BRCAAway - a Randomized Phase 2 Trial of Abiraterone, Olaparib, or Abiraterone + Olaparib in Patients with mCRPC with DNA Repair Defects - Maha Hussain

August 2, 2022

Maha Hussain is discussing the BRCAAway with Alicia Morgans, based upon Dr Hussain's presentation at ASCO 2022.  The BRCAAway Trial is a randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with mCRPC with DNA repair defects either in the tumor or germline. The PARP-inhibitor olaparib is approved for mCRPC patients with deleterious germline or somatic homologous recombination repair gene mutations. PARP1 interacts with androgen signaling, and castration-resistant tumor cells exhibit increased PARP1 activity. Preclinically, PARP1-inhibition synergizes with androgen receptor targeted therapy. BRCAAway is a biomarker selected, randomized, open-label, multicenter phase 2 trial evaluating the efficacy of targeting androgen receptor vs PARP vs combination in first-line mCRPC patients with germline and/or somatic homologous recombination repair gene mutations in BRCA1, BRCA2, or ATM.  Eligible mCRPC pts underwent tumor next-generation sequencing and germline testing. Pts with inactivating BRCA1, BRCA2 and/or ATM alterations were randomized 1:1:1 to Arm 1 abiraterone (1000 mg daily) + prednisone (5mg bid) (Abi/pred), Arm 2 olaparib (300 mg bid) or Arm 3 olaparib + Abi/pred. The primary endpoint is progression-free survival (PFS) analyzed using Kaplan-Meier estimates and Cox regression. Secondary endpoints include measurable disease response rate (RR) by RECIST, PSA-RR, undetectable PSA (≤ 0.2 ng/ml), and toxicity. Arms 1 and 2 pts were allowed to cross over at progression.

Dr. Hussain concluded by discussing the randomized phase 2 BRCAAway by emphasizing that in mCRPC patients with inactivating BRCA1, BRCA2, and/or ATM alterations, abiraterone + prednisone + olaparib was well tolerated and resulted in longer PFS and better PSA response versus either agent alone.


Maha Hussain, MD, FACP, FASCO, is the Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine, and the Deputy Director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine, Chicago, Illinois.

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

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Alicia Morgans: Hi, I'm so excited to speak with Dr. Maha Hussain of Northwestern University who's going to speak with us today about the BRCAAway trial that she presented at ASCO 2022. Thank you so much for talking with me today, Dr. Hussain.

Maha Hussain: Thank you very much, Dr. Morgans. It's really a pleasure. Again, thank you for the opportunity to discuss the BRCAAway trial results that we presented at ASCO. The BRCAAway is a randomized phase II trial of abiraterone, olaparib, or abiraterone plus olaparib in patients with metastatic castration resistant prostate cancer in those patients who have DNA repair defects in their tumors or germline.

The trial, I'm going to just give you a little bit a brief background. As you know, olaparib has been approved for patients with metastatic castration-resistant prostate cancer who have deleterious mutations, both in germline or somatic, in the DNA repair pathway or HRR mutations. There has been some long history, I would say, probably easily 10 years, where the original data regarding the potential synergistic effect of co-targeting the androgen signaling pathway and the PARP pathway. The idea for this trial actually began from a previous trial that was NCI funded, where we actually looked at co-targeting the two pathways, specifically with another agent called veliparib with abiraterone versus abiraterone and prednisone. That trial was part of the Stand Up To Cancer effort. What was interesting is that there were some observations that both came in from the Stand Up To Cancer effort and also from the patients that went on the trial, where their tumor was genomically evaluated. That led us to the design of this particular trial, and I'm happy to share a slide, perhaps, with the trial design.

