Zachary Klaassen: Hello. My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. Delighted to be joined back on UroToday with Dr. Ben Maughan, who is a medical oncologist at the Huntsman Cancer Center in Salt Lake City, Utah. Ben, thanks so much for joining us.

Benjamin Maughan: Zach, it's such a pleasure to be here. Always love visiting with you. You're so amazing. You dress better than anybody I know. And UroToday is such a fabulous organization. Grateful to be here.

Zachary Klaassen: We're going to talk about your recent publication in PCAN, discussing the OASIS project, really looking at first-line apalutamide treatment in metastatic hormone-sensitive prostate cancer. So maybe just by way of background to get our listeners up to speed, just talk briefly about the doublet landscape for metastatic hormone-sensitive prostate cancer.

Benjamin Maughan: Yeah, this has been-- thanks for the question. This has been an evolving paradigm ever since I very first started as an oncologist in training. That's been the CHAARTED study read out by Sweeney and his group of international collaborators showing that intensified therapy improves outcomes for patients with metastatic hormone-sensitive prostate cancer. And the fascinating thing to me is that all of these-- and then there's been a series of other doublets that have shown similar improvements over ADT monotherapy.

And the fascinating thing to me is that none of these trials are new drugs. All of these things, for the most part, are FDA-approved in the castration-resistant setting. And so just by doing a combination instead of sequential single agent therapy, we're seeing these dramatic improvements in overall survival and the order of absolute improvement in overall survival of 13 months, et cetera, in these phase three trials.

Now we have a number of combination therapies that have read out in phase three trials showing improvement of various ARPI or synthesis inhibitors with abiraterone, et cetera. Now the newest generation trials are looking at triplets versus doublets. So this is a very exciting era to be in, where we're seeing these massive gains in patient outcomes with, I will say, little consequence in terms of toxicity.

If you-- with that comment, you do have to exclude the docetaxel. It does come with obviously significant toxicity. But all of these trials have done pretty extensive patient-reported outcome work that does not show much difference in toxicity. On average, individual patients may vary, right. But on average, there's not really much additional toxicity risk with the combinations.

Zachary Klaassen: Yeah. Great summary. So let's lead into the OASIS project. What was the genesis or background to launch this project?

Benjamin Maughan: Yeah. So what got me thinking about this and interested in it is that, obviously, what we see in the clinical trial patients is fantastic. And that's wonderful. But oftentimes, what we see when we look at real world data is that you can still measure those same benefits. But the magnitude of the benefit is typically muted or less robust.

And so I was curious to know if the magnitude of benefit we were seeing in these prospective trials, which was quite consistent. Every one of these prospective trials was very consistent in terms of the magnitude of benefit we're seeing. So would that perhaps translate to a real world disease population, where you're dealing with just a lot more complexity in terms of-- some of the patients certainly fit the eligibility criteria, but a lot of patients don't.

Zachary Klaassen: Yeah.

Benjamin Maughan: Maybe age or they're highly symptomatic, so they wouldn't be eligible for a trial. I don't know. A lot of various factors, comorbidities. Maybe the population location. So maybe you're practicing in a location where you don't have access to clinical trials, very rural setting. And so it's just a lot more difficult. So I wanted to-- I was really curious to see how the quality of the data stacked up in a real world disease population.

Zachary Klaassen: Awesome. And so maybe just a little bit of methodology. What database did you guys use? How did you set it up? Maybe how many patients you included in the study?

Benjamin Maughan: Yeah, great question. So there's a number of ways that you can do real world data sets. But if you're trying to capture a large population, some of the most effective ways, at least in my opinion, are to-- there are a number of companies that collect clinical data from urologist's office, medical oncologist office, et cetera. So we tapped into this concert AI data set, which collects data across a number of predominantly medical oncology clinics across the country.

Capturing not just ICD-9 codes and stuff, but it collects it in a much more robust, vigorous way in terms of actual PSA data values, et cetera. It doesn't collect everything, but it collects a much more robust data set than you could get if you were just doing like, I don't know, Medicare claims data or something like that.

Zachary Klaassen: Yeah, absolutely. I know you've put together a few slides for key results. You want to share those with us and walk through those?

Benjamin Maughan: Oh, yeah. Sure. So to answer the rest of your question here, in terms of the number of patients, I figured this would be an easy way to show it. As you can see, I am particularly interested in the apalutamide ADT combination and how that compares to the TITAN trial, which is the corollary phase, prospective phase three trial.

But at the same time, there's this clinical question of like, OK, now we have a lot of doublets approved. How do they compare to each other? So we collected data on the others. As you can see, we didn't collect any data on the triplet therapy with ADT, docetaxel, and darolutamide. I mean, we did but we didn't include it. We didn't analyze it because there were such limited numbers of patients.

But as you can see, there's quite a few patients overall. There's something like 4,000 patients that we included. The largest group was abiraterone plus ADT. I suspect in part because it's been around the longest. It received the first FDA approval of the ARPIs of the hormone therapies.

