Maha Hussain: Thank you.
Neeraj Agarwal: Maha, congratulations for presenting the overall survival data on the BRCAAway trial. The Phase II trial, which I thought to us and to many of us in the field, was quite practice-informing about upfront consolidation with the ARPI and PARP inhibitor versus sequencing those therapies. Could you please tell us more about the trial design first, and then results?
Maha Hussain: Sure. The concept started from roughly about the days when we reported the results of the Stand Up to Cancer data, showing the role of the genomic platform of prostate cancer. Then there were two clinical trials that were part of the study. One was with veliparib, the other one was with olaparib. The olaparib trial showed responses. When you look at the genomics of the patients, those who had the HRR mutations were the responders. At that time, there was data coming in from my colleagues at Michigan showing that co-targeting AR and DNA repair, this is preclinical data, that could potentially give you a better outcome in terms of attacking-
Neeraj Agarwal: Dr. Karen Knudsen's lab.
Maha Hussain: Yeah, Karen Knudsen, absolutely. There was work that was being done, and that was published around, I want to say, maybe 2015, 2014 or something. Based on that work, the data that we had from the Stand Up to Cancer, and other data from when I was at the days of University of Michigan, I decided to design the BRCAAway trial. The whole idea was to see is co-targeting AR and DNA repair better than targeting each pathway alone? The whole idea is this, is it better? And also, can you get away with sequential treatment because why dump the kitchen sink on patients with potential toxicity, physical and all of that effect, and financial if you can get away with it doing it sequentially? I want to point out, and this is not to brag, but this was designed long before any of the combo trials that we have. In fact, it was about the time when we were talking about designing PROFOUND, the trial.
That tells you in the second line down there. The BRCAAway, the design was intended to basically screen patients, pre-select those who had the HRR mutation, based on the preclinical work, the idea to go with the key mutation pathways, BRCA1, 2, and ATM. Then we wanted to also include patients who didn't have these genes, but have other HRR mutation, again, based on the Stand Up to Cancer work and other work, if they would have a response. This was a really remarkable effort and phenomenal collaborative effort. You were one of the team, major accruers, yourself, your site, and your team. We had 15 sites. We screened patients and we did it. I would say, at the end of the day, I feel like it delivered. Yes, it's not a Phase III trial and all of that stuff, but the key thing that I think it delivered is the fact that sequential therapy is not as good as combination therapy. The other part that I think is remarkable, which is when we're showing the data which is purely US-based, when you're looking at the outcomes, there were so many men who progressed from localized disease to metastatic disease to castration-resistant disease in very short period of time. We're talking less than two, three years.
Yet they went on the combination on this trial, and especially those on the combination, they actually were in remission for years down the road. I have a gentleman right now, he just progressed about a year ago, so I'm treating him with different things, but this is a guy who was in his mid-forties when his prostate cancer diagnosis started. I do think it's very important from that perspective. The other part I would say that I think is critical about it is that the duration of response can be remarkable. One of the issues that we have to think about as these drugs are moving into the hormone-sensitive space, how do you juggle all of this? With all of the evolution of the treatments in the hormone-sensitive space, the triplet therapy and all of that, how do you add a PARP in a BRCA patient or something like that? It's very interesting, and I'm really very delighted with the results that we're seeing. As you saw yesterday, the curves' separation is absolutely amazing.
Neeraj Agarwal: Happens early on. I still remember the progression-free survival data we initially saw you presented in ASCO GU 2024 where the combination abiraterone plus olaparib was associated with a PFS of 39 months, and individual monotherapy arms combined with sequencing were 16 months exactly. Now, we are seeing maturation of data, which is reflected in 68-month median overall survival of the combination arm. Pretty much half of that with olaparib and even worse with abiraterone.
Maha Hussain: Yes, exactly.
Neeraj Agarwal: These are really remarkable practice-informing results, in my view. May not be a registration trial, as you said, but very important trial. I think we should be doing more trials like this.
Maha Hussain: Well, and I think the other part is great to have the Phase III trials that show the combos are better. But I would say one unique design issue with this trial, and it's my baby so, of course, I'm very proud of it, but the point here is they never had a control arm of PARP inhibitor alone. That's the other part where there is an issue. Yes, like we did PROFOUND, we allowed people to crossover, but that's in this downstream. In the frontline situation, I think ideally you would have wanted to see a control arm of a PARP inhibitor alone. Obviously, I don't think it's ever going to happen, but I do think that while the BRCAAway is not a large study, it does have a clear signal on the value of combination upfront.
Neeraj Agarwal: Correct. The message here is, looks like this is an emerging theme in metastatic prostate cancer setting, that combination therapy tends to work better than the sequencing.
Maha Hussain: Yes, absolutely.
Neeraj Agarwal: We had ARPIs available in CRPC, we moved them to upfront, and we see a remarkable, clinically meaningful improvement in overall survival. Now we see the same story with PARP inhibitor plus ARPI.
Maha Hussain: Correct, yes.
Neeraj Agarwal: It looks like we look forward to seeing more combinations making a difference in our patients.
Maha Hussain: Yeah, and I think that's going to be critical. One of the things in another session I was in, the discussion was we were chatting about things is like could you potentially move things into the hormone-sensitive space in settings where you're using a triplet treatment in somebody who might be HRR mutated, after they finish docetaxel, add a PARP inhibitor, go for a period of time, and see how things go, does that impact outcomes? I do think, as I was mentioning to the people I was chatting with, is consider actually do randomized Phase II trials just to see if you see a signal. Now, stuff like this is going to need really collaborative effort across multiple centers. The companies need to help there. I would say ideally, the cooperative groups, because you can get a larger-scale patients, because that will hopefully give you a better or faster response.
Neeraj Agarwal: Perfect platform for these studies, this cooperative group, I think, giving opportunities to younger investigators like you gave to me a long time ago with the SWOG trial. I think this can be a very valuable experience for young investigators and for all of us.
Maha Hussain: Yeah. No, I think there is plenty of opportunities. I have to say the other thing, historically in the older days, there wasn't a lot of collaboration with pharma companies. It was more certain diseases like breast, lung, and things like that. Now, I think there's really a great effort going on between pharma, the academic crowd, and the different physicians across not just the US, but international to try to focus on GU cancers, and prostate is a critical part. When all is said and done, I mean, it is the number one cancer in men, no matter where you are, and still major cause of death, so I do think there is plenty of room to impact the field.
Neeraj Agarwal: Absolutely. As usual, Maha, thank you so much for sharing your wisdom with us, and thanks for taking the time.
Maha Hussain: My pleasure always, and thank you so much.