Niraparib Makes an Impression in the Frontline Setting of Advanced Ovarian Cancer

Kathleen Moore, MD

The PARP inhibitor niraparib (Zejula) is currently approved as maintenance therapy for patients with advanced ovarian, fallopian tube, or primary peritoneal cancer after front-line chemotherapy as well as in the recurrent setting. Research presented at the 2021 American Society of Clinical Oncology’s Annual Meeting suggests that efficacy and survival can be improved by moving niraparib to the frontline setting for patients with BRCA-mutated cancers.

An analysis of the PRIMA/ENGOT-OV26/GOG-3012 (PRIMA; NCT02655016), ENGOT-OV16/NOVA (NOVA; NCT01847274), and NORA (NCT03705156) trials aims to answer the question of whether frontline niraparib treatment can improve survival in these patients. In total, 526 patients across the 3 trials with a BRCA mutation were included in the analysis.

The PRIMA study, which looked at niraparib in the frontline setting, found that the progression-free survival (PFS) rate was 22.1 months for those who received niraparib and 10.9 months for those who received a placebo. In NOVA, which examined the agent in the later-line setting, the PFS was 21.0 months for those who received the agent and 5.5 months for those who received a placebo. In NORA, which examined the agent in the later-line setting, the PFS was not reached for patients who received niraparib and was 5.5 months for those who received a placebo.

In an interview with Targeted Oncology, Kathleen Moore, MD, the director of the Oklahoma TSET Phase 1 Program and associate professor in the section of gynecologic oncology at the University of Oklahoma College of Medicine discusses the effects of niraparib for ovarian cancer in the earlier-line setting in more detail and how she anticipates it will change clinical practice. 

TARGETED ONCOLOGY: Can you discuss the recent FDA approval of niraparib population and what its significance has been for these patients?

MOORE: Niraparib has multiple FDA indications, the most recent of which moves it into the frontline, which is really where we think 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 and what it did was take women who were in response to their platinum-based chemotherapy at first diagnosis. It identified women who had particularly high clinical risk in this study. Seventy percent of them were treated with neoadjuvant chemotherapy, about 35% were stage VI, and about 30% only had a partial response to their chemotherapy. So, it is a very unique population of advanced ovarian cancer. They could have high-grade serous or high-grade endometroid [disease] and of course, it allowed women with BRCA mutations, but randomized them to receive placebo or the niraparib.

The study was stratified by the presence of what we call homologous recombination deficiency (HRD), which is tube test at least for now 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, and importantly, more likely to respond to PARP inhibitor therapy. The primary end point for PRIMA was PFSin the whole group, but also in that group of patients who were homologous recombination efficient. Then, there were some exploratory analyses where they pulled out those BRCA-associated cancers, those with BRCA wild-type, but HRD tumors, and then those are what we call homologous recombination proficient unknown tumors.

The study showed benefit in all subgroups. So, both primary end points were very positive and met their statistical threshold. This resulted in an FDA registration approval for use of niraparib following response to frontline chemotherapy in all advanced ovarian cancer patients who again, were in response to chemotherapy. So, it’s a very broad label that allows physicians to kind of individualize the maintenance therapy that they would choose for their patient.

Can you briefly discuss the design of this analysis of the 3 studies together?

What we were looking at was a safety analysis. So, we have quite a bit of cumulative data now for women who have been treated with niraparib after the frontline in the PRIMA study, or as a part of second-line maintenance. We have both the NOVA (NCT01847274) and the NORA (NCT01473641) studies, which are randomized double-blind studies in platinum-sensitive, recurrent disease. So, this population of patients includes very large group of patients with BRCA mutations, those without, those HRD, and those without HRD. We have the opportunity to combine a large number of patients and look at them from a safety standpoint, and just give some approximations of signals. More appropriately, we can give an approximation of how safe PARP inhibitor use or niraparib is, in these 2 populations.

What were the results that you found?

If you look at the 2 treatment settings, the first thing to note is that there's really not any big difference in the adverse events that we're seeing in either setting. The adverse event profile is very consistent across both treatment settings where we see not unexpectedly, the class effects with PARP inhibitors is hematologic and gastrointestinal-related toxicities, and that's what we see here with thrombocytopenia being the most common hematologic toxicity, although declining with individualized dosing for niraparib. Anemia, which we see across all PARP inhibitors with about a quarter of patients experiencing grade 3 or higher. Then we see fatigue, nausea, dysgeusia, and other toxicities that are predominantly low grade, but are relatively common. Over time providers have become very fast at mitigating the drug toxicities with good expectations as well as preventative medication. So there were really no new safety signals and a very consistent efficacy signal across both settings and all 3 trials, especially amongst patients with BRCA-associated cancers.