Zachary Klaassen: Yeah.

Benjamin Maughan: The reason I wanted to point this out is-- and this isn't like a complete list from the manuscript of the baseline characteristics. But as you can see, a number of these baseline characteristics seem pretty similar across the different treatment combinations. For instance, if you look at age as broken down by age decile, they seem relatively similar.

But there are some notable differences. Like for instance, if you look at the docetaxel, DTX, plus ADT column, the proportion of patients with visceral metastatic disease is notably quite higher than the other groups. Again, this is a retrospective analysis. There was no randomization, et cetera, in this. There were also some very critical prognostic indicators we were not able to collect, like Gleason score, et cetera. So we weren't able to account for that.

Certainly there's a very robust body of data now looking at genomics or other molecular features that do demonstrate significant prognostic capacity. We didn't collect any of that. So we identified these patients to help identify who is eligible for the study. Patients had to be on ADT therapy demonstrated through like a medical claims.

Be there like an orchiectomy or a Lupron order, et cetera. And they had to have a minimum of a couple of PSA tests afterwards so that we could evaluate their outcomes. And so the time points that we collected this from spanned around 2018 so that we had time since the approval of these drugs through 2023.

Zachary Klaassen: The one thing I note there, Ben, just before we jump to the next slide, you mentioned these are patients that may not be eligible for clinical trials. And certainly, you see about 20% of patients, ECOG two to three. These patients would have probably not been in a clinical trial. Correct?

Benjamin Maughan: Yeah, that's correct. Occasionally, some of our trials allow for an ECOG of two. But there are no trials that allow for an ECOG of three or four. And to put that in perspective, in ECOG of two, even though it sounds like a low number, means the patient's like bed bound or chair bound for more than 50% of the day. An ECOG of two is a pretty significantly impacted patient. So to the point we've discussed before, thanks for pointing that out, Zach. Yeah, this does include a lot of patients that just are not eligible for clinical trials.

Zachary Klaassen: Absolutely.

Benjamin Maughan: So I think the best way to understand the comparison of the data from OASIS to the real world-- from the real world OASIS data set to the prospective clinical trial data set is through an undetectable PSA. So I'm sure that you've talked with other people on this channel before about their work on PSA metrics and the strong prognostic implication that has. So for our short discussion today, suffice it to say that achieving an undetectable PSA at some time point, relatively quickly at three months or six months, is strongly prognostic for good overall survival outcomes.

So what we saw in the TITAN trial, for instance, is that about 61% of patients in the combination ADT plus apalutamide treatment achieved an undetectable PSA by six months. And if you look at the OASIS data, for the ADT apalutamide therapy, a very similar percentage of patients are achieving an undetectable PSA. And I also included the ADT only group here just to highlight, again, the substantial improvement in outcomes by doing intensified therapy.

So it was very encouraging to me to see that in a real world data population, we're seeing strikingly similar outcomes in terms of PSA metrics at least between the OASIS data set and the TITAN data set. So that's very encouraging to me. And here you can see it graphically. Here we evaluated each of these doublets and the apalutamide and ADT group in the purple line. And notably the ADT alone is the yellow. So at three months, it was 44% for purple and 32% for yellow.

So there's a significant improvement in outcomes with the intensified therapy even in a real world population. And you can see that the PSA metrics in terms of achieving an undetectable PSA happen fairly early. I find that this is super helpful in visiting with patients. I usually don't tell patients they don't achieve this metric. Like, oh, terrible for you. But for those patients that do achieve it, it really helps me frame my expectations and the expectations for the patients.

So like when I see them in clinic, I'm making sure that we're-- have them plugged in with cardiology or their primary care if they're actively managing their cardiac status. Because I expect these patients to be living for eight years or something. And so their other comorbidities are super important. Plus it's always nice to share good news with patients.

Zachary Klaassen: They see the PSA in the chart, right? I mean, that's the easiest thing to talk to them about.

Benjamin Maughan: Yeah. Yeah. It really is. And now we know that it's not just something to collect, but it's super important for framing those conversations.

Zachary Klaassen: Yeah.

Benjamin Maughan: And here to that point, you can see that played out in terms of overall survival. Each of these combinations is referenced against yellow, which is ADT alone. So ADT is the reference one. You can see the important thing here is that every intensified therapy-- as we see from the prospective clinical trials, every intensified therapy is better than ADT alone.

I should make a mention. The one doublet that we didn't include here was the docetaxel group. Simply because it was so divergent. I didn't highlight it. But if you pay attention or remember from the last slide, that was actually the one curve that was worse than ADT monotherapy. But that's likely due to an imbalance of prognostic factors. The proportion of visceral disease was much higher et cetera.

My takeaway from this in terms of comparing these doublets is that each of them is better than ADT monotherapy. Now certainly, a lot of people are wondering, which doublet should I pick? And so because we knew that was going to be a question, we did do some comparison analysis. But here what you're seeing is each of these referenced against ADT alone, not against each other.

