Alicia Morgans: Hi, I'm so excited to be here today at APCCC 2022, where I have two wonderful friends and colleagues to discuss PARP combination therapy, and thinking about how that may be, or may not quite be, ready for primetime use in clinical practice. I have Dr. Maha Hussain, who is a Professor of Medicine at Northwestern University and, of course, a GU Medical Oncologist, and Dr. Fred Saad, who is a Professor of Urology and the chair of that department at the University of Montreal. Thank you both so much for being here today.

Maha Hussain: Thank You.

Fred Saad: It's A pleasure.

Alicia Morgans: Wonderful. I know you're both very involved in these PARP trials and in PARP combinations, and I'd love to hear your thoughts. Why don't we start just briefly recapping some of the data Maha, would you mind sharing with us some of the data and then we can let Fred take the other study?

Maha Hussain: Absolutely. I think, from my end, I began with my interest in the PARP, probably around 2010 or so, when there was data coming up regarding the potential synergistic effect of targeting the PARP pathway and the androgen receptor. And so we designed clinical trials that were part of the Stand Up To Cancer at the time, which suggested some interesting trends, and then subsequently, of course, the definitive trials were done with PROfound, again, demonstrating that in the second or post-second line therapies in heavily pretreated patients preselected for DNA damage response defects, these patients benefited from PARP inhibition. One thing that's clear, is not all pathway elements or alterations are equal, and pretty much, a lot of the data positivity is in the BRCA2, however, there is certainly benefits in other HRR mutation areas.

So I do think that we have come a long way and we're looking at combination treatments, and of course, you've seen the data that was presented ASCO GU in the front-line setting. And I would say the data is very interesting, but there are a lot of subtleties that we need to go through, basically.

Alicia Morgans: Absolutely. And, Fred, would you mind just sharing a recap of the MAGNITUDE and PROpel trials, which are really the studies that looked at these combinations presented at GU ASCO 2022?

Fred Saad: Yeah. It was really a lot of fun being able to present the data for the first time, and it's really building on, on Maha's work on PARP inhibition and with the olaparib and the PROfound study that Maha led. Clearly, patients who have these mutations do very well when they've failed an AR-targeted therapy. And these are later lines of therapies, but even from PROfound, I think we learned that if you start earlier in these patients, they do better than delaying, because the trial allowed crossover. And patients who crossed over, didn't come close to doing as well as the patients who started earlier.

So taking that approach of saying, "Well, maybe we need to start, at the time, a first-line mCRPC," And taking into consideration some preclinical evidence that if you combine a PARP inhibitor with an AR-targeted therapy, there might be potential for synergistic effects that might lead to even better outcome. And obviously, I think we would all be convinced that patients who harbor BRCA mutations and maybe other HRR mutations would benefit from earlier introduction of these therapies.

The phase II study showed that, whether or not you had mutations, it looked like you can get benefit. It was only 140 patients, but they looked like they had benefit, and we published that a couple of years ago.

So, the PROpel study really used the strategy of saying, "Let's take all-comers with first line mCRPC who have not yet been exposed to novel hormonals, especially abiraterone, which was the backbone of the study." So, everybody in the study of 800 patients got abiraterone, which I think all of us would agree is the standard of care, or one of the standard of cares, for first-line mCRPC, and half got olaparib over and above the abiraterone. The first results were the primary endpoint of rPFS, which showed a very significant improvement in rPFS of about 8 months and a 34% reduction in progression or death. So, almost the same results as we saw with abiraterone against a pure placebo several years ago. So that was very insightful, that we were able to do better than the standard of care for now, at least in terms of rPFS.

And then in the subgroups, every subgroup appeared to gain benefit from the combination over the mono-therapeutic approach. And this included patients who had had docetaxel in the hormone-sensitive setting and, importantly, did well, even in patients without HRR mutations, which was almost 70% of the patients. Almost 30% did harbor mutations. So this is our first prospective study unselected that tells us that it's somewhere in between 25% and 30% of patients harbor mutations, of which the minority were BRCA. And those patients, obviously, it even looks like they're doing even better than the ones that are not mutated, but importantly, the non-mutated look like they were getting benefit, at least in terms of rPFS, with hazard ratios that are respectable, and we're still waiting for the updated results from that trial.