But, essentially, this was a front-line metastatic castration-resistant patients who underwent germline or somatic testing for HRR mutations, and then patients who had the BRCA1, 1, or ATM were randomized 1:1:1 to either abiraterone plus prednisone or olaparib or olaparib and abiraterone plus prednisone. And for the patients who were on the single agent, either Abi or olaparib, at time of progression, they could cross over. The patient on the combination arm, of course, at time of progression, they came off. The trial, when we designed it, we also allowed to include patients who have the non-BRCA or ATM alterations, and it's an exploratory cohort where they get olaparib only.

The trial was designed to look at the primary endpoint, being progression-free survival. And, of course, we had several secondary endpoints, including progression-free survival, looking at PSA response rate, looking at undetectable PSA response rate, and RECIST, and others, obviously toxicity and so on. The trial recruited, basically, 61 patients from multiple centers across the country, and the patients, again, were randomized. And there were a fair balance between the arms overall.

What was interesting is this, that the bulk of the patients, to my personal surprise, had germline mutations. So, if you take the overall population, the rate of germline mutation was 54% and then somatic was in 46%. As you might expect, BRCA2 was the predominant gene for the primary cohort, where, basically, 75% of the patients who were enrolled actually had BRCA2 alterations. Then, next most common was ATM, it was in 18%, and then BRCA1 was in just about less than 10% of the patients.

The overall results, essentially, I'm going to just keep it simple. The trial demonstrated the feasibility of actually pre-selecting patients in multiple centers and enrolling them into this study. The overall tolerability of the agents were really comparable between the arms, so there was really no major significant toxicities in the combination arm overall. And what was very interesting was the fact that the patients who were on the combination arm had a, relatively speaking, higher rate, again, this is not powered for significance, but they had a higher rate of undetectable PSA and, essentially, the median progression-free survival was not reached in the combination arm. And it was 10.4 months in the abiraterone arm in 11.3 months in the olaparib arm. At this point, the 12-month progression-free survival rate as we presented was 40% in the Abi-Pred arm, 49% in the olaparib arm. So when you think about it, it's fairly comparable. But interesting is that 95% was in the combination arm.

And so, at this point, we're obviously waiting to see the final results of the arms and finalize them, and we're looking at also data from the crossover, because the question comes up is, the intent is not to dump everything at one time, the intent is, is two better than one? And the other question is, is one after the other just as good as two given together? Because from my end, the intent is to maximize benefit, but also to minimize risk for the patients. So, we will see what the data looks like. But again, when I look at the trends, and I'm happy, again, to share the slides, the separation of the curves is pretty impressive.

Alicia Morgans: I would agree. I really also want to emphasize that. I thought it was really interesting that there was a similar median PFS for the patients treated with Abi and olaparib because we know abiraterone is actually a very strong agent in this setting.

Maha Hussain: Yes.

Alicia Morgans: And to demonstrate that similarity, I think, is very, very important, because we haven't seen that for olaparib against a very active control when olaparib is used as a single agent. What are your thoughts there?

Maha Hussain: No, I fully agree with you. I would say, unlike the phase III trials, and again, the phase III trials are very powerful, the PROpel, the MAGNITUDE, and several of the other trials that are in the works. What's unique about this study is the fact that we actually had a control arm of a PARP inhibitor alone, and so I think that will give us some signal as to how do single agents look like. And again, in this trial, we allowed crossover both ways, so it'll be interesting to see that. Now, clearly, the sample size is not huge, but to me, the signal is strong. So, it will be interesting to see. Several patients, I think, are beginning to cross over or have crossed over, so I'm hoping for us to report the data, I'm hoping by sometime this summer.

Alicia Morgans: Oh, that is absolutely exciting. And I do think, though, having that median PFS be not even reached for the combination arm is really exciting. I don't know if it will hold out, as you said, once we do the sequencing if the combination is better. But, would love to hear your thoughts, because it looks really, really favorable.

Maha Hussain: Well, the way I see it, fingers and toes crossed that it is better, because at the end of the day, what we want to do is give the patients the best chance. Obviously, these types of observations will need to be validated, and I would say the MAGNITUDE trial, certainly, in the context of patients pre-selected for DNA repair defects, it does certainly suggest the combination is better.

