Neeraj Agarwal: It's such a pleasure to have Dr. Pedro Barata with us today on this UroToday video. Dr. Barata is an Associate Professor of Medicine and Oncology and an Endowed Chair of Clinical Research at such a young age at Case Western Reserve University/University Hospitals in Cleveland. Welcome, Pedro.

Pedro Barata: Thank you, Neeraj, for calling me young. I love to be young. I appreciate the time to sit down and talk about prostate cancer.

Neeraj Agarwal: So let's talk about the recent trials in metastatic hormone-sensitive prostate cancer, starting with the positive AMPLITUDE trial, and then we can talk about the CAPItello trial. But more importantly, Pedro, I really like to have your insights on not only the results of the trial, but the testing. The testing rates are so low in the real world. These patients are not getting NGS testing, and then the CAPItello trial has brought up another testing platform, which is IHC testing.

So all the challenges you have published on the low utilization of NGS testing, and what should we do? So let's start with the results of the AMPLITUDE trial first.

Pedro Barata: Sure. So just a line or two on the context, right? We're talking about patients who show up in clinic, either the first time they were diagnosed or after an attempt to be cured—unfortunately they weren't—with recurrent metastatic disease. So you have that group of patients with metastatic hormone-sensitive disease. That means for them, the backbone of treatment will be lowering testosterone, if you will. They may not have been exposed to prior ADT in the past for a limited amount of time, if you will.

So the other line I would make is patients get there in different ways and their tumors will behave differently. We know this, right? So not only from clinical characteristics or baseline characteristics, some will have visceral disease, some will have multiple bone metastases, some will just present in the nodes. And we actually know the volume of the disease and the location of the metastases are prognostic factors. In other words, patients don't all do the same.

So with that understanding, we take one step further and we go after, what about the molecular characterization of those tumors? Are those tumors all the same? And the answer is no. It's different when we have a tumor in the context of a BRCA mutation, or ATM mutation, or a PTEN loss, or a tumor that doesn't have any of that and happens to have SPOP mutations that you have published on.

And it's different because from one perspective it speaks to the prognostic value of those alterations. From another perspective, in some cases there's a predictive value. There is therapeutic implication of the genetic information or the molecular features of those tumors. So we're getting smarter, and I'm not even getting to the gene expression signature, RNA-seq data that's coming up as well to look at who's benefiting from what—chemo, ARPIs, combinations, et cetera.

So with that in mind, one other point I'll make is, yes, PARP inhibitors are perhaps the best example that we have in our precision oncology era in prostate cancer—the first biomarker-directed therapy approved with survival gains for men with prostate cancer, a little bit later for patients who have progressed despite low levels of testosterone in the mCRPC setting.

We had olaparib, we had rucaparib available by itself, and then we got three combinations with niraparib and abiraterone, enzalutamide-talazoparib, and abiraterone again with olaparib.

Neeraj Agarwal: And we just saw in metastatic hormone-sensitive prostate cancer just a few months ago, the AMPLITUDE trial, which included patients with mHSPC plus HRR alterations, and it showed positive results. What do you think about those results?

Pedro Barata: Absolutely. So after we established that indeed combining an ARPI, an androgen receptor pathway inhibitor, with a PARP inhibitor improves outcomes—in the case of abiraterone and niraparib, we saw that remarkably well in the BRCA population, right?

The next step was, "Okay, but what about the patients who present with metastatic disease and they are sensitive to ARPI?" So you're really talking about a triplet therapy strategy there compared to the standard of care. So in that trial, patients were selected by HRR-positive status. You're really focusing on BRCA, really. You look at the numbers, more than half of the patients have BRCA1/2, and you're really offering them one of the two arms: abiraterone with ADT—that's a standard of care, doublet treatment intensification—or abiraterone-niraparib with ADT.

And really, the combination is the same that we got in the CRPC setting. The dose of niraparib is 200 mg with abiraterone at the standard dose. And really, the idea is to see, are we able to control the disease in a meaningful way, and are those patients going to live longer?

