease state? If someone has relatively low PSMA expressing, and we know that generally speaking, the higher the PSMA expressing is correlated with better responses to lutetium, though we don't have hard numbers and it hasn't been validated as a perfect biomarker yet. But if someone were to have a bunch of visceral metastases or symptomatic, it looks like aggressive disease, chemotherapy can still be a very good option for these people.

So if someone needs a quick response as of aggressive disease, I think chemotherapy makes the most sense. But most patients, I think both options are on the table, and you have to take into account the patient's health, the patient's preferences, whether or not they want to do chemotherapy or not, and the patient's considerations. So for example, I had some patients who are caregivers for their spouse full-time. And the radiation safety concerns that even if the patient's healthy enough, they cannot be a direct caregiver to their spouse for a few days around the time of the lutetium administration. If we can delay giving lutetium then until after chemotherapy, maybe chemotherapy may be a better option for them. So there's plenty of considerations when making this decision.

Dale Shepard, MD, PhD:

You've kind of hit a little bit a couple times here now about the radiation safety part, but let's just sort of solidify that. What's the guidance for patients? You're injecting radioactivity, it's going to come out. What do you give in terms of practical advice just for people who don't normally do this?

Christopher Wee, MD:

Yeah, generally speaking, you are radioactive. Not that things you touch are radioactive, though your bodily fluids can be radioactive such as urine. So our general rule of thumb is 72 hours, 3 feet away from other people. For other individuals who are pregnant or children, we have a more conservative approach, perhaps seven days of being 3 feet apart. But those are the general considerations. There are obviously individual considerations that patients should talk with their doctors about.

Dale Shepard, MD, PhD:

I guess two things about ability to give. One would be, you talked about this is something that targets that PSMA, and we talked about this in the previous podcast, but maybe need to reiterate again. How do we determine who's eligible, what kind of testing's involved? And practically speaking, how many people end up being eligible?

Christopher Wee, MD:

So the majority of patients have some sort of PSMA expression if they have prostate cancer. That's the interesting part about these theranostics is that PSMA is both a therapeutic target as well it can also be used for diagnosis. And PSMA PET scans, and there's different tracers available, these are becoming more ubiquitous, more available as different sites are able to get them. So you do need a PSMA PET scan though, and ideally sooner so that way we know and can start considering it.

What you don't want ideally is someone to progress on first line therapy, then you need to get the PSMA PET scan, then you need to wait. So I try to get my PSMA PET scans earlier. Now, if you could get a PSMA PET scan immediately preceding administration of lutetium, that would also be ideal just to help monitor response to therapy. But the actual protocols and when you re-image, that's still up in the air and currently under investigation.

Dale Shepard, MD, PhD:

And if you think about a hundred people with metastatic prostate cancer, what percentage of them are likely to have PSMA expression and able to get drug?

Christopher Wee, MD:

Yeah, the vast majority. So the indication is for PSMA-expressing. It doesn't have a cutoff. So I don't remember the number off the top of my head, but it probably has to be over 80, 90%.

Dale Shepard, MD, PhD:

And then I guess you mentioned before about saving a therapy and making those choices, chemo versus PSMA. I guess a consideration would be that since you have to have PSMA expressing, there's certainly patients that have sort of mixed scans. So you'll do your scan and they may have metastatic disease that doesn't express. And so have you lost that window?

Christopher Wee, MD:

Yeah. So if someone were to have PSMA non-expressing sites of disease that appear active, yeah, that would be a consideration for when I would want to do chemotherapy at that point.

Dale Shepard, MD, PhD:

It'd be about losing that window. You also talked about availability. I know when this first came around, it was sometimes sites didn't have the ability to either do the scans to look for eligibility or to give the treatment. Is that getting better?

Christopher Wee, MD:

Yeah, definitely the scanning aspect is getting better. The company that makes this, Novartis, does have a... You could look at the sites that are able to give it. We just expanded beyond our site and main campus. So now offer this at Fairview, Hillcrest, and Akron General. So this is becoming more easily accessible to more patients. We want to get it to the right patient at the right time. And ultimately, I think we're moving toward that.

Dale Shepard, MD, PhD:

Where do you think this is going in the future? Combinations even earlier in the course of treatment?

Christopher Wee, MD:

That's a great question. So PSMA addition tested this in the first line, so hormone sensitive setting, and we were one of the sites for this. They presented their early data showing, not surprisingly, radiographic progression-free survival data. It's not yet approved. So that could be a place where it is used. It's currently being studied in other situations, but we're also seeing other particles also being studied, such as actinium-225. We have a clinical trial here at Cleveland Clinic that uses that isotope. And it's a very exciting time, because I think when we look at the big picture, these are relatively new technologies, lutetium-dotatate, which was used in neuroendocrine tumors within the past 10 years. And I do see that potentially these particle-based radioligand therapies will have an expanding role once we identify more targets in different disease states.