What did these findings imply about niraparib in this patient population? Are there still any unmet needs despite this practice-changing data?

This combined analysis was really looking at 3 relatively large studies of niraparib in the frontline and the recurrent setting amongst patients with BRCA-associated cancers, and it tells us a few things. One thing is we all know PARP inhibitors work incredibly well amongst women with BRCA-associated cancers, maybe a little bit better in BRCA2 than BRCA1, but it doesn't really change our management. BRCA-associated cancers do benefit from PARP inhibitor use, and I think it's important to mention the magnitude of benefit of the PARP inhibitor appears greatest in the frontline, even though the hazard ratios may look similar in different settings, the magnitude of the benefit is in the frontline. That's why the emphasis here is on moving PARP inhibitors to the frontline, niraparib of course, being 1 of the 2 that's currently approved in the frontline setting.

The second take-home message is surrounding the safety. There have been mentions over time of whether women with germline, especially BRCA mutations, may have a different side effect profile. We've given PARP inhibitors to women with somatic mutations, and of course, women that don't have any germline predisposition to PARP at all. And there have been a variety of retrospective studies and some subset analyses that have tried to parse this out with conflicting results. Some say more hematologic toxicity, some say less. Again, this isn't a primary analysis, it's a combined analysis, but it is a large number of patients that don't demonstrate any new or worse safety signals than what has been previously demonstrated. That's been borne out in more recent studies which I think is very consistent with other messages that we have seen that there's not a higher safety risk or safety profile for women with germline BRCA-mutated cancers as compared with those who have wild-type disease. 

The one thing that we really didn't address with this particular poster, because of the lack of follow up, is there may be a difference in acute myeloid leukemia or myelodysplastic syndrome. It's something that we're following, and that just requires longer follow up.

What is the greatest finding that came out of examining these 3 trials that was not evident when looking at them individually?

We're looking at these 3 relatively large studies, we're talking about approximately 1500 women who participated in PRIMA in the frontline, NOVA and NORA, in the second-line. About 1000 patients were treated with niraparib, and I think 1 of the takeaways is that we don't see any big or meaningful difference in terms of the toxicity profile when you move PARP to the frontline setting, as opposed to using it in the second-line setting or as maintenance. And that's important. Safety is important in both settings, but it's important because in the frontline, we still do have the potential to cure women. Carboplatin and paclitaxel alone have an unacceptably low but present rate of long-term disease-free survival, 7 to 10 years of 15% or advanced stage epithelial cancer and hopefully with PARP inhibitors, we're going to improve upon that.

When you're adding something to that frontline setting that could have a negative effect in terms of an adverse event that could counter that, you have to be careful because you definitely didn't want to harm women on their frontline therapy. What you use needs to be tolerable and really can't demonstrate negative impact on longevity, subsequent response to therapies, or overall survival (OS). So, we can't really comment in any of these, except for NOVA, which did preliminarily present their OS data, the other 2 are premature. What we can say is that we don't see any big or meaningful differences in the toxicity profile when we use it in the frontline setting. And that gives us quite a bit of confidence in incorporating this and other PARP inhibitors into the frontline setting from a safety standpoint.

From a multidisciplinary approach, what is your key takeaway from this trial? 

We've had dramatic shifts in either the standard of care if you're talking about parameters for BRCA and in my opinion, HRD tumors, or additions to acceptable standard of care with bevacizumab (Avastin) changes in surgery. The treatment paradigm for the first 2 regimens of therapy for epithelial ovarian cancer has really evolved significantly in the last 2 to 3 years. 

Women who are diagnosed with advanced ovarian cancer deserve an expert team, and those team will going to look very different. Those teams can be sort of 1 person who does surgery and understands the therapeutic side well enough to really incorporate molecular diagnostics and treatment selection in the frontline and in the second-line with evidence-based practice behind them. There could also be teams of surgical oncologists, or gynecolgic oncologist, and medical oncologists who are experts at the therapeutics. Whatever that team looks like, it can all provide exceptional care to women. But that's the team that women deserve so that we can incorporate PARP inhibitors at the right time for the right patient, which is really frontline, at least for BRCA and HRD-positive disease.

I think we can argue that this is probably 1 of the highest unmet needs in our field is how best take care of women with tumors that are homologous recombination proficient. This just adds to that breadth of knowledge that we can disseminate to academic and community providers who are taking care of our patients and allow them to make the best decisions for their patients at the right time.

_Reference:

_{Martin AG, Matulonis UA, 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}