BRCAAWAY Trial: Impact of Abiraterone and Olaparib Combination in Prostate Cancer - Maha Hussain

February 22, 2024

Alicia Morgans interviews Maha Hussain about the BRCAAWAY trial, a phase two study exploring the efficacy of combining abiraterone and olaparib for patients with metastatic castration-resistant prostate cancer harboring BRCA1, BRCA2, or ATM mutations. Highlighting the journey from the inception of the trial to its execution, Hussain delves into the rigorous selection criteria and the strategic design aimed at evaluating whether a combination therapy upfront can offer superior outcomes compared to sequential single-agent treatments. Dr. Hussain discusses the manageable adverse event profile, emphasizing the importance of personalized care and shared decision-making with patients. This groundbreaking study not only paves the way for more tailored treatment approaches but also underscores the collective efforts of the research community and the pivotal role of patient participation.


Maha Hussain, MD, FACP, FASCO, Professor of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA

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Alicia Morgans: Hi, I'm so excited to be here today with Professor Maha Hussain. We're talking at GU-ASCO 2024 about her presentation on BRCAAWAY.

Thank you so much for being here.

Maha Hussain: Well, thank you, Alicia, for inviting me.

Alicia Morgans: Well, I of course wanted to invite you. This is such an exciting study, a phase two, looking at the combination of abiraterone and olaparib versus those agents as single agents, and there's crossover built in, which to me makes it even more exciting. So can you tell us a little bit about the study design laid out for us and then what you were really trying to understand?

Maha Hussain: Maybe I can begin by giving you a very brief history. So my interest in actually looking at the homologous recombination pathway and the DNA damage repair goes back to literally the late 2000s when we started with looking at where there was data coming in, looking at PARP inhibitors with alkylators, and we did trials there and a trial there with an old PARP inhibitor, and that did not translate. Then I had a clinical trial that looked at the combination of abiraterone with veliparib, and that was part of the Stand Up to Cancer. It was a CTEP trial, and the premise for that was the fact that essentially co-targeting both pathways can come up with a synergistic effect. Unfortunately, what was interesting is this, while that PARP inhibitor that we used with the abiraterone did not translate, it seemed like when we looked at the genomics of the patients, the patients who had the HRR mutations seemed to do better no matter what, which really prompted the design of the BRCAAWAY trial.

And I should point out that we conceived it in the late 2015s, 2016, and then activated it in 2017, long before any other trial that was actually designed. And the whole idea was to pre-select the patients to better personalize care. So the design basically preselected men who had frontline metastatic castration-resistant disease, and specifically we stuck with the BRCA1, BRCA2, and ATM. And this was actually a trial that we had to go to the FDA with and all of that stuff. And the FDA basically required these specific genes. And then anything that was aside from the BRCA1, 2, or ATM was an independent arm, separate arm. And partly because there was no data yet in that space.

The trial design essentially was intending to show if single agents sequentially are as good as combination upfront. And the idea was that why put burdens on the patient, whether it's physical burden or financial burden upfront if you can do it sequentially, and so was the design. This was an investigator-initiated trial. I believe we had 17 sites that participated. So it was a lot of effort from all co-investigators, and I'm so grateful to all of them. We actually registered the patients, so we didn't pre-screen and do that, we wanted to include everybody so we can have as much information. So 165 patients were screened, of whom 61 actually had the qualifying mutation, and then they were randomized roughly 20 per arm. It was like 21 and 19. It's just 60 patients that were randomized.

Alicia Morgans: And it's so interesting, I think because I want to give you the opportunity to share your data because even with a relatively lower number of patients, the signal was so strong that you found statistically significant differences in their progression-free survival between these arms.

Maha Hussain: Correct.

Alicia Morgans: So, please.

Maha Hussain: So basically, once we randomized the patients, and I should point out it was 61 patients that were randomized, the signal was very, very powerful, favoring clearly the combination treatment. And in fact, as they say, this is not like you can put a laser pointer between them. The gap was really quite big. The median progression-free survival was 39 months. So this is over three years median compared to the abiraterone arm, which was about eight and a half months, and then 14 months for the olaparib. Then actually, when you look at the rate of undetectable PSA and PSA response and all of that, everything was very clearly favoring the combination.

Now, one of the issues, as I said, from the objectives, was whether sequential therapy is just as good. In reality, of the 20 patients, roughly per each arm of the single-agent arm, less than 10 in each one of them crossed over. And there were many reasons why they didn't cross over, for different reasons, patient choice, physician choice, health-related issues, and things of that sort. So we just looked at the patients who crossed over and then looked at the totality of the median, the same thing. Interestingly, the patients who crossed over, the median for them was about the same per arm, 16, in terms of progression-free survival. So clearly, the upfront combination is definitely much better.

