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Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm excited to have on UroToday Dr. Jack Andrews who is a urologic oncologist at the Mayo Clinic in Arizona. Jack, thanks so much for joining us on UroToday.

Jack Andrews: Hey, thanks, Zach. This is just a really fun thing to chat with you today. And I'm really happy to be here. I appreciate the invite.

Zachary Klaassen: Absolutely. Well, you have some exciting research we're going to talk about today, recently published in Clinical Cancer Research, looking at the impact of PSMA positive extracellular vesicles and its role as a biomarker in stereotactic ablative radiotherapy. I'd love for you to walk our listeners through some background and some of the key findings of your study.

Jack Andrews: Sure, I'd love to do that. So this is a paper we published recently in Clinical Cancer Research. And the STOMP trial and ORIOLE trials are two randomized controlled trials that suggested that there might be a role for metastasis directed therapy in oligometastatic prostate cancer. And that's really an interesting topic, whether or not there's a role for metastasis directed therapies.

If we think about our systemic therapies in prostate cancer as we get into the advanced disease state, it's all about androgen deprivation therapy. And there's this thought that if we can delay the initiation of androgen deprivation therapies, we can delay the initiation of castration-resistant disease.

And that's another interesting thing to think about. Men ultimately die from this man-made phenomenon called castration-resistant prostate cancer. And so we're looking for therapies that may be beneficial and delay that ultimate initiation of androgen deprivation therapy. And metastasis directed therapy is one of those options.

Now, the STOMP and ORIOLE trials looked at predominantly SBRT to bone metastases in oligometastatic prostate cancer. In about 15% to 20% of patients, you see a really durable response. Now, I don't want to say that these patients are cured. Some may be ultimately. But certainly, these patients have a durable response.

But when you put their outcomes in the mix of the whole cohort, it really dilutes out the benefit that we see in these select few. So really, the question comes, how can we select those patients that are most likely to benefit from metastasis directed therapy?

So we sought to investigate a novel liquid biomarker that we have at Mayo Clinic. It's PSMA positive extracellular vesicles or PSMA positive EVs. And we were seeking to evaluate them as a prognostic biomarker and a predictive biomarker of response to SBRT, particularly in these oligometastatic prostate cancer patients, ultimately, to help improve patient selection and find out what patients are likely to respond.

So there are two trials, the STOMP trial and the ORIOLE trial, which are randomized controlled trials. And we sought to get samples from those trials. And we were able to get plasma from the ORIOLE trial. The STOMP trial did not have plasma available.

But lucky for us, the PIs, Piet Ost at Ghent University in Belgium and Carol Mercer at the Iridium Network in Belgium had continued to enroll patients even though STOMP, the actual trial, was over on their STOMP protocol. So we were able to get plasma from about 176 patients to evaluate in our study looking at PSMA positive extracellular vesicles.

Now, what are PSMA positive extracellular vesicles? What are EVs? EVs are molecular particles that are circulating in our bloodstream that are shed by, in this case, the tumor cell. And so you think of circulating tumor cells. Well, this is a smaller component of that cancer cell floating around. And we are able to capture those cells.

And so we get the plasma. We spin it down. And we tag it with an antibody. And then we use nanoscale high-resolution flow cytometry to quantify the concentration of these extracellular vesicles. So we were able to do that. We've also shown in previous studies that we can correlate PSMA positive EV concentration with burden of disease. But now we wanted to take a step further and see is there a role for this in clinical practice? And can we find a signal that this might be both prognostic? And we were hopeful that it would be predictive. And that's what I'm going to show you here shortly.

So we pulled both cohorts between the ORIOLE trial and the STOMP-like trial protocol patients. And when we used a cut point for low and high values, we found that the PSMA EVs with low values had a significantly improved biochemical progression-free survival, as well as a significantly improved radiographic progression-free survival. So we're seeing here differences in their probability of survival just stratified by their PSMA EV status.

Now, we looked at a lot of variables, and PSMA EVs were by far the most powerful prognosticator of outcomes. But then when we added PSA into the mix, we really had striking results here. So we did all four permutations of high and low PSMA EVs and high and low PSA levels. And if you look in both the biochemical progression-free survival and the radiographic progression-free survival, if you had a low PSA value and a low PSMA EV value, you had significantly improved survival in both biochemical progression and radiographic progression.

But if you have high PSA and low EV or low PSA and high EV, it didn't matter, your outcomes were pretty dismal. And so really, we're able to select here about 20% of these patients that are highly likely to respond. And so really, not only is PSMA EV a prognostic biomarker, we think that PSA plus PSMA EVs is really an even more powerful prognostic biomarker.

And then we wanted to look at, is it a predictive biomarker? And so you kind of have to look at predictive biomarkers a little bit different than prognostic biomarker. Predictive biomarkers are specifically looking at is the biomarker predicting a better response to a specific treatment. Whereas prognosis and prognostic biomarkers are really just looking at the overall outcomes of patients. And so you need an observation cohort to truly assess if a biomarker is predictive.

So in the ORIOLE trial, we had access to both observation samples and treatment samples. And so we looked at patients who had PSMA EV low values and were treated with SBRT and were watched with observation. And we see a significant divergence in this table here on the left for biochemical progression-free survival. And then when we look at PSMA EV high or the high levels of PSMA positive EVs, we no longer see that divergence. And this is really the first signal that this is a predictive biomarker.

