Oliver Sartor: Hi, I'm Dr. Oliver Sartor. I'm here on UroToday with Martin Schoen, who's an assistant professor at SLU and, by the way, about to be promoted. Marty has done a really interesting study on veterans, helped to lead that study. And Marty, first of all, welcome. And second of all, tell us a little bit about the study that is on veterans in prostate cancer.

Martin Schoen: Yes. Well, thank you so much for inviting me to talk about our study of the treatment of de novo hormone-sensitive prostate cancer that's metastatic at presentation. The treatments have changed over the last 10 years. And we wanted to look at how the treatments have been changing and what has actually been happening in clinical practice to show the use of novel agents like the androgen receptor pathway inhibitors as well as chemotherapy like docetaxel. And so the goal was to show how treatment has changed and also to see if that treatment was associated with changes in survival.

Oliver Sartor: Interesting. So we all know, first of all, ADTs have been around forever. And we use with the older anti-androgens things like bicalutamide, flutamide. And then we have the CHAARTED study really opening up docetaxel. And then we had a whole series of studies with ARPIs. So take us over the period of your study. When did you start? When did you stop collecting data? And let's, first of all, talk a little bit about some of the changes you've seen in this real-world experience in the VA patient.

Martin Schoen: Yes. And so we used a 10-year period of time starting in 2013. And we went to 2022. So in 2013, that was really our baseline. CHAARTED study had not come out yet. And in 2014, Dr. Sweeney had announced the results at ASCO. And we noticed an increase in the use of docetaxel in 2014. And then when the manuscript was actually published in 2015, the use of docetaxel increased.

Now, the thing is that docetaxel never really got above 18% of patients with de novo metastatic disease. And in other populations, that might have been higher. But in the VA, it really didn't become the dominant treatment. And the majority of treatment was just ADT alone until 2017.

2017 is when the LATITUDE trial and the STAMPEDE substudy was also shown that abiraterone was effective for metastatic hormone-sensitive. And then after that, the use of the ARPIs really increased. And by the end of the period in 2022, approximately 53% percent of people were getting ARPIs and another 10% to 15% were getting docetaxel. So combination therapy was used in 60% to 70% of patients.

Oliver Sartor: Well, that's not a bad number. And I would imagine-- I don't know if you did any analysis on this. Some of the people who were not receiving the intensified therapy were probably older and had substantial comorbidities. I would imagine that there might be a bias toward the younger patient getting the combination and the older patients not. Is that what you found? And if so, is there a way to quantitate that in a brief way for our listeners?

Martin Schoen: Definitely. I mean, what you said is exactly right. The median age of patients who received ADT monotherapy was 75. And that was significantly older than the median age of patients who received ARPIs, which are-- or they were-- it was 72 to 73 years. So two to three years older. And then the patients who received docetaxel, their median age was actually in the late 60s-- 67 to 68. So almost five years younger.

So as you're well aware, docetaxel is really only used in the younger, fit patients, and that a lot of the patients with severe comorbidities, who are 75 or older, were mainly treated with monotherapy. So exactly correct.

Oliver Sartor: Well, you've already made an interesting observation that the docetaxel really caps out at about 18%. But with the ARPIs, you're pushing well above 50. So, that's a really important observation right there. Now, let's talk briefly-- what did you find? What were the results in terms of overall survival? What about time to progression? Those sorts of things.

Martin Schoen: Definitely. And so we did find that combination therapy, whether with docetaxel or with an ARPI, was associated with longer survival. It was approximately five months. And the hazard ratio was about 0.8. And so, in many clinical trials, the hazard ratios have been sort of mainly in the 0.6 or 0.7. But in a real world population, it's not quite as robust.

But it's definitely a significantly improved survival in patients that receive combination therapy. And we even did other subanalyses that matched patients to try and look at what is the effect of these different covariates. And we found that overall, the combination therapy was associated, even when accounting for things like age and comorbidities, for longer survival.

Oliver Sartor: Yeah. Let's drill down a little bit more. Because that's one of the questions I was going to have is, gosh, do people getting ADT maybe a little older a little more comorbidities. And perhaps, that influence the survival even more than the therapy that was administered. So how did you address that? And tell me what you found after you did? You alluded to it top line. But I want to drill down a little more on that issue.

Martin Schoen: Yes. And so we used a multivariable model to try to adjust for unmeasured confounding. As you're exactly right, there's going to be confounding present in any observational research to-- that accounted for both the age, the comorbidities. We also included PSA because you can imagine people with higher PSAs also have higher risk of prostate cancer progression. And so in our multivariable model, we looked at those things.

