Niraparib Plus Abiraterone Acetate/Prednisone Shows Potential as Frontline Option for HRR Gene–Altered mCRPC

Niraparib (Zejula) plus abiraterone acetate (Zytiga) and prednisone showed encouraging efficacy in the frontline treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) mutations, according to Eleni Efstathiou, MD, PhD, who added that although the combination appears to be tolerable, with the addition of a PARP inhibitor, it is important to monitor patients for select toxicities.¹

Data from the phase 3 MAGNITUDE trial (NCT03748641), which were presented during the 2022 Genitourinary Cancer Symposium, showed that at a median follow-up of 18.6 months, the niraparib combination resulted in a 47% reduction in the risk of disease progression or death in patients harboring BRCA1/2 mutations, and a 27% reduction in the risk of disease progression or death in all patients with HRR gene alterations compared with abiraterone acetate and prednisone alone.

“With the addition of niraparib, we need to watch out for further decline in hemoglobin when monitoring these patients,” Efstathiou said. “There was an important delta that we need to focus on because these men are prone to other events and may need some support. We should not leave that out in our regular monitoring. The same thing applies to thrombocytopenia.”

In an interview with OncLive^®, Efstathiou, section chief of Genitourinary Medical Oncology at the Houston Methodist Oncology Partners, discussed the combination of niraparib and abiraterone acetate and prednisone in patients with mCRPC and HRR gene alterations, results from MAGNITUDE, and next steps for research.

OncLive^®: What was the rationale for the MAGNITUDE trial?

Efstathiou: MAGNITUDE was primarily designed to interrogate the question of whether combining a PARP inhibitor with an enhanced androgen-signaling inhibitor—an androgen biosynthesis inhibitor, in this case, abiraterone acetate—would augment the impact of either of these 2 agents alone. We had some background preclinical data to support that notion.

What was the eligibility criteria for the trial?

The trial was mainly prioritized for men who harbored either germline or tumor somatic events aligned with DNA damage repair [DDR] deleterious mutations. [The trial] also included a smaller component: a series of men who did not harbor such mutations, to look for a preliminary signal in those [patients with] wild-type DDR.

Specifically, patients who were included in the trial had to have received initial treatment for hormone-naïve prostate cancer [that had failed]. Those patients had then progressed to mCRPC but had not received any other treatment in that disease setting. [Patients] were primarily selected a priori, based on the presence of a HRR mutation.

[Approximately] 35% to 40% of the cohort was designed to have BRCA1 or BRCA2 mutations. That is an important consideration, because we know they are the common mutations, and we already have data to support that BRCA2 mutational status is more susceptible to these treatments. Importantly, these men may have received chemotherapy in the hormone-naïve setting, but not in the CRPC setting.

What were the methods used in the trial?

The study design of the trial was straightforward. We identified men who had an HRR mutation, then we randomized them 1:1 to receive what we know to be an active agent, abiraterone acetate, plus prednisone, while continuing on their androgen deprivation therapy [ADT], or abiraterone acetate plus niraparib. Since [the trial] was double-blinded, the abiraterone acetate–alone arm did include placebo.

Then, the patients were followed with predetermined times to reimaging until there was progression by imaging criteria and independent review. Of course, we would like to see investigator-based reviews be aligned, but it is important to include that we had independent review of progression by imaging as our primary end point. Another important detail is that we allowed men who had already initiated abiraterone acetate in that setting [to participate], if it was within 4 months of enrollment and initiation of treatment.

What were the key efficacy findings?

The results [were] in line with what was anticipated from the basic science. We expected, and we already had a first signal in far-advanced disease, that niraparib would be an active agent in men with DDR mutations. We saw that when [niraparib was] combined with abiraterone acetate plus ADT vs abiraterone acetate plus ADT alone, [rPFS] was much more improved as an outcome by a statistically and clinically significant difference between the 2 [arms].

This was also reproduced in all secondary end points, except for overall survival, which has not yet met maturity. We will have to wait [to learn more about that, since] not enough events have occurred [yet].

[I should note that this was a kind of] 3-tier result analysis. Once we had accrued 200 men with no evidence of such mutations predefined, then we did a futility analysis to look at whether these men had a significant benefit. Early in the study, we did not see that significant benefit. As such, that cohort was aborted, and we did not accrue further.

When we focused on the [patients harboring] HRR-positive deleterious mutations, we saw that if we focus on the BRCA2 subset alone, you get this statistically and clinically significant outcome as a primary end point. However, [I believe that] when you look across the group, we are soon going to see interesting data on gene-by-gene analyses that [will be] quite compelling.

What should be known in terms of safety?

What was surprising was to see was that the tolerability [of this approach] was acceptable. The safety profile was better than I had expected. However, looking carefully at the safety profile [and the data that were] presented, we need to keep in mind that we mainly want to focus on the delta. We have used abiraterone acetate, and we understand there are cardiovascular implications. However, now we need to learn how to use PARP inhibition.

When it comes to cardiovascular events, we did not see any difference at this time, which is a very good thing. Another aspect that we need to focus on is the more subjective findings, such as the extent of fatigue that 2 agents combined may add. This will be more evident in real-world practice. We must always remember that when we put the patients on trial, we have criteria that are stringent about their physical condition or performance status. [There will be] some more information to come, but the combination seems safe, as long as we monitor patients well.

What are the clinical implications of these data? What should your colleagues take away from this research?

We have come a long way. [We have gone] from the introduction of an agent such as abiraterone acetate in our clinics, to introducing more precise targeted agents in combination with androgen signaling inhibition. We have been taking these steps forward over the past 2 years with applying assays that [help us] determine how to better target this disease, while always taking into consideration the patient and their safety. That is what we like to call the therapeutic index: having a good ratio of efficacy and safety. Overall, we are making progress.

My cautionary statement [would be that] sometimes, we try to oversimplify, and we try to make [certain approaches] accessible to everyone. I would disagree with that notion. Many of us who participated in this trial were adamant about being precise in determining the patient cohort that will derive the maximum benefit [from this combination].

We are now met with a question: Are we going to persist on following the precision medicine approach and reach improvement in both efficacy and safety [outcomes], or are we going to revert to a more agnostic approach? [I do not have an answer for this, but] many variables will come into play. We will listen to what the FDA says, and we will take it from there.

What are the next steps for research?

The next big question [will focus on whether we] can make a difference in the lives of men who are diagnosed with metastatic hormone-naïve prostate cancer who harbor such mutations. We know that such a trial is ongoing. Moreover, can we introduce a trial design where we include men with locally advanced prostate cancer who harbor such mutations? We know that men who harbor such mutations, whether germline or somatic, have a grim prognosis. As long as we are able to identify it [early on], and what is why I am a big proponent of early genetic testing, then we can target it. This is the future, and it might just lead to an incremental change and cure. I know I am saying a big word, but that is how we make things happen.

Reference

1. Chi KN, Rathkopf DE, Smith MR, et al. Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2022;40(suppl 6):12. doi:10.1200/JCO.2022.40.6_suppl.012