The trouble, of course, is the overall survival is not yet reported. And the unique thing about this trial is allowing the crossover, and that will give us a clean signal. Because, again, I am a firm believer that you want to give the best possible treatment, but if, in fact, it's not needed right away, why dump, as I say, the kitchen sink right away, when you increase pressure on patients for no good reason. But my gut feeling is the combination will turn out to be better, but obviously, we'll need to validate it.

Alicia Morgans: Yes, I agree. And that will be important, and kudos on the design that allows us to understand that sequence and actually mandates crossover, because you won't have that delay in getting to that next therapy, which is so, so important. Just to close the loop in thinking about the efficacy, but also the side effect profile, what are your thoughts on the combination versus single-agent from a side effect and toxicity program?

Maha Hussain: Sure. And as I mentioned, I think the remarkable thing was, Dr. Morgans, is that we really did not have any grade 5 toxicities that were related to treatment. There was a couple of events that were not treatment related, and there was only two situations with grade 4 events. Everything was grade 3 or less, and we're talking in less than 5% of patients, except for some vascular issues. But, overall, I would say predominantly grade 1 and grade 2. Grade 3 were seen, but in very small percentage, in less than 10% of patients. So I think treatment was very well tolerated.

Now, I should point out. These patients were treated at very specialized centers, and of course, they were carefully selected. They had to qualify by different eligibility criteria and so on. And so, the reality of it is, the question is, how applicable it is for the general population. But as you know, both the PROpel and the MAGNITUED were done internationally, and the treatments, overall, were reasonably well tolerated. Clearly, there were much more adverse events reported in these trials than what we have observed, but the nice thing, again, is, at least based on our experience right now, patients have been tolerating it very well.

I just recently, today, in fact, I saw a gentleman who was on this study, and he's BRCA2, he's a young man, and he has been on this study since 2018. And today, recently his PSA has gone up, but his imaging continues to be stable. So, to think about somebody with aggressive disease, young age, all of that stuff, and to be in remission for that long, it's pretty remarkable. So, fingers and toes crossed that this is something that can be confirmed and hopefully applied to patients.

Alicia Morgans: Well, let's just emphasize that, 2018 to 2022. That's a long time for a BRCA2 patient, which, as you said, has a poorer prognosis in general.

Maha Hussain: Yes.

Alicia Morgans: Congratulations to him and let's keep up the good work. What would your message be to listeners as they're really awaiting for the results from BRCAAway as well as from PROpel and MAGNITUDE?

Maha Hussain: Well, I think that the field has expanded, as you know, even compared not to our training time, well, not your training time, but my training time, has moved significantly. But the truth of it is this, I think we've entered a totally different era in prostate cancer. Clearly, research is what will cure cancer, and this is going to require partnership with the patients, with the colleagues, with researchers, with support systems and families, and everything. I do think we've entered a huge different era in this disease.

As I always say, and I think you might have heard me say, when I was in training and I was a junior faculty, the median survival was under a year for patients with castration-resistant prostate cancer, literally, I think, in the range of 9 months, even. And now, we've really gone into many years and certainly, the tail on the curve is getting longer and longer. So I do think we're catching up and I think we're getting better, but we need to do more. And I think, at the end of the day, again, excellence in care, excellence in medicine, and excellence in research is going to impact patients. And partnerships. If we don't do these trials, if patients don't participate, there's no chance for any of these things to make it into the everyday practice.

Alicia Morgans: I could not agree more. I just wanted to say, thank you and congratulate you for continuing to move us into the next era and to bring your expertise and your innovative ideas so that we can continue to move forward into the future. And thank you for your time today as well. Thank you, Maha

Maha Hussain: Thank you. Thank you very much, Alicia. And by the way, you participated in the trial, so I got to give you credit, also. You get credit with that. Absolutely. And thank you for this. Yes.