Neeraj Agarwal: And there was a 50% reduction in risk of progression or death—

Pedro Barata: Right. So when you look at—

Neeraj Agarwal: —by adding niraparib, right?

Pedro Barata: Right. So it's a really remarkable result, particularly for patients with BRCA, which I believe is what you're referring to. So the hazard ratio's in the 0.5 range, if you will. It'll be higher for the intention-to-treat population, which in other words is not really surprising, but I think that's an important lesson. PARP inhibitors in combination with ARPI also work in the hormone-sensitive space, in this case, niraparib and abiraterone.

The other lesson to me that's truly relevant is to look at the control arm and see how it underperforms. So you're going after, particularly BRCA. You can see their time to CRPC is measured at about two years or less than that, which is again what we saw in the CRPC setting in the MAGNITUDE trial where patients progressed within a year or so—particularly when you look at BRCA, it was around that.

And so it does speak to the poor prognostic factor. There's a lot of real-world data basically showing the same thing. So the question is, where do we go from here? I would argue for AMPLITUDE it will be important to understand the overall survival gains. So the overall survival data are immature.

I don't think we saw different safety signals. In other words, as we use more and more combinations with PARPs, we are getting better at handling things like anemia, for example, or just cytopenias in general, the fatigue, some GI alterations. And then of course, paying attention to what about thromboembolic events? What about second malignancies? This is something that requires longer follow-up for us to truly appreciate as we're moving these agents earlier on.

So I actually think it will be a conversation in the next year. It won't be just niraparib; it'll be a conversation around PARP inhibitors in general. I do anticipate data from TALAPRO-3 to read out, which is testing another combination, enzalutamide with talazoparib in the same setting, also looking at patients with HRR alterations. So again, a biomarker-based trial.

And so to me, overall, we'll speak about, "Okay, what is the role for an HRR-directed therapy, whether it's just BRCA or BRCA and non-BRCA HRR gene alterations? Can we use that?" And I think that brings us back to one of your original questions which has to do with, can we identify those patients? Because that implies that we are testing everybody that comes into the clinic with metastatic disease, and we get those results in a timely fashion so we're able to act on those results. And to me, that's one of the biggest challenges.

Neeraj Agarwal: And that makes me think of another aspect of this. If we do NGS testing, we often find these mutations, which also have implications for germline testing. And then once we see these mutations in tumors, that may convince our patients to pursue germline testing.

Often, they deny germline testing because of the potential implications for their family members. They are more amenable to doing somatic tissue testing, at least in my experience. But sometimes I'm able to convince these patients to do germline testing if I find these HRR mutations in the tumor tissue. What is your experience with that?

Pedro Barata: Yeah, I agree, Neeraj. I think just for folks who are hearing this, in general, we see a higher allele fraction, right, for germline alterations. Sometimes there's a suggestion a germline alteration might be present when we get a report from somatic testing. In other words, we're testing the tumor. And so there's a suggestion, right, because the tumor started in our own body. So there's usually an allele fraction that's higher.

I do agree it facilitates the conversation. I want to remind us that in fact we should do both. And so what do I do? Well, for newly diagnosed disease, it's a no-brainer, in my opinion, because most of those patients do indeed have pathologic confirmation of prostate cancer.

Neeraj Agarwal: And fresh tissue.

Pedro Barata: And fresh tissue.

Neeraj Agarwal: Yeah.

Pedro Barata: So to me, that's less of an issue. And in fact, when we look at all those trials, we enroll about 60 to 70% of patients with newly diagnosed disease. But it's not the reality; it's a selection bias. We tend to select patients with more aggressive disease for studies. In reality, we see a lot more—in real life, we see a lot more patients with recurrent metastatic disease because they got surgery or radiation, they got hormones. Maybe they stopped treatment, they get PET scanning and we find metastatic disease.

And those patients are the ones where tissue might be very old or not really available. And so the question at that point is: are you going to go after very old tissue? Is it available to begin with? Are you going to rebiopsy—

Neeraj Agarwal: Or liquid biopsy?