Dale Shepard, MD, PhD:

If we think about the expansion or the improvement in prostate cancer, and you mentioned things like actinium, do you think the primary limitations to benefit now are related to the target, the antibody part, or do you think it's more related to the particle or a little of both? What are the biggest things that need to be improved at this point?

Christopher Wee, MD:

I think trying to manage the toxicity and trying to figure out how much does someone need to get. And we don't know that yet. It's currently under investigation how to assess responses. Does someone need all six cycles of lutetium? Should we reassess sooner, like a PET-directed approach like they do in Hodgkin's lymphoma? We don't know the answer to that yet. We do know that PSMA-targeted therapies can still have activity, such as actinium after prior lutetium. So I don't think that just because someone's got on lutetium, that means we can't continue to target PSMA. But there are other trials going on targeting other targets with T-cell engagers, such as xaluritamig or pasritamig are currently under investigation. So I think the targeted therapies in prostate cancer are certainly... Their opportunities are growing.

Dale Shepard, MD, PhD:

If we think about other diseases within the genitourinary space, are there similar things with radionuclides that are interesting right now?

Christopher Wee, MD:

We haven't so far had any major breakthroughs that are really close to being primetime, I would say. Obviously, antibody drug conjugates are very interesting in both bladder and potentially kidney and even prostate cancer. So I think those are probably closer to the finish line potentially becoming. But I'm always open to learning about new technologies and certainly investigating and offering clinical trials for patients that were on these clinical trials. Not only could they potentially be getting a better treatment, but they have access up to... We're very closely monitoring them, and it's helping the science. So I think a lot of patients feel very good about being on these clinical trials for a lot of reasons. I would always encourage every doctor and patient to consider clinical trials if it's an appropriate option for them.

Dale Shepard, MD, PhD:

Makes sense. So clearly, you see a lot of prostate cancer, you have a lot of experience with these different modalities. I guess as a takeaway, give us a little idea about how you think through sequencing at this point. You have all these options and things we didn't really even touch upon. You briefly mentioned things like PARP inhibitors. When you see a patient, how do you think through the sequencing part?

Christopher Wee, MD:

So currently, as it stands based on approved therapies that we have, if someone were to have metastatic hormone sensitive prostate cancer, is it high volume or low volume? And we're still using CHAARTED criteria as kind of a general thought process. Is it synchronous or metachronous? In other words, did they have prior localized prostate cancer or is this de novo? Those are considerations on whether or not a patient should get androgen deprivation plus an ARPI or androgen deprivation plus an ARPI plus docetaxel chemotherapy. Obviously, the higher the volume, the fitter the patient, the more aggressive the disease biology, more likely I'm going to want to consider chemotherapy, though there are no head-to-head data comparing three versus two. In the real world, a lot of patients unfortunately are still not getting the ARPI with ADT, which is problematic because there are survival benefits across multiple controlled trials.

But assuming that everyone gets that ARPI, if someone has not previously gotten docetaxel, then in the first line castrate resistant setting, assuming they don't have a BRCA or something that could be targeted with the PARP, the question then becomes lutetium or docetaxel assuming that it's also PSMA positive. And these are where we have these considerations on how bright are the spots on PSMA PET, knowing that we don't have a strict cutoff, how healthy is the patient, the patient preferences, etc.

Whatever you get at that point, if someone gets lutetium, most often then if they have progression, they will go to docetaxel if they previously have not gotten it or cabazitaxel if they've previously gotten it. If someone got docetaxel though in the first line castrate-resistant prostate cancer, then the question is, do you give cabazitaxel or lutetium? Again, we don't have a right answer. The TheraP trial, T-H-E-R-A-P, randomized patients with prior docetaxel to lutetium or cabazitaxel, similar survival, though lutetium had a better toxicity profile. So oftentimes, I'll consider giving lutetium at that point given the safety and quality of life considerations.

So that's the general thought process I go through this. Most patients, if they are healthy enough, will see multiple therapies. So the matter is choosing what is most appropriate at this time based on the patient's disease status, their health and their preferences.

Dale Shepard, MD, PhD:

Perfect. So certainly good to see. Exciting new therapies. Looks like even more things coming up in the future. Appreciate your insights.

Christopher Wee, MD:

Thank you so much.

Dale Shepard, MD, PhD:

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