Niraparib Maintains Safety, Efficacy in BRCA+ Ovarian Cancer, Irrespective of Setting

Maintenance niraparib (Zejula) has been shown to result in a significant progression-free survival (PFS) benefit in patients with BRCA-mutated ovarian cancer following response to platinum-based chemotherapy, according to Kathleen Moore, MD, who added that the agent still has a favorable toxicity profile even when used in the frontline setting.

A recent analysis examined data from 3 phase 3 trials, PRIMA (NCT02655016), NOVA (NCT01847274), and NORA (NCT03705156) to gain insight into the overall safety and efficacy of niraparib in the treatment of patients with BRCA-mutated ovarian cancer. Results, which were presented during the 2021 ASCO Annual Meeting, demonstrated that maintenance treatment with the PARP inhibitor resulted in hazard ratios (HRs) for PFS of 0.40 (95% CI, 0.27-0.62), 0.27 (95% CI, 0.17-0.41), and 0.22 (95% CI, 0.12-0.39) in the PRIMA, NOVA, and NORA trials, respectively. Notably, this benefit was observed across all subgroups examined.

Across the trials, the treatment-emergent adverse effects of any grade that were most commonly reported in the overall population, irrespective of BRCA mutational status, included thrombocytopenia, anemia, neutropenia, and nausea.

“We didn’t see any big or meaningful differences in the toxicity profile when [niraparib was] used in the frontline [setting], which gives us quite a bit of confidence in incorporating [these agents] into this setting from a safety standpoint,” Moore said. “When we consider the sequencing of PARP inhibitors, the natural history of this disease, and what's going to happen next for many of our patients, we have to ask ourselves how we can situate someone [so that they receive] the best first-line therapy [possible]. How do we set them up for success later? This sort of analysis [supports the addition of] PARP inhibitors to the frontline [setting].”

In an interview with OncLive®, Moore, associate professor and gynecologic oncologist at the Stephenson Cancer Center at the University of Oklahoma College of Medicine further discusses data from a combined analysis of 3 trials examining niraparib in patients with BRCA-mutated ovarian cancer, the lessons learned in terms of safety, and other areas that are ripe for future exploration.

OncLive®: What is the role of niraparib in patients with advanced ovarian cancer?

Moore: Niraparib has multiple FDA indications, the most recent of which moves it into the frontline [setting], which is really where we believe PARP inhibitors have the highest efficacy and the biggest opportunity to transform some women into what we call the ‘cure fraction.’ This was based on the PRIMA study, which was led by Antonio González-Martín, MD, of Clinica Universidad de Navarraand Bradley J. Monk, MD, FACS, FACOG, of Arizona Oncology.

[The study] enrolled women who were in response to their platinum-based chemotherapy at first diagnosis and identified those who were at particularly high clinical risk. About 70% of [these women] were treated with neoadjuvant chemotherapy, about 35% had stage IV [disease], and about 30% only had a partial response to their chemotherapy. As such, this is a unique population of [patients with] advanced ovarian cancer.

Patients could have high-grade serous or endometrioid [cancer], and [the trial] allowed women with BRCA mutations. [The study] randomized [patients] to receive placebo or niraparib. Importantly, [patients were] stratified by the presence of homologous recombination deficiency [HRD], which is a tumor test that tries to assess tumors that have some inherent vulnerability in their ability to repair DNA. These are the tumors that are more likely to respond to platinum [chemotherapy], and more likely to respond to PARP inhibitor therapy. The primary end point for PRIMA was progression-free survival in the whole group, but also in that group of patients who were HRD.

In some exploratory analyses, they pulled out those with BRCA-associated cancers, those with BRCA wild-type but HRD-positive tumors, and then those with homologous recombination–proficient tumors and showed benefit [with niraparib] in all subgroups. Both primary end points were very positive [and] they [were] met; all [of the] subset analyses, were positive, as well. As such, [these data] resulted in an FDA approval for the use of niraparib following response to frontline chemotherapy in all [patients with] advanced ovarian cancer who were in response to chemotherapy. [This is] a very broad label that allows [us] to individualize the maintenance therapy that they would choose for [our] patients.

What was the design of the combined analysis that evaluated 3 niraparib studies?

This was really a safety analysis. We have quite a bit of cumulative data now for women who have been treated with niraparib either in the frontline with the PRIMA study or as a part of second-line maintenance. We have both the NOVA and the NORA studies, which are randomized, double-blind studies [that were done] in [patients with] platinum-sensitive, recurrent disease.

[This] very large population of patients also includes those with BRCA mutations, those without, those with HRD, and those without. As such, [this research] just gives us the opportunity to combine a large number of patients and look at them from a safety standpoint [to get] some approximations of any [safety] signals. [It also allows us to] more appropriately give an approximation of how safe PARP inhibitor use, specifically niraparib, is in these 2 populations.

What were some the results presented during the 2021 ASCO Annual Meeting?

