Alicia Morgans: Hi, my name is Alicia Morgans and I'm a geo medical oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today, Dr. Kim Chi, who's a professor of medicine and a geo medical oncologist at the University of British Columbia. Thank you so much for being here with me today.

Kim Chi: It's great to be here. Thank you.

Alicia Morgans: Wonderful. I wanted to talk with you about a presentation that you gave at GU ASCO 2022 on the MAGNITUDE trial. Can you tell us a little bit about this study?

Kim Chi: Yeah (affirmative), I had the pleasure of being able to present this study on behalf of all the investigators and co-authors, and we're very proud of the study. Anyhow, the MAGNITUDE study is a phase three trial looking at the combination of niraparib plus abiraterone and Prednisone as first line treatment for patients with metastatic castration-resistant prostate cancer. Now what's a little bit different about this study is that we were trying to evaluate that combination niraparib, PARP inhibitor with abiraterone, acetate, and prednisone in patients with and without homologous recombination repair alterations.

So the design of the study was that it was a randomized double line placebo controlled trial. Patients were eligible if they had metastatic CRPC and had not had prior treatment for metastatic CRPC, except they could have had up to four months of abiraterone. And the reason we did this is that it allowed patients to get pre-screening for biomarker status, and I'll get to that in a minute. Patients could have also had prior treatment for metastatic castration-sensitive disease with taxing chemotherapy or AR inhibitors or non-metastatic CRPC with AR inhibitors.

So a very pragmatic design in terms of eligibility. So where this trial is important is that we were trying to really test and understand the hypothesis that niraparib and abiraterone, PARP inhibitor and an engine receptor access inhibitor could benefit either patients with biomarker positive disease, meaning having a homologous recombination repair alterations, such as BRCA2, or patients that didn't have an identified biomarker that were homologous recombination repair gene intact.

And so this is a key thing because really there's a hypothesis that PARP inhibitors only benefit patients with HRR gene alterations, but they could also benefit patients that don't have a gene alteration. So two cohorts were enrolled, biomarker positive, biomarker negative, and then subsequently randomized to receive either niraparib plus abiraterone, versus placebo plus abiraterone. So the key finding that we found is that in the biomarker negative patients, there was no benefit of niraparib plus abiraterone.

This was based on an early futility analysis, looking at the composite endpoint of PSA progression and radiographic progression, hazard ratio was 1.09, and based on that analysis, the Independent Data Monitoring Committee recommended stopping accrual in the biomarker negative arm. For the biomarker positive arm, the accrual completed as planned and roughly 200 patients were randomized to either arm and they were well balanced between the two arms.

Numerically, it was a little less in favor of the niraparib. There was more patients with ECOG Performance Status one, and there was more patients with visceral metastases. So for the primary endpoint, which was radiographic progression-free survival for patients with BRCA1/2, this was a pre-defined subgroup.

There was a statistically significant improvement in radiographic progression-free survival, hazard ratio was 0.47, and it was statistically significant. For the overall biomarker positive cohort that included BRCA1/2 alterations, but as well as others, including ATM, PALB2 and so on, there was also a statistically significant benefit for radiographic progression-free survival, hazard ratio, 0.27. And then as well, all the secondary endpoints were also in favor for the biomarker positive group for the combination of niraparib and abiraterone.

That included time to cytotoxic chemotherapy, time to symptomatic progression, time to PSA progression, the median was almost doubled and as well, objective response rates were almost doubled between niraparib and abiraterone versus abiraterone alone. I think an important thing that came out though, was that patients with BRCA1/2 alterations really did poorly. The radiographic progression-free survival in this group was 10 months and that's very short.

So I think we've recognized that these patients can have a poor prognosis, therefore, giving the combination treatment really improved that progression-free survival for those patients. Overall, the treatment was well tolerated. Adverse events were more, but it was within what we understand about PARP inhibitors, including some hematologic events, as well as nausea.

Overall, I think what MAGNITUDE shows us is that it's important to identify patients with homologous recombination repair gene alterations, and there's three reasons for that. One is prediction. So these patients are eligible for treatment with a PARP inhibitor and in this case, niraparib plus abiraterone is supported for helping these patients. Number two, it's prognostic, they seem to do poorly. And number three, there's certainly a risk for a hereditary cancer syndrome, especially with BRCA2 alterations.

Alicia Morgans: Absolutely. Well, congratulations on this, a phenomenal design, and I just want to point out how appreciative I am, and I'm sure that the patients are, that you had this futility design built into the original plan, that if you didn't see a signal in those biomarker negative patients, that you would close that part of the study, I think that's really smart and I commend you on that. I also am really impressed with the Adverse Event Profile and the tolerability there, and so glad that this seems to be a good approach in terms of an option for patients. Now in clinic, if you have these patients who are BRCA2 positive, as you said, and really they do have quite a poor prognosis as this study also demonstrates for us very effectively, are these patients, those that you're going to right off the bat, if they've progressed into mCRPC, are these patients uniformly going to be patients that you recommend the combination for?

Kim Chi: Well, it's not approved for that indication yet, but if it does get approved for that indication, definitely. I think those patients are at high risk for progression. There is a high risk that they may not even respond to abiraterone as a first line therapy. So I would want to go in with a combination right away. Currently we have olaparib for these patients when they progress after an AR pathway inhibitor, but what's important is that we recognize these patients very early on. So really an emphasis to the community that if a patient has metastatic disease, they should really get testing as soon as possible to see if they harbor one of these homologous recombination repair gene alterations.

Alicia Morgans: Absolutely, germline and somatic testing, both very important. As you also think about other studies, the PROpel study, for example, that was presented actually side by side with the MAGNITUDE study, what are similarities, differences that you've noticed that you could point out for viewers?

Kim Chi: Well, it was a great session. We have two trials, evaluating a combination of PARP inhibitor plus abiraterone for patients with Metastatic CRPC showing benefit. Both trials were positive, so that's great. And in particular, one of the important similarities is that it demonstrated, both trials, that patients with these homologous recombination repair alterations do badly. Furthermore, that the combination really helps them do much better. So I think that's a similarity and that's an important one and an important take home lesson that we need to identify these patients with these alterations, and they're good candidates for PARP inhibition.

I think where the controversy is, is the patients that are homologous recombination repair gene alteration negative, so the biomarker negative population. So in MAGNITUDE we didn't see a benefit, in PROpel we may be seeing a benefit, but we need to see more data from the PROpel study in terms of how they were tested for homologous recombination repair and those other details. So I think the jury's still out on that and as well, for both studies, I think we'd all like to see an overall survival advantage emerge and the followup's just too early for that. So I think they'll be looking forward to more data on this.

Alicia Morgans: Absolutely. Well, thank you so much for sharing your expertise and congratulations again to you, to the team, to the patients, answering these questions so efficiently, very quickly, because it seems like just yesterday that this study launched, and again, congratulations on the very efficient design that closed that piece that did not seem to show an efficacy benefit there. So thank you for your time and for your expertise.

Kim Chi: Thank you.