And so some of the take home message is that I would say here is, this is really the first data that demonstrates that there's a role for extracellular vesicles as a liquid biomarker in prostate cancer. We've shown here that PSMA EVs are a prognostic biomarker in oligometastatic prostate cancer. And that PSMA EVs plus PSA is probably an even more powerful prognostic biomarker.

We've shown that PSMA positive EVs are predictive biomarkers. It needs validation. We need a lot more patients. But there is a strong signal here that PSMA positive EVs are a predictive biomarker of response to SBRT metastasis directed therapy in oligometastatic prostate cancer. And there's a lot more fun stuff that will come from this. And I'm excited to dive into some of that.

Zachary Klaassen: Jack, great presentation. Beautiful work. Really, I mean, you basically have hit the prognostic and the predictive biomarker status for both of these. So when we look at this from a clinical perspective at a high level, what does it mean for a patient discussion if we have PSMA positive EVs as both a prognostic and predictive biomarker tool?

Jack Andrews: Well, I think it's important on multiple levels. So the hope is that one day this will be in clinic. But before we get something like this to clinic, well, we have to have the clinical trials that definitively show that metastasis directed therapy benefits patients.

And that's really a struggle right now. That's a controversy that some people don't believe in metastasis directed therapy at all. And I think one of the major limitations here is that we're enrolling all comers. And if we use a biomarker to stratify patients and get the right patients on the right trial, not only are we helping patients, but we're also going to have a trial that's going to read out more positive because we're treating the patients who we actually want to treat with that.

Additionally, when you look at this biomarker, we're trying to identify the patients who are likely to benefit from metastasis directed therapy. So certainly, it could be a tool to help those patients. But additionally, it helps the patients who have a poor PSMA EV level, who have a poor prognostic or predictive range—because you don't need to mess around with something that's not likely to benefit them. You can escalate or intensify their therapy likely with systemic therapy and really stop or forgo that pit stop in metastasis directed therapy.

And I think that's really where it'll be helpful to say yeah, you know what, metastasis directed therapy does help patients but it helps the right patient. And we need to make sure that we're treating the right patients. And the patients who aren't likely to benefit, it can go to a more intensified systemic therapy plan.

Zachary Klaassen: Yeah, great answer. I think that's awesome. When we look at—and you kind of alluded to it on your last slide, there's a lot of exciting things to come. What other disease spaces are you looking in? What other validation studies are you guys planning for PSMA positive EVs?

Jack Andrews: So we have a trial. So a lot of this work is done with one of my PhD collaborators, Fabrice Lucien, at Mayo Clinic in Rochester. And then one of my medical oncology colleagues, Dr. Jacob Orme has a trial now at Mayo Clinic in Rochester where we're validating these results.

So basically, similar patients that are oligometastatic prostate cancer patients identified on PSMA PET. And this is something that it's important because ORIOLE trial was with bone scan. The STOMP trial had a lot of choline. We want to look at the imaging that we're actually using now.

But oligometastatic patients staged with PSMA PET and then are stratified to get SBRT alone if they have PSMA EV low levels or if they have PSMA EV high levels to be stratified to SBRT plus intensified systemic therapy. So I think that's our first step into how do we validate these results and see what happens when we look at larger cohorts.

In terms of other things, particularly with EVs, EVs are really interesting because you can detect them at lower disease volumes. So that's a real struggle for circulating tumor cells, is you struggle to detect them when you have microscopic metastatic disease or in the localized disease setting. But EVs, we can capture them across the entire spectrum of disease. And we've correlated localized disease, oligometastatic disease, and widespread disease based on their concentration of PSMA EVs.

What I'm particularly interested in is not just the concentration of the PSMA positive EVs, but the expression of PSMA on those EVs. And so we have studies where we're looking at quantifying that degree of expression on patients who are receiving PSMA theranostics and using that as a liquid biopsy for dosimetry doses delivered to the tumor.

And then lastly, as we're getting further into the proteomic and genomic stratification of patients will be the next layer of peeling back the onion of extracellular vesicles and that's the molecular cargo that they carry. So we can capture these EVs. We can identify that they are coming from these cells. Then we can see what's inside.

And we're not there yet. We know how to capture them. We know how to get what's in those cells or in those vesicles. But we don't know what to do with the data yet. And that's where I think things will open up for us as we learn more and more about the disease and these molecular and proteomic markers that we'll be able to explore further with extracellular vesicles.

Zachary Klaassen: That's awesome. I mean, congratulations on this great work. Taking a great idea, already informing clinical trial design is just awesome. So congratulations on that. Anything we didn't touch on you want to hit on? Any last minute comments for our listeners?

Jack Andrews: No, I think the last thing I would say is I think biomarkers are going to have a huge role over the next 5 to 10 years. And we need to not only seek to utilize them, but get patients on trial and design our trials based on biomarker stratification. And then lastly, metastasis directed therapy does benefit some patients. We've just got to find the right ones. And I think we just need to continue to push to find those right patients.

Zachary Klaassen: Yeah, great summary statements. Jack, congratulations again. Always great chatting with you. Thanks for joining us on UroToday.

Jack Andrews: Thanks, Zach. Pleasure to be here.