PRIMA [examined niraparib] as frontline [treatment], while NOVA and NORA examined the agent] as second-line [treatment], both in the maintenance setting. The first thing to note is that no big difference in adverse effects [AEs] was observed in either setting. The safety profile is very consistent across both treatment settings where [we see] the class effects with PARP inhibitors is [comprised of] hematologic and gastrointestinal-related toxicities.

Thrombocytopenia is the most common hematologic toxicity [that we see], although [this is] declining with individualized dosing for niraparib. Anemia [is another toxicity] that we see across all PARP inhibitors, with about one-quarter of patients [experiencing this effect at a severity of] grade 3 or higher. [We also see] fatigue, nausea, dysgeusia, etc., are predominantly low grade, but relatively common [with these agents]. Over time, providers have become very facile at mitigating [these AEs] by setting good expectations with patients and [utilizing] preventative medication. [We saw] no new safety signals and very consistent efficacy across both settings in all 3 trials—especially amongst patients with BRCA-associated cancers.

What are the clinical implications of these data? What should be taken away from this research?

This combined analysis was looking at 3 relatively large studies of niraparib in the frontline and the recurrent setting in patients with BRCA-associated cancers. [The results] tell us a few things. PARP inhibitors work incredibly well in women with BRCA-associated cancers, maybe a little bit better in [those whose tumors harbor] BRCA2 [mutations compared with [those who have] BRCA1 [mutations], but it doesn't really change our management. BRCA-associated cancers really do benefit from PARP inhibitor use and the magnitude of benefit [with these agents] appear to be greatest in the frontline [setting], even though the hazard ratios may look similar in different settings. The emphasis here [has to do with] moving PARP inhibitors to the frontline, niraparib being 1 of the 2 [agents that are] currently approved [for use] in [this] setting. This is just a nice look at the magnitude of benefit in both settings and arguing for moving [the agent] forward [in the treatment journey]. That's the first take-home [message] here.

The second takeaway has to do with safety. There have been questions over time of whether women with germline BRCA mutations have a different safety profile. We've given PARP inhibitors to women with somatic mutations, and those who don't have any germline predisposition to PARP inhibitors at all. A variety of retrospective studies and some subset analyses have tried to parse this out with conflicting results, some [reporting] more hematologic toxicity, some [reporting] less. Again, this is a primary combined analysis, but [it does include] a large number of patients, [and it does] not demonstrate any new or worsened safety signals than what has previously been reported. This has also been borne out in more recent studies: there's not a higher safety risk for women with germline BRCA-associated cancers as compared with [those with BRCA] wild-type [disease]; they have the same risk.

Were there any specific findings regarding niraparib that were revealed by this analysis that had not been evident when the 3 trials reported out individually?

One of the key takeaways is that we don't see any big or meaningful difference in terms of the toxicity profile when you move PARP inhibitors to the frontline, as opposed to using it in the second-line [setting] and that's important. Safety is important in both settings, but it's important because in the frontline, we still have the potential to cure. Paclitaxel and carboplatin alone have an unacceptably low but present rate of long-term disease-free survival; hopefully, with PARP we're going to improve upon that. When you’re adding something to that frontline treatment setting that could have a negative effect in terms of an AE, [it is important] to avoid harming women during their frontline [treatment]. This is their opportunity to be potentially cured and this is the setting where they'll usually have their longest interval of time off of platinum-based chemotherapy. [As such,] what you use needs to be tolerable and can't demonstrate a negative impact on longevity, subsequent response to therapies, or overall survival.

Are there any remaining questions that ongoing efforts are being made to address?

The one thing that we didn't address because of the lack of long-term follow-up, is there may be a difference in acute myeloid leukemia [AML]/myelodysplastic syndromes [MDS]; however, that [remains to be seen]. This is something that we're [looking into] and requires longer follow-up. There has been a belief that the risk is higher in women with BRCA-associated cancers and that certainly looks in some studies [to be] true. However, recent meta-analyses are [evaluating] data on the lifetime risk for BRCA-associated cancer being more associated with AML and MDS with exposure to PARP as compared with wild-type [disease]. That story has yet to be told as we consider unanswered questions in this population.

One of the key [questions] is whether there is a higher risk of AML MDS in women with BRCA-associated cancers or BRCA germline mutations at baseline. [Does] PARP contribute to the development of AML MDS over the lifetime of women with and without BRCA mutations for ovarian cancer? Is their lifetime risk of developing AML MDS different whether or not they received a PARP [inhibitor]? We're actively looking at [addressing several questions] with many large studies. As these data mature, they will be an important piece to [this puzzle]. From a safety standpoint, that is one of the biggest questions that we need to answer, and I'm glad to see there's a lot of attention being paid to it.

Reference

1. Gonzalez-Martin A, Matulonis U, Korach J, et al. Niraparib efficacy and safety in patients with BRCA mutated (BRCAm) ovarian cancer: results from three phase 3 niraparib trials. J Clin Oncol. 2021;39(15):5518. doi:10.1200/JCO.2021.39.15_suppl.5518