Now, I want to tell you a brief story if I have a minute. One of the gentlemen that were recruited to the trial by one of the sites was actually a young man who developed metastatic prostate cancer at a very early age, in his 40s, and progressed to castration-resistant prostate cancer, literally minutes after. I don't mean literally minutes, but a very short period of time. He ended up being randomized, he was tested and turned out to be BRCA2, and was put on the study. And surprising to me, he was in remission for almost five years.

Alicia Morgans: Wow.

Maha Hussain: Okay.

Alicia Morgans: Wow.

Maha Hussain: So to me, that is absolutely remarkable, and I do think that this adds additional information, albeit the numbers are not big, but the trends are so strong that I think, especially my counseling to oncologists who are going to treat these patients, go with the doublet and not do sequential.

Alicia Morgans: That is really incredible. There's really so much to really dig into with what you just discussed. And I think one of the things that's so important, just to comment on the attrition essentially of patients from these arms where they were getting sequential treatment, it very much seems to mirror what happens in our clinical practices where approximately 50% of patients actually do not proceed from one line of treatment to another. And in this case, my hope is that these patients were going on to other therapies for one reason or another, but it is very possible that some of them did not get any further therapy or had other issues. And this is another reason from my perspective, that we get one first best shot. And having that combination, I think, gives us the opportunity for those patients who are fit to make that shot.

Maha Hussain: Yes. And that's exactly what I tell patients. The issue is not dumping the kitchen sink upfront for no reason. The intention upfront is to attack the cancer based on what we have in terms of data. And I do think the totality of the data, including the phase three trials, although all of them did not have a control arm of a PARP inhibitor, I would say we probably could extrapolate from my study, albeit I should clearly highlight it's not a large volume of patients, but I do think the signal is so strong that I do think it's going to be important for oncologists and or urologists who deal with these patients to make sure that the patients are counseled and given the combination upfront.

One thing I should point out also is that the FDA indication in terms of the HRR mutations and all of that needs to be looked at specifically from the... Because again, we live in a country where you have to get insurance approval and coverage and to make sure that one is applying whatever the FDA indication in terms of the pathway.

Alicia Morgans: Absolutely. I think one of the main concerns from folks who have said, "Well, perhaps sequential treatment is actually just as good." And of course, these comments were made before your data was presented. But one of their concerns has been the adverse event profile, the potential need for blood transfusions, the patient experience, and what that might be like. Can you speak a little bit to the adverse events that were identified during this trial? How tolerable in your practice, in your hands, was this combination?

Maha Hussain: Sure. So in the single-agent arm, basically, the adverse events were what you would expect. In the combination arm, interesting again, when you look at it, there were, first of all, no grade four toxicities or grade five toxicities that are treatment-related. And essentially overall, the tolerance was quite well. So as I mentioned, this gentleman that I'm describing to you who was on treatment for almost five years now, that gives you a feel. Now granted, he's younger, he's healthy otherwise, and all of that. But I have had many patients from different sites who were able to continue treatment.

And as I said, the fact that the progression-free survival was over three years, that tells you that a lot of these patients did not withdraw. They continued when they were in response. None of the side effects we've seen are anything that is out of line with what you might expect with the drug, basically.

Alicia Morgans: Okay. So really, with the totality of this data, albeit in a relatively smaller study but one with such power to show statistically significant differences, I think, in this meaningful endpoint, from my perspective. What is your bottom line? What is your message to patients, to clinicians who are thinking about this?

Maha Hussain: So I think the first message is for the physicians, managing physicians, oncologists, urologists, and to the patient, absolutely applying the evidence as much as possible, but tailoring it and personalizing it to the patient. Our job as physicians is to counsel the patients on what their best choices are. Ultimately, it's the patient that will have to decide, is this worth it for them or not? And what I would say, it's always a shared decision. Now, it does take time to go over these things, and patients are scared, and it's critical to give them time. This is not an emergency decision. So I usually counsel the patients, give information to the patients, and ask them to go home, think about it, talk to their significant others, and come back. And I would say the approach has been, from my perspective, quite functional.

Alicia Morgans: Great. Well, congratulations to you and the team. It is no small effort to do a multi-institutional investigator-initiated trial, but particularly one that is selected for these alterations. This is no easy feat, and certainly, the patients who participated are to be thanked as well. But thank you today for your time and continued efforts.

Maha Hussain: Thank you so much. And I'm incredibly grateful to the team because without them, this would've not been possible, and obviously to the patients and their families and support care people. We've come a very long way in prostate cancer, and I'm delighted where we are. When I was in fellowship, the median survival for castration-resistant prostate cancer was less than 12 months.

Alicia Morgans: Well, I'm grateful to be sitting across the way from you because I know you've actually done a huge amount to improve those numbers.

Maha Hussain: Thank you. There are a lot of great people working in the field, and I'm hoping that we, at some point, might be curing some of these patients, but we'll see.

Alicia Morgans: Well, let's keep working at it.

Maha Hussain: Yes.

Alicia Morgans: Thank you so much for your time today, Maha.

Maha Hussain: Thank you, my dear. Take care. Thank you.