BRCAAway Trial: Where Combination Treatment Improve Patient Outcomes in mCRPC - Daniel George

February 6, 2024

Zach Klaassen and Daniel George discuss the highlights from ASCO GU 2024 including the BRCAAway trial, a study focusing on the combination of PARP inhibitors and novel hormonal agents for treating metastatic castration-resistant prostate cancer. Dr. George explains the trial's innovative design, which explored the efficacy of abiraterone and olaparib, both separately and in combination, in patients with HRR alterations. Highlighting the trial's results, he notes the combination therapy significantly extended median radiographic progression-free survival to 39 months, far surpassing the outcomes with either treatment alone. This finding suggests a synergistic effect rather than an additive one, emphasizing the need for combination therapies in prostate cancer treatment. The conversation also touches on the importance of genetic testing in identifying eligible patients for such targeted therapies, underscoring its underutilization in clinical practice and advocating for a systematic approach to genetic assessment in prostate cancer management.


Daniel George, MD, Medical Oncologist, Professor, Departments of Medicine and Surgery, Duke Cancer Institute, Duke University, Durham, NC

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA

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Zach Klaassen: Hi, I'm Dr. Zach Klaassen, a urologic oncologist in Augusta, Georgia at the Georgia Cancer Center. And we are here live in San Francisco at GU ASCO 2024, and I'm pleased to be joined by UroToday regular, Dr. Dan George. We're going to talk highlights today. Dr. George is from Duke Cancer Center in Durham, North Carolina. Thanks for joining us again, Dan.

Daniel George: My pleasure, Zach.

Zach Klaassen: So let's talk about BRCAAway. This was presented at the oral abstract session of this meeting. So give us your thoughts on the genesis of this trial and sort of lay out the background for us.

Daniel George: Yeah. Zach, this was a really important kind of follow-up study to what we saw over the last year or two with a number of PARP inhibitor studies looking at castrate-resistant prostate cancer, combining novel hormonal agents with PARP inhibition, either in all comers or specifically in patients with HRR alterations. And so now we've had these indications with HRR alterations, but the lingering question remains: is it really better to give these drugs together, or is it just as good if you start with a novel hormonal agent and follow with a PARP inhibitor or vice versa?

So those original trials didn't really look at that. They just looked at a novel hormonal agent alone, or the combinations. BRCAAway, by Maha Hussain, was a really ingenious design study where they took patients, screened them for HRR alterations, and this included BRCA1 and 2, but also included some other alterations including ATM, which is a little bit more controversial in terms of how sensitive it is to PARP inhibition.

But parking that aside for a moment, they looked at these patients with these HRR alterations -- and most of them were BRCA, so that worked out okay -- divided patients into three groups. It was randomized three ways. Patients either were treated with abiraterone, treated with olaparib, or treated with a combination. And for the patients that started on abiraterone, they got to switch over to olaparib. Patients who started on olaparib switched over to abiraterone. And the combination, they just stayed on until progression and then standard of care.

So, really looking at those initial responses, PSA responses and, importantly, time to radiographic progression, huge difference. The combination median rPFS, 39 months. Enormous, really.

Zach Klaassen: Enormous.

Daniel George: I mean, this is really out of the league of the other ones, which were kind of eight to 14 months, about eight or so months for abiraterone. Not surprising, in an HRR-driven tumor, abiraterone doesn't work quite as well as it does in unselected. And the PARP, which you want to see a good result, we did, 14 months, but nowhere near that combination. And even with crossover, looking at time to second progression, it still doesn't add up to 39 months. So it's really kind of validation that there's a real synergy going on here.

This isn't just two good drugs working additively. There's something about blocking through a novel hormonal agent like abiraterone that's sensitizing even further above and beyond what we see with an HRR defect and creating even a greater duration of response. And that's, I think, I won't say surprising, but really validating to this idea that there's real synergy going on. Just monotherapy after monotherapy, kind of what we've been doing in prostate cancer for the last 20 years, isn't good enough. We need to understand where combinations really build on each other mechanistically. And there's a good rationale for this. It's really great to see that kind of validated here.

Zach Klaassen: It's interesting because, with smaller groups, roughly 20 patients per group, but a true biomarker-driven trial. And as you mentioned, when you see those rPFS numbers stacked up, it really is impressive. Where does this data go from here?

Daniel George: Yeah, so this is really important because I think right now, first off, this really validates the indications that we have to use these drugs together. But I think where this leads is where we're using these drugs, most of all, in the metastatic hormone-sensitive setting. And that's where we're starting to see some of these trials come together with TALAPRO-3 and with AMPLITUDE, and now most recently with EvoPAR.

The interesting thing here is just how dependent is this mechanism on HRR, in particular BRCA? Or is there a synergy now also even in settings where there isn't necessarily an HRR defect, but where we are seeing really profound responses to that hormonal therapy? Is that enough to create some synergy? And that's what EvoPAR will look at. They'll look at the combination in all comers stratified by HRR. So I think we've got some unanswered questions.

There was some tantalizing evidence from PROpel that didn't quite meet the FDA's benchmark for approval, but at the end of the day, certainly suggested that there is activity in all comers, granted at a little bit lower level. We'll get to see that now, hopefully in a few years in this earlier disease setting where these novel hormonal agents are even more active. And we'll also be able to see, does using these PARP inhibitors and this kind of combination strategy work even better when we use them in this earlier metastatic hormone-sensitive disease state?

Zach Klaassen: Absolutely. I think before we wrap up, I want to dovetail just a little bit to genetic testing because these patients don't get into these trials if they're not genetically tested. We know, in the real world, genetic testing is still woefully underused, even in the mCRPC and mHSPC space. There is data this week presented from the VA looking at a remote way to test, which was very interesting data, and just mailing out questionnaires, interested, contacting patients, and then really finding genetic mutations in these patients in the VA system. So having said that, how do we improve our genetic testing in the real world?

Daniel George: Now that we're seeing these kinds of effects, now that I think this HRR alteration is being recognized more and more in the context of hormonal agents and when we use them, it's more important than ever that we do this. We really need a systematic approach to how we do this. When we see patients with recurrent prostate cancer, metastatic hormone-sensitive prostate cancer, that's really the indication to say, "Okay, we got to assess these patients." Just like we want to assess for bone health, just like we're going to really assess for cardiovascular risk going on hormonal therapy, we also-

Zach Klaassen: Should be on the checkbox with all of it, right?

Daniel George: Yeah, yeah. We've got to be able to say, "Okay, these are the patients we can't miss on." And even frankly, if you've got a high-risk patient from the get-go that is like a 50% or greater chance of relapse, go ahead and get it. Send that tissue while it's fresh in your mind, so to speak, and get that testing or do that genetic testing, even if it's just germline. Even if it's just firing off a little buccal swab or blood, anything is better than nothing, and I think, ideally, both germline and somatic. But these are the things I think we just got to make kind of almost routine, like brushing our teeth.

Zach Klaassen: Yeah, absolutely. Dan, thanks so much for your time as always. It's a busy meeting. We appreciate you taking some time to chat with UroToday.

Daniel George: My pleasure. Thanks, Zach.