Alicia Morgans: I am so thrilled to be at ASCO 2022, where I have the opportunity to speak with Dr. Shahneen Sandhu about the MAGNITUDE trial and a pre-specified gene-by-gene analysis that she presented at ASCO. Thank you so much for being here.

Shahneen Sandhu: Thank you for having me.

Alicia Morgans: Well, I am thrilled to listen to you. You really explained to us how you did this work and what you found. Before we dive into your presentation, I'd love to just have you recap, if you could, the MAGNITUDE trial, just to remind everyone of what this study was.

Shahneen Sandhu: The MAGNITUDE clinical trial is a phase III clinical trial evaluating the efficacy of niraparib with abiraterone acetate and prednisone in patients with and without homologous recombination repair deficiency. So at GU ASCO, we presented the primary endpoint data. So, the primary endpoint patients were randomized to either abiraterone acetate in conjunction with niraparib and prednisone versus abiraterone acetate and prednisone alone. And at GU ASCO, we reported the primary endpoint of blinded radiological progression-free survival. And in that presentation, we showed that there was significant progression-free survival benefit for the BRCA1 and BRCA2 altered patients receiving the combination of abiraterone acetate in conjunction with niraparib compared to control, with a median rPFS of 16.6 months versus 10.9 months, with a hazard ratio of 0.53.

Shahneen Sandhu: Additionally, we also showed that in the overall HRR-positive cohort, there was a corresponding improvement in the primary endpoint of rPFS. And in addition, both the BRCA1 and BRCA2 and the overall HRR cohort also showed evidence of efficacy across multiple secondary endpoints, such as time to pain progression, symptomatic progression, PSA progression. So, pertinent clinical endpoints for patients, essentially.

Alicia Morgans: That was really exciting. And what I think it's going to be so exciting, too, is to really explore on a gene-by-gene level what was driving this benefit that we saw in progression-free survival. And I do want to commend you and the team for really pulling out the HRR-positive patients and then the negative patients. Of course, there was no benefit in terms of PFS in the HRR-negative population, and you figured that out early and stopped enrollment and continued follow-up with that cohort, which I think is a really important piece of this whole study. That was beneficial to patients to not participate if it wasn't going to be efficacious. So I would love to hear, what did you report at ASCO?

Shahneen Sandhu: So, at ASCO, we're providing some additional insights about the efficacy across the other homologous recombination gene defects beyond BRCA1 and BRCA2. So of course, in fact, the community increasingly understands the prognostic implications of having a BRCA1 and BRCA2 alteration, and also the efficacy that we see with the use of PARP inhibitors in patients with BRCA1 and BRCA2 alterations. But there's so much less that's known for the other homologous recombination deficiencies, particularly in the context of this clinical trial. It is the first data set that is actually evaluating or showing the gene-by-gene clinical benefit seen with the combination of both niraparib in conjunction with abiraterone acetate. So that's what we're showing in this analysis.

Alicia Morgans: Wonderful. So what exactly did you demonstrate in this study?

Shahneen Sandhu: So, it was a pre-specified analysis looking at the primary endpoints and all the secondary endpoints in patients with at least one gene alteration in the HRR-positive cohort. And so this included patients with ATM, CDK12, PALB2, BRIP1. And we evaluated both the rPFS as well as the key secondary endpoints, such as time to cytotoxic chemotherapy, time to PSA progression, symptomatic progression, all those endpoints that are clinically meaningful for patients, essentially.

The other thing we did was because of the rarity of some of these genes, we looked at groups that were functionally similar. So, we looked at a group of Fanconi HRR genes, so which included BRIP2 and PALB2, and we also looked at an HRR-associated group, which certainly included CHEK2 and HTEK as well.

And in terms of what we saw, we certainly saw that there was benefit. Clinical efficacy was seen across these groups, namely for PALB2, CHEK2, and HTEK. All the benefits were seen for both the primary endpoint of rPFS as well as all the key secondary endpoints, as well. Very similar to what was actually seen in the BRCA1 and the BRCA2 cohort that was previously reported at GU ASCO. When we then look at the groups of HRR associated and the Fanconi HRR groups, again similar benefits were seen across all those primary and secondary endpoints.

I suppose some of the key genes that are particularly interesting in terms of our understanding, the feel is in the ATM group, there were also clinical benefits seen for many of the secondary endpoints, including time to cytotoxic chemotherapy and PSA and responses, as well. And likewise, with CDK12, there was some benefit in time to PSA progression, but not the primary endpoint.

So overall, I think the overall message from this analysis is that it's certainly new insights that have not been provided previously about the efficacy seen across the different genes that made up the HRR-positive cohort. And clearly, there is clinical benefit with some of those secondary endpoints being very clinically meaningful. And in addition, it reinforces the data that was presented at GU ASCO, and there was no additional efficacy signal.

Alicia Morgans: I think that's so helpful, though. And I love that you and your team, of course, pre-specified this analysis, which is so important because it's not then a fishing expedition and all of these different genes. This was pre-specified. And I also love that you help us as clinicians and as a field think about these HRR mutations in buckets, because I think that's also so important. These genes are involved in very different processes, even though they all may contribute to HRR. They are different processes. And so to think about them in these groups is really, I think, important in structuring or understanding and helping us to think through how do we approach a certain mutation in a given patient when we have this data. And this is very exciting.

Shahneen Sandhu: Yeah, I completely agree with you. I think it's important to know the level of efficacy across the different groups. I think the reality is we are trying to molecularly stratify prostate cancer and also try to personalize treatment as best as possible for the individual patient that you are seeing. And therefore it's really critical to just try to really understand the level of benefit that is actually seen so that you can inform the patient about the benefits in conjunction with the side effects.

Alicia Morgans: Absolutely. Well, wonderful. So, if you had to take this information, assuming someday this combination is approved in first-line metastatic CRPC, how would you apply this gene-by-gene analysis in your clinic? Are there some alterations where you would say, "I think this, in the right patient, would be a good combination to try, or in this patient perhaps not?" Or does it come down to that individual patient, which I'm sure it always does? How do you think through this in practice?

Shahneen Sandhu: I think you would consider both factors. So you'd consider the genomic makeup of the tumor in terms of making a decision about the value of combination therapies, and also some clinical factors that always come into the equation. I certainly see these treatments moving forward in the frontline setting. And my expectation is, certainly there is evidence to support its use, more strongly in the BRCA1 and BRCA2 altered group, but also beyond that in the HRR-positive group as well, as we've shown in the MAGNITUDE study. And hopefully, the ongoing clinical trials will also prove that that is relevant in the metastatic hormone-sensitive space.

Alicia Morgans: Well, thank you so much for sharing your insights and really helping us as a field get things a little bit more organized and characterized. I really appreciate your time and congratulate you and your team for your efforts.

Shahneen Sandhu: Thank you.