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Neeraj Agarwal: Welcome to UroToday. My name is Doctor Neeraj Agarwal, Professor of Medicine and Director of the Genitourinary Oncology Program at the Huntsman Cancer Institute at the University of Utah. Today, we have Dr. Pedro Barata, who is a medical oncologist and a Miggo Family Chair in cancer research and an Associate Professor of Medicine in the Division of Hematology/Oncology at Case Western Reserve University Hospital in Cleveland. We'll be talking to Dr. Barata about the findings he presented at the ASCO GU 2025 Symposium on the under-utilization of testing in patients with metastatic castration-resistant prostate cancer. Pedro, welcome.

Pedro Barata: I appreciate it, Neeraj. Thanks for the kind introduction and the chance for us to highlight this work. So Neeraj, again, this is work that we just presented at ASCO GU 2025. And you’re really well aware of the importance of homologous recombination repair gene defects in men with metastatic prostate cancer. You’ve done fantastic work on it.

And as you know, we are expecting to see those alterations in a quarter of patients with advanced prostate cancer, somewhere around 25%, 30%. So it’s really important to test those patients for HRR. But we also know that the testing has been historically suboptimal over and over again.

But as we understand, with the good pressure that we got from novel therapeutics developed as biomarker-based approaches, it’s interesting to see that year after year, things can change. So with that in mind, we wanted to get a contemporary cohort, a picture of really what the reality is now. And so for that, we went after the recent data based on the Adelphi real-world prostate cancer program, which basically, as you know, gets data from chart review—retrospective data collection from physicians who treat and manage patients with prostate cancer.

So we looked at that data from November 2022 to summer of 2023, so roughly a nine-month period. And as you probably know, but just a reminder, we included patients managed by physicians that treat four or more patients with prostate cancer, either urologists or medical oncologists, during that time frame. And then we get the information from clinical data, genomic data on those patients, and we get it together.

So in this particular study, we got a little bit shy from 450 patients treated or managed by 70 physicians—more med oncs than urologists—diagnosed and managed with mCRPC. So the first figure, you’ll see here that, not entirely surprisingly—perhaps slightly better—but you can see that almost half the patients did not get HRR testing, 47% of them, compared to about 53% who got it tested.

And then when you look specifically at BRCA1/2 versus non-BRCA testing, you can see, among tested patients, most of the time they’re getting BRCA testing. We can debate or discuss why that is. I think we have some explanations that might be plausible to explain that.

We also wanted to understand exactly the time points where these tests are being done. When are providers actually ordering those tests? And as you can see here, on figure 2 in the middle, that bar there with the breakdown, you see the 45% of people not getting tested. And then the other 53%, you can see that 23% get tested at time of metastatic disease, whereas you find 13% at time of CRPC, and then another 16% and 4% subsequent lines. So what you can conclude from here is providers are offering and ordering HRR testing more commonly upon mCRPC, whether it’s first line or upon progression.

And finally, we also were interested to understand exactly what are the factors associated with testing or lack of testing. And that’s why we put together—on the very right side of this slide for us, to simplify the reading, you can see that patients with known family history of cancer are more likely to get tested. You can also see that patients with lower Gleason scores and localized disease—meaning metachronous metastatic disease—are also more likely to get tested compared to the others. You can see probably signals from other factors, like location of metastatic disease, but that was, at least in this analysis, not statistically significant.

So in summary, we continue to see suboptimal testing rates in the US with a large cohort of patients—a contemporaneous cohort, I should say. We do identify disparities, meaning factors that seem to be associated with testing or lack of testing in this context. And the time points of testing continue to be upon mCRPC or later on, versus getting it upfront when we get to know them—when they are diagnosed with metastatic disease.

So that’s really the highlight of the data we just put together. And I’m happy to comment a little bit further on these data, and again, the opportunity to present it. Thank you, Neeraj.

Neeraj Agarwal: So Pedro, this is a very nice presentation and the data you just talked about and presented at the ASCO GU. So half of these patients—half of our patients, these are our patients across the US, who are mostly seen by medical oncologists—are not getting comprehensive genomic profiling or tumor NGS testing. And this is just last year. This is very recent data. We’re not talking about 10 years ago.

And if I want to put things in perspective for our viewers today, olaparib and rucaparib were approved in 2019 in the US for mCRPC. Before that, pembrolizumab was approved for TMB-high, MSI-high prostate cancer in 2017 and 2018, respectively.

And these data you just obtained are from 2023. And it has been more than five years since targeted therapies are approved. But we are not seeing half of our patients getting tested by NGS testing.

And the story doesn’t stop here. I mean, our colleague, Dr. Swami, presented the data that, to make it worse, actually, patients who had BRCA1 and BRCA2 mutations, almost half of them did not get PARP inhibitor treatments, despite the fact that, especially in these patients, PARP inhibitors are associated with months to years of benefit. So not only are we seeing low rates of testing, but also lower utilization of these evidence-based therapies. And you have published so much in this field on a separate note. So let’s start with the first thing. What is the reason for patients not getting tested?

Pedro Barata: Yeah, Neeraj, fantastic summary of the context where we are right now. And I would argue the numbers are actually even worse than the ones we’re seeing or presenting. I’ll tell you why—because I think one thing is looking at it objectively, rates of testing, and the other thing is actually the timing when you do the testing and can you do something about it.

So in my pragmatic approach to things, I call it—we have a percentage of patients getting tested as like a desperation move. In other words, they get access to different therapies in clinical practice. And then when the physician thinks there’s nothing else available, they get a genetic test order. Sometimes, it takes weeks, as we know, to get that—whether it’s a liquid biopsy or going after archival tissue. And in a lot of those cases, we know that the results won’t be back in time to actually do something about it.