And that combination therapy was still associated with longer survival. But you're completely right that there is unmeasured confounding. This is not a randomized trial. And therefore, there is likely additional things that we can't measure. I would say one thing that is important to highlight is that many of our patients did not develop castration resistance.

And so it actually highlights-- well, the thing that you just brought up, that maybe they die of another cause, they die of their comorbid illness before they develop castration resistance. It's hard for us to identify always the cause of death. But it is hard to die of prostate cancer if you don't go develop castration resistant. Normally, that is the standard pathway.

Oliver Sartor: Of course. So I know that you also looked at some kind of regression analysis. And I wonder if you could share with our listeners what you found in that kind of progression type analysis.

Martin Schoen: Definitely. And so we focused on the time to progression mainly in the two different types of combination therapy and the docetaxel group as well as the ARPI group. Because I think that is an unknown question in our literature, that we do not have any randomized trials that compare docetaxel to ARPIs. And so we wanted to look at the time to progression in both of those groups.

And we found that the time to progression with ARPIs is significantly longer than with docetaxel. And that does make some clinical sense. Docetaxel, per the CHAARTED trial, is only given for six doses. And we saw a separation of the curve and changes in progression-free survival after six months, which would mean after the docetaxel has stopped, whereas the ARPIs are given consistently or for an unlimited duration.

And that is likely what contributed to why the ARPIs were associated with a longer progression-free survival. It is important to note that regardless of which strategy, both groups had the same overall survival. And most patients who had docetaxel actually crossed over or went to the next therapy, which would be an ARPI.

Oliver Sartor: That's what I was going to ask next. And obviously, you're looking at about 50 plus percent of the patients having an ARPI from the beginning. But what about on the back end? Did you look at those sequence of therapies? And how many people stayed on ADT monotherapy then went over to an ARPI when they developed CRPC? Did you get a handle on that?

Martin Schoen: Yes. Actually, quite a few. Actually, the majority of patients who developed castration resistance then were treated with an ARPI. So of the docetaxel group, it was more than 90% of patients who had ADT alone. I believe it was in the 80% of patients ended up receiving ARPI. I mean, it is the standard of care during this period of time for castrate-resistant disease. And so it was the predominant therapy.

Oliver Sartor: Yeah. And it's nice to see. Because obviously, the ARPIs for castrate resistance came in way back in 2011, 2013 type of frame, whereas the utilization upfront for the hormone-sensitive disease is much later. But I'm pleased to hear. Really interesting results. And I'm pleased to hear that intensification is now becoming the norm rather than the exception. But I wonder, Marty, what take homes would you like to leave with our audience? What are the things you'd like to leave with our audience as we finish up on this topic?

Martin Schoen: Definitely, I think that combination therapy should be our standard. We should be asking ourselves why we are not doing combination therapy rather than why we should be doing it in these cases and that we actually even have now triple combination, adding both agents together, especially for those younger, fit patients that would be fit into the ARASENS or PEACE-1.

So I think that the days of ADT monotherapy for everybody or not-- that's not our current situation, that a majority, probably 90%, should be receiving some sort of combination. But there is always going to be certain people who may receive ADT alone. And nothing is ever 100%.

Oliver Sartor: Well, it's an interesting real world study, particularly in the veteran population where we actually don't have a lot of data. Honestly, congratulations for your helping to lead the study and leading to what I think will be an impactful publication. And then furthermore, I think really getting a handle on the intensification over time. So these are being adopted in the real world. It's nice to see. Any final thoughts, Marty, before we make a conclusion? Anything else you'd like to share with our listeners?

Martin Schoen: Yes. And it's been great to work in this area where we really can show that treatments are applying to veterans. We also have shown that these treatments work in our African-American veterans, which is not well-represented in many trials. In our data, we have 26% of patients that are of African-American descent or African descent.

And so it really is good to know that we're applying these therapies across the board and that they continue to have efficacy in all patients. And that wasn't known as well. And that I look forward to further analyses and looking into the role of triplet therapy as we continue to expand our armamentarium and add other medicines like lutetium PSMA into the up front setting, such as with PSMAddition or PSMAfore. I'm hoping that we'll continue this trend of adding therapies and improving survival.

Oliver Sartor: Great. Well, thank you. Marty Schoen from St. Louis University leading the VA study. Appreciate you going over things with our listeners this evening.