Eleni Efstathiou, MD, PhD, expands on the updated interim data from the MAGNITUDE trial and sheds light on the utility of PARP inhibitor combinatorial strategies in patients with mCRPC and HRR gene alterations.
Niraparib (Zejula) plus abiraterone acetate (Zytiga) and prednisone continued to provide a substantial clinical benefit for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations, as seen in the second interim analysis of the phase 3 MAGNITUDE trial (NCT03748641). The data underscore the need for genomic testing in those with this disease, according to Eleni Efstathiou, MD, PhD, who added that for those who are found to harbor BRCA mutations, a combination strategy should likely be considered.
Initial results from the trial demonstrated a significant improvement in radiographic progression-free survival (rPFS) by blinded independent central review (BICR) with the addition of niraparib vs abiraterone and prednisone alone in all patients who were HRR biomarker positive (HR, 0.73; 95% CI, 0.56-0.96; P = .0217).1 The rPFS improvement derived with the niraparib combination was particularly pronounced in the subset of patients whose tumors harbored BRCA1/2 mutations (HR, 0.53; 95% CI, 0.36-0.79; P = .0014).
Data from the second interim analysis was presented at the 2023 ASCO Genitourinary Cancers Symposium. With a median of 26.8 months of follow-up, niraparib plus abiraterone and prednisone resulted in a 45% reduction in the risk of progression or death vs abiraterone/predisone alone.2 The regimen was also found to prolong time to symptomatic progression (TSP) and time to initiation of cytotoxic chemotherapy (TCC) in the HRR-positive and BRCA-mutated populations.
Based on data from MAGNITUDE, a new drug application (NDA) seeking the approval of niraparib plus abiraterone acetate and prednisone in BRCA-positive mCRPC was submitted to the FDA on March 1, 2023.3
“What is great about the second interim analysis [is that] we show the consistent benefit with giving abiraterone plus niraparib and prednisone to men with BRCA mutations or HRR alterations,” said Efstathiou, section chief of Genitourinary Medical Oncology at Houston Methodist Oncology Partners, Houston, Texas, in an interview with OncLive®.
In the interview, Efstathiou expanded on the updated interim data from the MAGNITUDE trial and shed light on the utility of PARP inhibitor combinatorial strategies in patients with mCRPC and HRR gene alterations, including BRCA mutations.
Efstathiou: This year is all about PARP inhibitors. During the 2023 Genitourinary Cancers Symposium, we’ve seen some new data [from the second] interim analysis of the MAGNITUDE trial. Initial data [from the trial] was previously reported and will soon be published in the Journal of Clinical Oncology.
Patients enrolled in the trial underwent a very rigorous biomarker prescreening. This is done by looking at both a 9-gene panel on a liquid biopsy and in a tissue biopsy. For a patient to be considered HRR negative, both assays needed to be negative. Patients [were then] enrolled in either an HRR-positive or -negative cohort. Each cohort was randomized 1:1 to abiraterone plus prednisone plus niraparib vs abiraterone plus prednisone plus placebo. We prespecified that we were going to hold [data] accrual once we hit the 200-patient mark in the HRR-negative [cohort]. Then we looked at these patients to see if [there was] an initial benefit in PSA and rPFS and saw no obvious big benefits.
We [decided to put a] hold on the HRR-negative [cohort] and continue with the HRR-positive [cohort]. We already knew from previous data, that HRR-positive mCRPC is an aggressive disease and has a poor prognosis. [However], some benefit has been shown with single-armed PARP inhibition [in this population]. About a year ago, we reported an initial benefit in the HRR[-positive] subgroup and in the BRCA subgroup, [which] is of special interest. This year, we added another 8 months to the subgroup analysis.
We reported the updated primary end point of rPFS by blinded independent central review, as well as secondary end points.When we look at the outcomes for patients with advanced metastatic disease, [in whom] initial hormonal therapy [has failed], we must be objective. That is why we choose rPFS [as the primary end point]. We also have a keen interest in [understanding] what [other benefits] the patient [derives] from this treatment. [This includes] whether there will be a delay in their symptoms, a delay in subsequent treatments that may be toxic, such as chemotherapy, whether there will be a delay in pain interference, and some protection of their quality of life. [We want to know whether it provides] an overall survival benefit, as well. Finally, one of the most important parameters is [whether the regimen] is safe. It is important to know these things in the clinic.
The BRCA-positive subgroup is arguably the one of the most aggressive subgroups in prostate cancer. We have clear, retrospective data to suggest that these men performed very poorly on standard-of-care chemotherapy or novel hormonal agents. We designed the trial to [focus heavily] on our statistics from that initial BRCA-positive subgroup.