So the ability to act on those results, it’s significantly diminished if we are ordering it too late. And to me, too late, when you look at real-world data—when about 50% of people get second-line treatment, and about a quarter or less get a third-line treatment—that means you lose patients as you go from one line to the next line for metastatic prostate cancer. So if you add all that, I actually think the result is exactly what you just said: the very minimal number of patients who end up getting biomarker-based therapies-- because even those, that includes those patients who never got tested.

If you don't look for it, you don't find it. And number two, even if you get tested, but you get tested too late, you won't be able to act on it. And I think those components would help explain the very low utilization of biomarker-directed therapies, of which PARP inhibitors are probably the best example we have in metastatic prostate cancer.

Neeraj Agarwal: There are other biomarker-based therapies, like pembrolizumab. It works beautifully in patients with MSI-high prostate cancer. There could be 3% if you add another 2% or 3% with TMB-high prostate cancer patients. We are talking about 5% to 6% of these patients. You add PARP inhibitors, we are talking about 30% of these patients. You add PTEN-deficient tumors—of course, that is [INAUDIBLE]. And hopefully, more tumor-targeted therapies get approved next year. We are going to be seeing almost half of these patients being eligible for some kind of targeted therapies.

I’d like to step back a little before we conclude this session. Until now, or until very recently, we got confusing messages from different guidelines, like who should be tested, who should not be tested. And there used to be long lists of who should be tested—family history and this kind of disease or first-degree relative.

And based on my own discussion with my colleagues out there in the real world, in the community, the one reason I think testing was not incorporated universally was because of the conflicting—if not conflicting, at least not so straightforward—guidelines regarding who should be tested. And in this context, I think the ASCO guidelines—they just got published on January 9—are very clear. It says anyone with metastatic prostate cancer should be tested for both somatic and germline testing. And if patients do not have tissue available, they should have ctDNA testing. And there are even statements on repeat testing after disease progression. What is your practice?

Pedro Barata: Great question, Neeraj. You touched on very important points. I summarized them quickly in my mind as you were talking. A few things.

So one is germline and the other one is somatic testing. The guidelines for germline now are clear about patients who have very high-risk disease, recurrent or metastatic prostate cancer should be offered germline testing. That doesn’t change; you have the genes you’re born with from your mommy and daddy, and you get it done once.

In fact, initially when we were going after the criteria that you mentioned for germline testing, including family history, you know you can miss almost 40% of the cases if you use that as a trigger to get germline testing. Actually, these data show that. You can see that patients—like we just presented—patients who have family history are more likely to get tested. We should actually go away from that and test everyone with high-risk, very high-risk, recurrent or metastatic disease, because you don’t want to miss the cases that are not linked to a family history and still have a germline alteration of interest. So that’s one part.

The second is the somatic testing. The argument that I hear a lot has to do with, well, I’m going to do it at time of CRPC because that’s when I have biomarker-based therapies. That’s not wrong. But the news is that’s actually going to change.

I agree with your summary about what we can do about it. I actually would add the chemotherapy that you can do. So, in addition to MSI and MMR and TMB in tumor tissue, and HRR for PARP inhibitors, you also have aggressive-variant disease where you actually have data that intensification of chemotherapy is more beneficial than monotherapy taxane. And that’s based on alterations in the tumor suppressor genes TP53, PTEN, RB1. So I actually use that in addition to the other examples you gave. Even for chemotherapy, it helps me.

But in the future, we’re going to have good news, including PTEN alterations, as you mentioned, in the metastatic hormone-sensitive space, as we will see the first—for PTEN-altered or deficient, if you will—tumors in the hormone-sensitive setting. We know the CAPItello-291 trial is positive. So I think it’s going to create a lot of buzz and probably be an additional good pressure to get patients tested early on.

And then of course, we have to talk about, are we going to do NGS for everyone, or are we going to start thinking about immunohistochemistry in addition to NGS, or are the panels going to be able to do both, because the PTEN deficiency, as you know, on that particular study for that biomarker, has been done based on IHC?

So I really think, to be fair, we have been seeing this story go like this: We have a treatment that has been shown to make people live longer and preserve quality of life for a longer period of time. You presented that data and others, and that pressure has led clinical practitioners to start incorporating testing more. And I think we’ll continue to do that, and we’re going to continue to see a shift—slow, but hopefully steady—towards getting tested sooner.

So to answer your question finally, as soon as I see a patient with metastatic disease, I actually get both germline testing and somatic testing. And the reason why I get somatic testing is because I don’t want to wait for those results. I get tissue available, I’ll do it. If I don’t have tissue available, the patient has started on systemic therapy, then I wait until they develop CRPC, because the chances of finding circulating tumor DNA when patients have started on ADT or ARPI—one month later, as you know—that’s when we get the right results. So in that, now, we—

Neeraj Agarwal: And also, tissue loses its quantity and quality with time. So if you wait for CRPC to start—in the PROfound trial, for example, about 30% of these patients did not have a sufficient quantity or quality of tissue to allow testing. So I agree with you. Let’s test them early on whenever you see them.

So I’d like to conclude. First of all, thank you, Dr. Barata, for spending time with us and sharing these wonderful insights. Patients with metastatic prostate cancer should be tested with germline and somatic tumor tissue testing as soon as we see them. Let’s not wait for onset of CRPC because it may be too late for the patients, and tissue may lose quantity or quality. And there should not be any ambiguity that patients with metastatic disease—all guidelines support both germline and somatic testing. With that, I’d like to conclude and want to congratulate Dr. Barata for all this research.

Pedro Barata: Great. Thanks for having me, and always a pleasure sharing with you. Thank you.