Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today, Dr. Cora Sternberg, who is a Professor of Medicine and the Clinical Director of the Englander Institute for Precision Medicine at Weill Cornell in New York. Thank you so much for being here with me today, Dr. Sternberg.

Cora Sternberg: It's really a pleasure to be here.

Alicia Morgans: Wonderful. I wanted to talk with you about the MAGNITUDE study, which was presented at GU ASCO 2022, and of course, is an area that is pretty hot right now, this idea that we can combine an AR-targeted therapy approach plus a PARP inhibitor in patients who are receiving treatment in a first-line for metastatic CRPC and perhaps make some meaningful differences with that combination. So, can you tell us a little bit about the MAGNITUDE study?

Cora Sternberg: The MAGNITUDE study was presented by Kim Chi and it was a very, very interesting design. They screened all the patients for their biomarker status. They had a 9-gene panel looking for homologous recombination defects, and they only put those patients into the trial, differing very much from the PROPEL trial where they let all-comers into the trial. And once they did that, they had two different cohorts. It was almost as if there was two different studies. There was a biomarker-positive cohort with 400 patients and then there was a biomarker-negative cohort that started it out as having 600 patients. They stratified patients as to whether or not they'd gotten taxanes in the past or whether or not they even got abiraterone in the past, and then they randomized the patients in these two different studies and two different cohorts to either receive another PARP inhibitor called niraparib plus abiraterone or placebo and abiraterone, obviously on top of ADT, in both of the studies.

But the way the biomarker-negative study was written with the 600 patients, that they had a kind of a futility analysis, and after 200 patients, they stopped the study in the biomarker-negative population because they felt that it was not good enough to continue in those patients.

And then they presented two different sets of data on the biomarker-positive data, again, there was 400 patients there and some of them were just biomarker-positive and some of them were BRCA1 and 2 positive and they had different data for them. But in those biomarker-positive data, I think that the results were really quite fascinating for the combination of niraparib, ADT, and placebo. In the patients particularly with BRCA, they saw like a 47% reduction in the risk of death, which was really, to me, astounding in those patients who we know have the most aggressive disease. The results were not as significant, but we're also significant in the others who had other abnormalities such as ATM and CHEK and PALB2 and all of the other biomarkers that we know are associated with homologous recombination defects.

Then putting them in the two separate populations, both of those populations benefited from the combination for first line treatment of metastatic CRPC with niraparib and abiraterone. So I think the results were really quite interesting and astounding, and I liked the way that they did that study. The way that they, they took out the patients who were biomarker-negative at a certain point and did a futility analysis. So it was kind of three different studies all in one, but it was very interesting.

Alicia Morgans: Yeah. I agree with you. I think that the approach where they prospectively analyzed the biomarkers and then did not expose the biomarker-negative patients to ongoing therapy was actually very patient-centric. I really appreciated that, because that futility analysis saved several hundred patients from being exposed to a treatment that we did not expect to be beneficial to them. And I think that's really important and a testament to the study organizers dedication to making sure that patients were enrolled who could benefit. And so I also agree that's a really interesting design and such an important way to do this study.

Cora Sternberg: But there was a criticism of that by Tia Higano, the discussant, and she said that they took off patients who had radiologic progression-free survival, some 65 patients, and some 83 just for PSA progression. And we all know well, the PSA progression may not always correlate with what's going on. So I think that they still did the study in a right way. I wouldn't really criticize that. But if you have to say anything, that maybe the patients were taken off for PSA progression were taken off or earlier, but they decided that with the futility analysis that was planned, to not study those patients any further.

Alicia Morgans: I think that's fair. At the same time, I think that the difference in the benefit that we are looking for in this setting is really a blockbuster drug type of a difference. And if we aren't seeing a very strong and compelling signal early on, I think that it's completely reasonable to take those patients off of a phase III that's a registration study and say, "Maybe we need to investigate this more in a phase II type of an approach, but this phase III is not going to demonstrate the benefit sufficiently to warrant that combination."

Cora Sternberg: I think did Tia made some really good points saying that we really can't even compare the MAGNITUDE and the PROPEL trials because they were different patient populations. If you look at the placebo arms, the placebo arm in the MAGNITUDE arm didn't do as well. They did like 13.7 months as what we're used to seeing with abiraterone alone in the COUGAR-302 was a 16.5 months. And that was what they saw in the combo arm. Whereas in the PROPEL trial, for some reason, they must have had much better patients because their placebo arm had 16.4 months and over 27 months in the combination arm. So, if you look at it, there's different patient populations probably done in different countries, different criteria, it's very hard to compare among the two different trials, but I do like the way that they did the MAGNITUDE trial and the way that they took out the biomarker-negative patients.

I think in the future, why are we doing this genetic testing, and why are we looking at homologous recombination defects if we don't believe in it at all? And I'm sure the people from the PROPEL trial will go back and look at what their biomarker was and how many people did well or didn't do well based on that. And they may be coming up with more interesting data also based on the PARP inhibitors with patients that have had homologous recombination defects. But the MAGNITUDE trial, I think, was designed extremely well, in my opinion,

Alicia Morgans: I would agree. So when you look at all this information and recognizing that it was a poorer prognosis population in this study, as we can see from the control arm, as you mentioned, how do you think about potentially incorporating this into clinical practice or thinking about doing it in the future, of course, because this was a progression-free survival endpoint?

Cora Sternberg: Well, we do not have a role survival yet, and if I were in Europe, I wouldn't have the possibility of using that. I think in the United States where these drugs are more readily available and where we know, particularly patients with BRCA, that they have a more aggressive disease and if you see a patient with BRCA coming in with high-volume aggressive disease, I might really consider doing that even before we have the OS data. But that's just my own opinion. I don't know that if the agencies will agree to that or not.

Alicia Morgans: Well, I think that, at the end of the day, all we have is our own opinion, and we so value yours and really appreciate you using your worldly expertise from both sides of the pond to help us try to figure out how to think through this data. I sincerely appreciate your time and your expertise.

Cora Sternberg: Thank you so much, Alicia.