Alicia Morgans: Absolutely. And the MAGNITUDE study was interesting, looking at niraparib and abiraterone also in the first-line mCRPC setting. But in this case, the benefit was really confirmed in those patients who had BRCA1/BRCA2, but did not seem to be conferred to those patients who did not have those DNA repair defect alterations, which was interesting. So, really, those patients who had the DNA repair defect alterations, all of those included in the study, versus those who did not, those patients seemed to benefit

Fred Saad: Importantly, it was really the BRCA that was driving all the positive results, because the non-BRCA patients didn't appear to be getting much benefit. Obviously, subgroups and all the rest. And, really, the primary endpoint was the BRCA-mutated patients, where a lot of the data is supportive for looking at those patients in earlier introduction. So I think two positive studies, at least for patients that are mutated. The question that's going to be, I guess, debatable or questionable is, are we ready for the prime-time, like you asked upfront?

Alicia Morgans: Yes. And especially in that population that does not have the DNA repair defects, what's the truth there? Is it the combination allowing that sensitivity that we think may be conferred with the combination? Or is there something else going on? Is it perhaps just something that, if we follow them longer, we won't actually see that benefit? Dr. Hussain, what do you think about the non-mutated, the DNA repair defect-negative patients?

Maha Hussain: I question the value there. And this goes back to the days where we did the combination trial that was, again, part of the Stand Up To Cancer effort. Granted, not everybody got the genomic testing, because it's just the patients that had the availability of tissue. But what we saw in that trial, and just as a reminder for the audience, this was a trial that basically looked at combination abiraterone plus veliparib versus abiraterone alone in front-line metastatic castration-resistant disease. And then a large percentage of the patients who were recruited to this study, in fact, did have tissue available, or some of them underwent biopsy of metastatic disease for the purposes of this study.

What the data showed, basically, is that, again, overall, there was no advantage to the addition of veliparib with regard to the primary endpoint of this study. But when we looked at the breakdown again, this is post-hoc analysis, just for clarity, what was clear is this, is patients who had the HRR mutations or the DNA repair defects did better no matter what. So, if they were in the combo arm or the single-agent arm, did better than the patients who had intact tumors. And this is where comes up my bias, I guess, with the data from the PROpel trial. There's a lot of subtleties, of course, and different drugs are different.

I think that the another trial that we are reporting at ASCO this year looked at, again, the issue of combination versus single agent in both. So none of the phase III trials, even the control arms have always been the AR inhibitor. In our trial, again, albeit phase II trial, actually, it's AR inhibitor, PARP inhibitor, versus combination. And there's clearly trends. The issues is going to be is this. Is the sequential therapy.

That's where I think it's going to be important from both trials, PROpel and MAGNITUDE to actually see, if you have sequential therapy and people do just as well for overall survival, do you really need to subject them to the added physical, monetary, whatever cost of combination upfront versus not? My gut feeling is, like anything else, combination therapy tends to do better. So if I were to guess, I think it's going to be, at least in the HRR positive patients, there's going to be the trend of benefit there. But we'll have to see what the data looks like.

Alicia Morgans: Absolutely.

Fred Saad: Yeah. And your own PROfound, I think, would suggest that earlier appears to be better.

Maha Hussain: Yes. Yeah, yeah.

Fred Saad: So, the question is, do you need to combine? And I think for patients starting mCRPC, we need to give them the best standard of care.

Maha Hussain: Yes.

Fred Saad: Now, whether that's best standard care started in hormone-sensitive is a whole other question. And that's where the field is going.

Maha Hussain: Yes, I agree. I agree.