Pedro Barata: —or do you do a liquid biopsy? But if you're going to do liquid biopsy, you need to be careful and not do that, or you're not going to be successful if you do it after you started ADT, which in a lot of clinics, in a lot of places, is just an almost automatic reaction.

Neeraj Agarwal: I think this is a vicious cycle in the clinic that we start patients on androgen-deprivation therapy when we see them, high PSA, bone metastases, order the tumor tissue testing. And then after a month we realize that tumor was not sufficient in quantity or quality. Now you want to do something else, and we realize that PSA is so low that ctDNA testing cannot be done.

Pedro Barata: Right.

Neeraj Agarwal: And I think the only way to get around that is to just order tumor tissue testing and a reflex liquid biopsy. So if tumor tissue is not productive, patients undergo liquid biopsy from the blood which was collected before treatment was started.

Pedro Barata: Exactly.

Neeraj Agarwal: And that strategy has been more successful, at least in my clinic.

Pedro Barata: Right. That's a similar thing that I do. I always think first, actually, liquid biopsy for the somatic testing because they're already getting blood for germline testing. So in our clinics, we do pretest counseling to explain the role of germline testing, and then for positive results on germline, we engage genetic counseling.

And so because I'm already doing a blood test anyway, I'm actually going to do both.

Neeraj Agarwal: That makes sense.

Pedro Barata: So a lot of times I do liquid biopsy and germline when they are treatment-naive. When they're not treatment-naive or I don't have tissue available or it's not amenable to biopsy, that's when I don't get somatic testing upfront, which in the context of where we are today, and we even talk about CAPItello and PTEN loss and more to come, I think it's going to put additional pressure on us to educate our colleagues who we work with to say, "Hey, do not start systemic therapy before we have a decent characterization of the tumor at the genetic level."

So we get that information and we then go over the details about, are you a candidate for PARP? Are you a candidate for a PTEN-based therapy with an AKT inhibitor, if that's available at that point? Are you a candidate for triplet therapy? Are you a candidate for ARPI with ADT, et cetera?

Neeraj Agarwal: Great point. So basically, we have to do tumor tissue testing in newly diagnosed patients with metastatic hormone-sensitive prostate cancer. And in addition, it looks like germline testing, liquid biopsy as we call it, in addition to CT scans and bone scans and CBCs. I don't think we have any option left to not do these testings if they're available and are affordable. Would you agree?

Pedro Barata: I agree fully. It is mandatory. It's almost criminal not to do it because now it's not just... You have a better informed conversation. Patients want to know. Most of the patients ask me.

Neeraj Agarwal: I mean, I agree. These can have medicolegal implications—

Pedro Barata: Absolutely.

Neeraj Agarwal: —if we miss, say, a BRCA2 mutation in germline in a family member and one of the family members develops breast cancer after five years. I agree with you.

Pedro Barata: And even if we didn't have those therapies available, the ability for you to predict, because we spend a lot of our time actually predicting the future—it's, "What's going to happen?" which is what patients ask. It's, "Doc, you're going to give me treatment A. What is the chance it's going to work? And for how long do you think I'm going to be on this?" Right?

So knowing the data helps us to have an informed conversation about that. So patients want to know. They have the right to plan their lives accordingly, right? So if we have a BRCA2, for example, we just quoted the data from AMPLITUDE. We can use other data for that matter. We know what they're going to do and we know when we're expecting to see movement, right?

We know if we need to be more rigorous around scanning or not, pay more attention to progression in scans or symptoms, even sometimes without PSA progression.

Neeraj Agarwal: Very good point. Very good points. So ultimately, we have to be testing all our patients with metastatic hormone-sensitive prostate cancer with tumor NGS, liquid biopsy, and germline testing. And I think it's time for all of them to have this testing.

Pedro Barata: Absolutely.

Neeraj Agarwal: No excuses.

Pedro Barata: No excuses.

Neeraj Agarwal: Well, thank you very much, Pedro, for sharing your wisdom as always, and such a pleasure to have you.

Pedro Barata: Thank you so much, Neeraj, for the chance to talk about this very important topic.