We went a step further in this analysis by specifically looking at the abiraterone plus placebo arm. Men [in this cohort] have an rPFS of 10.9 months. If you compare these men with an unselected group [from] one of the legacy trials of abiraterone, [the phase 3 COU-AA-302 study (NCT00887198)], there’s a big difference in rPFS. In these [patients who received] abiraterone plus placebo, the [rPFS is] 10.9 months vs 16.5 months in the legacy [study]. [However], data from the 8-month follow-up [showed that] that rPFS in the abiraterone plus niraparib arm in this BRCA-positive subgroup is now reaching a median of 19.5 months; this is almost double [the rPFS reported] in the control arm and translates to a 45% reduction in the risk of progression or death if a patient has a BRCA mutation. This [result is] big. You’re looking at men who are not expecting a great outcome, and suddenly you’ve doubled [their rPFS].
Looking at an objective primary end point is one thing, but [we need] support from secondary end points. If I tell these men [that they will] do very well [on this regimen because they will] not progress on [their] scans for [a certain] amount of time, and don’t inform them about how [soon] this disease [will start to] interfere with their life, I’m not telling them what they need [to know]. The secondary end points [in our study], such as TSP and TCC are all supportive of the primary analysis.
The overall survival data are immature, which means that not a lot of our patients have passed away [while in] the trial. [Although] that’s something to be thankful for, [we still] had to find ways to look at the [survival] trends. We used the inverse-probability-of-censoring weighting [IPCW] analysis to correct for imbalances in baseline characteristics or from subsequent treatments of our patients. The moment a patient progressed, we immediately provided the investigators with information on [whether] the patient was on a PARP inhibitor or not. [This allowed the] patient to get another off-study PARP inhibitor. With that in mind, the IBCW analysis is already showing a clear trend [toward] improved OS. We’re [eventually] expecting to see [fully mature] OS data in the final analysis.
One important consideration when it comes to treating [these patients with] prostate cancer is that they’re not as fit. [This is] because they’ve been exposed to prior androgen deprivation [therapy], and because they have other comorbidities. It falls upon us, as physicians, to be extra careful [when] monitoring them. When [determining a] combinatorial strategy, you must consider that a PARP inhibitor does add some toxicity; this is shown across all trials. [These toxicities include] myelotoxicity and anemia, followed by fatigue and other gastrointestinal events.
One promising readout from this second analysis [is that] no new safety signals [were seen] with longer follow-up. That [means] that clinicians can see what’s coming up front and can course correct.
At the meeting, we saw some amazing reports on PARP inhibitor treatment in CRPC. [There has] been some debate [regarding whether] these trials [reached] different [conclusions]. Even though they were done completely differently, I would argue that all trials are pointing to one [takeaway]: If you have a patient whose tumor is harboring a BRCA mutation, you [should] consider combinatorial strategies. The risk of [this strategy] can match the outcome. There’s nothing better than reproducibility in clinical research, and we’ve got three major trials all showing the same [takeaway].
We’ll need to troubleshoot other trials that showed some degree of benefit in patients who do not harbor [a BRCA] alteration. The MAGNITUDE trial was not designed for this purpose. Our next research question is how to [identify] these men and figure out who else needs the treatment.
We [already] learned that [patients] who have germline alterations, such as BRCA mutations, need special care and attention. If we’re learning anything about the future, it is [that] we need to pursue further education in the field. [We should] reach out to every community practice and [inform] them that we now have the guidelines, reimbursement, and [lowered] costs [to support] system-wide germline and somatic testing for these patients. It’s a service not just to them, but to their families. It’s [important to understand] that we need genomic testing information on a patient’s chart in addition to the usual scans, bloodwork, and pathology [information].
[Next, we need to ask] how we can serve these men better. In medicine and oncology, we know that the earlier [we can] nip this in the bud, the better [the outcomes are]. The next big question is [whether] it makes sense to target these specific mutations in a [later] setting. That’s a big question because there’s long-term exposure to these drugs [in this space]. I hope that efficacy and safety [information on this] is coming in a couple of years.
This year’s meeting was very rich in data. We saw some great findings coming not just from the MAGNITUDE analysis, but also [data] from the [phase 3] TALAPRO-2 [NCT03395197], PROpel NCT03732820], and TRITON-3 [NCT02975934] trials. It’s wonderful to see [us starting to] resolve the puzzle [of leveraging PARP inhibition in mCRPC].
Editor’s Note: Dr. Efstathiou reports serving as a consultant or in an advisory role, receiving research funding, and serving on the speakers’ bureau for Astellas Pharma, AstraZeneca, Merck Sharp & Dohme, Myovant Sciences, Pfizer, Sanofi.