Fred Saad: And this is going to be the challenge in the future. How many mCRPC patients are going to not have been pre-exposed to NHTs in the past? But beyond HRR, and I think this is where we all, as a community, need to think, have we identified all the biomarkers of poor outcome? And we have biomarkers like chemotherapy in the hormone-sensitive setting, which might be growing over time. And these patients did really badly. They did as badly as the HRR-mutated patients in terms of how quickly they progress on Abi alone, and they did substantially better when they were combined to a PARP inhibitor.

We have the younger patients under 65. For some reason, they did exceptionally well with the combination compared to Abi alone. We have the patients who have visceral metastatic disease that don't do well on Abi alone that did substantially better in the combination. So I think we're going to all have to work on including, I don't think either of us would say we don't need to test genomic testing anymore. It's part of the equation of making a clear, informed, best approach for the individual.

Maha Hussain: Yes.

Alicia Morgans: Yeah.

Fred Saad: And, clearly, we won't be giving combination to everybody, but there are patients that come in and that I'm very concerned about. And I say, "These patients are not going to do well, and we need to do more than what we're doing today."

Maha Hussain: And I think what's going to confound things is the fact that you have the data from the triplets with darolutamide, the triplet with abiraterone in the hormone-sensitive space. And the question is, how does that paradigm shift? And of course there are trials in the hormone-sensitive space with PARP inhibitors and the issue, again, how does that impact things there?

I think the good problem, as I say, there are problems that are bad, there are problems that are good, the good problem is we have many choices for patients. There is a lot of investment in research in this patient population by comparison to even 10 years ago. So I do think that our job as the physicians is to actually go with what we think is the best process with regard to enhancing outcomes for patients, and clearly, quality of life and prolongation of life.

Alicia Morgans: Absolutely. And I know that both of you continue work in this space. I know, Maha, you're doing investigations into the basic biology to look for those unidentified drivers, because clinical features will only get us so far, but those expression profiles, those alterations that haven't been identified yet are in process. We're hoping Dr. Hussain can share those with us at some point in the near future. So, each of you, I'll give you a final word. Is combination therapy ready for prime-time in the clinic now? And if so, in whom? We'll give Maha the final word, so you get to answer first, Dr. Saad.

Fred Saad: I would say, yes, that it is ready for prime-time. The combination in first-line mCRPC. The low-hanging fruit are the patients with mutations, and I would go beyond BRCA, at least what we saw, but at the very least BRCA. But then I think the clinical parameters that we still don't understand why the biology of those parameters seem to indicate that the combination is better than simple abiraterone review. So I think we are ready for prime-time. I think it's going to be a question of selecting our patients that most need our help in doing better, because the reality is, many, many patients around the world are limited to first-line treatment and mCRPC, and don't go beyond that.

Alicia Morgans: Absolutely. Dr. Hussain.

Maha Hussain: I think I fully agree. I would just add to it, is that, pending the overall survival data based on the radiographic progression-free survival, I think the combination is, to me, clinically relevant, but I would say specifically in the patients who have the HRR mutations. So this is, if I were to offer it right now, I wouldn't offer it to all-comers. I would offer it to people who have the mutations. Again, pending the overall survival data.

If the overall survival data confirms the intermediate endpoint, so to speak, that would be great. The dilemma's going to be is if the overall survival data is no better. The question comes up is, how do you define risk benefit? And is sequential therapy going to be of value? And this is where our BRCA trial, again, not a phase III, small scale, but we're looking at sequential therapy crossing over and comparing front-line this versus that, and then crossing over. Will be interesting to see how that has resulted.

Alicia Morgans: Absolutely.

Maha Hussain: We're hoping to report it, hopefully, by the end of the year.

Alicia Morgans: Wonderful. Well, we will definitely catch up with you on that, and thank you both so much for sharing your thoughts on the PROpel and the MAGNITUDE data and how we think about that in clinical practice. It has truly been a pleasure.

Maha Hussain: Pleasure is ours, my dear. Thank you.

Alicia Morgans: Thank you.

Fred Saad: Thanks, Alicia.