In terms of overall survival, the same thing. But you can see it graphically here in terms of the Kaplan-Meier curve. Each of them is better than ADT alone, except for the gray bar. Again, that's docetaxel. But that's likely not because docetaxel kills more people than ADT monotherapy. It's just those patients are being selected for docetaxel because they had such bad disease. So it's their very poor prognostic factors that were driving the outcome.

So numerically, what we found is that of all the doublets, apalutamide had superior outcomes in terms of overall survival and PSA metrics. But this analysis for me is more important in terms of how does apalutamide play out in the real world population compared to the other doublets. Because there's a lot of important-- this wasn't randomized, or propensity matched, or anything based on a lot of key prognostic features.

So at the end of the day, it's a very helpful doublet that we're showing excellent performance characteristics with even in this more heterogeneous disease population. But to that point, if you look at the purple line versus the yellow line, we're seeing a substantial difference in overall survival even over a relatively short period of time of 12 and 24 months between doublet versus ADT monotherapy.

And for reference, this is the figure that I pulled from the TITAN prospective trial in-- I believe it's the Journal of Clinical Oncology. So again, you can see that if you eyeball the 12 and 24 months, it was slightly better in terms of overall survival compared to what we saw in OASIS. But it was still in the same ballpark. Here you're seeing somewhere about an 82% two-year survival in our OASIS data set, which included some patients that had worse underlying disease. In ECOG two or three, we saw a roughly similar rate of almost 70%. So these therapies are very effective for these patients.

I guess the last takeaway that I got from this analysis was just the whole story of ADT monotherapy. So Umang Swami, a wonderful colleague of mine, has been interested in this for a while and has been publishing from various data sets on what the use of ADT monotherapy has been. And I think he-- this is from his recent publication at ESMO last year.

He really is demonstrating that over the years, if you look at the very top row, ADT monotherapy, that rate is decreasing with time. And in 2023, from the Flatiron data set where this comes from, it was about 20% of medical oncology clinics. In the OASIS data set, it was about 25%. So we didn't break it down by year. But we're seeing a pretty similar reduction compared to some of the early data, suggesting it was about 50%, 40% of patients getting intensified therapy. So as a field, we're moving in the right direction, which is very encouraging to me.

Zachary Klaassen: Yeah, absolutely. And great data, and thank you for walking our listeners through those figures. I think when we look at-- and you mentioned a little bit about how you discuss PSA metrics with patients. How do we translate this data that you guys have looked at into the clinical practice? Whether it be our discussions, whether it be how we select therapies, what are your thoughts?

Benjamin Maughan: Yeah, there's a lot to unpack there. As a field, we're still trying to figure out how to totally optimize this. Can we use PSA metrics to de-intensify therapy? Start with the doublet and then de-intensify later. There's some ongoing clinical trials in that regard, like LIBERTAS, et cetera.

Now that we have doublets and we have triplets, there's some question about can you use that to intensify therapy? Start with the doublet. For people that don't achieve an optimal PSA outcome, then do delayed intent further, intensify the triplet therapy? There's some interesting studies in the cooperative groups that just recently started to add to this additional body of knowledge. But how do I use it today?

I really look at undetectable PSA. It can be really confusing and perhaps sometimes overwhelming because there's lots of different cut points and time points that have been studied and analyzed. PSA less than four, PSA less than 0.2, a PSA three months. What about six months? What about 12 months? But pretty consistently, an undetectable PSA, meaning 0.2 or less, seems to be a very important benchmark.

And as with many things in medicine, this is a continuum. It's really like a continuous number, not like a dichotomy that we like to simplify it into. So it doesn't mean that your patient that achieves a PSA of one is going to do terrible. But if they get up to, or close to, or better than an undetectable PSA of 0.2, I really do use that to guide therapy a lot in terms of how I discuss with patients how they're doing and how I think about their disease.

For instance, if they don't, then I'm really starting to think chemotherapy or now Pluvicto may be a second-line therapy. In our institution, sometimes it can take a while to get Pluvicto set up because there's multiple steps. You've got to get the PSMA scan et cetera. So I might be ordering that PSMA scan sooner before I've clearly documented they have disease progression. So that step is at least done.

Or maybe I'm getting their genomic testing done right away so that I can look at, well, are they eligible for a PARP inhibitor? So I use that PSA to guide how I think about their next step, how quickly do I need to worry about that. Whereas if someone gets an undetectable PSA, the probability is they're going to be on their intensified therapy for three, four, sometimes five years. So I may not jump to that right away.

Zachary Klaassen: Yeah, great breakdown. Always good chatting with you. Congratulations on a very nice paper. Any last minute thoughts that we haven't touched on or take home messages for our listeners?

Benjamin Maughan: I just-- it's always wonderful to be here. I love visiting with you, Zach. You have such great insights and thoughts about everything prostate cancer. It's wonderful. Thanks for inviting me.

Zachary Klaassen: Absolutely, Ben. Thanks as always for your time. And again, congratulations on a great paper. And we'll look forward to having you back on soon.

Benjamin Maughan: Thank you. Bye.