In an interview with Targeted Oncology, Ursula A. Matulonis, MD, discusses results from further follow-up of patients with ovarian cancer treated in the ENGOT-OV16/NOVA.
Niraparib (Zejula), an oral PARP 1/2 inhibitor first demonstrated improvement in progression-free survival (PFS) compared to placebo in patients with platinum-sensitive, recurrent ovarian cancer in 2016, according to the primary analysis of the of the ENGOT-OV16/NOVA study (NCT01847274) published in the New England Journal of Medicine.
The randomized study enrolled 553 participants, and assessed PFS as the primary outcome. Secondary outcomes included time to first subsequent therapy, chemotherapy-free interval, PFS2, overall survival (OS), time to second subsequent therapy, and change from baseline in functional assessment of cancer therapy-ovarian symptom index.
During the study, patients were randomized 2:1 to received niraparib or placebo once daily. Patients were split in to 1 of 3 cohorts: patients with a germline BRCA (gBRCA) mutation, patients with no germline BCRAmutation with homologous recombination deficiency (HRD)-positive tumors, and patients with no germline BRCA mutation.
Of the 553 patients enrolled, 203 were assigned to the gBRCA cohort, of which 138 received niraparib and 65 received a placebo. The remaining 350 patients were in the non-gBRCA cohorts, of which 234 were assigned the study drug and 116 a placebo. In the gBRCA cohort, the median PFS was 21.0 months versus 5.5 months (HR, 0.27; 95% CI, 0.17-0.41). In the non-gBRCA HRD+ group, it was 12.9 months vs. 3.8 months (HR, 0.38; 95% CI, 0.24-0.59). In the overall non-gBRCA group, it was 9.3 months vs. 3.9 months (HR, 0.45; 95% CI, 0.34-0.61; P <.001). The most common grade 3 or 4 adverse events (AE) reported in the niraparib group was thrombocytopenia (33.8%), anemia (25.3%) and neutropenia (19.6%). AEs were managed with dose modifications.
In an interview with Targeted Oncology, Ursula A. Matulonis, MD, the chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute discusses results from further follow-up of patients with ovarian cancer treated in the ENGOT-OV16/NOVA, which she recently presented the Society of Gynecologic Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer.
TARGETED ONCOLOGY: Can you briefly recap the initial findings from the Nova study?
MATULONIS: This study, which was originally published in the New England Journal of Medicine in 2016, enrolled patients who were either germline BRCA mutated, or non-germline BRCA mutated. They were high-grade tumors, predominantly high-grade serous cancers, advanced cancers, or recurrent platinum-sensitive cancers. These patients had to have a cancer response to their penultimate platinum but also their most recent platinum to gain entry into the trial. And then once their cancers did show either a complete response or partial response to chemotherapy, they were randomized 2:1 to either niraparib or placebo. And in both of the 2 independent cohorts of patients in the germline BRCA mutated group, or the non-germline BRCA mutated group, there was a significant improvement in PFS, mostly seen with the hazard ratio 0.27 in the patients with a germline BRCA mutated state or even in the non-germline BRCA-mutated state, and that hazard ratio is 0.45.
TARGETED ONCOLOGY: During your presentation, you mentioned that other PARP inhibitors hit the market and lead to discontinuations. Can you discuss those other PARP inhibitors and how they have shifted the treatment paradigm?
MATULONIS: Currently, at least in the United States and certainly increasingly worldwide, there are 3 PARP inhibitors that are FDA approved for ovarian cancer, and those are niraparib, olaparib (Lynparza), and rucaparib (Rubraca). So exactly in this situation for patients with recurrent platinum-sensitive ovarian cancer in the maintenance setting, often your PARP inhibitors have essentially overlapping and identical FDA approval. So as long as the patient's cancer is in response to platinum-based chemotherapy, she has recurrent disease, she can use a PARP inhibitor as maintenance therapy post chemotherapy. Once her blood counts come back up and she's in remission, she can receive one of those 3 PARP inhibitors as maintenance, and that's until either toxicities or progression. So unlike in the patients with newly-diagnosed cancer, where there's a set point of 2 years in the recurrent population in the NOVA, SOLO2 (NCT01874353), and ARIEL3 (NCT01968213) trials, patients continue on PARP inhibitors until progression or toxicities. There are other FDA approvals in the recurrent setting for each of these 3 PARP inhibitors and that's as standalone treatment for more heavily, pretreated BRCA mutated ovarian cancer and niraparib has the additional approval of an HRD cancer that's platinum sensitive.
TARGETED ONCOLOGY: For SGO 2021, you presented the long-term follow-up PFS2, OS, and safety results. Can you discuss those findings?
MATULONIS: I talked about these different kinds of secondary endpoints, PFS2, OS, and safety. As I pointed out during my SGO presentation, the trial was not powered for OS. And for PFS2, we continue to see a PFS2 benefit in both the germline BRCA-mutated patients as well as the non-germline BRCA2-mutated patients.
For overall survival, 3 issues come up for OS. One is that the trial is not powered for OS. Secondly, there are patients who switched over. At least 25% in the placebo arms crossed over, it's probably even more because of some missing data. So, it's possible that up to 50% in the placebo arm actually crossed over to PARP inhibitor. And then thirdly, there's missing data. So, if patients ended up withdrawing from the trial, they were not followed, and that tried to be corrected. We were able to capture about 50% of that missing data. But the bottom line is based upon the survival analyses that were done in patients who were non germline BRCA, we did not see an OS benefit for using niraparib. In the germline BRCA-mutated population, there was a trend of approximately 9.7 months in favor of niraparib despite the crossing over and the missing data. So, there was some benefit there, and we know that those are the folks who are going to really receive the most benefit from a PARP inhibitor.
With regards to safety, most of the hematologic toxicities occur in the first year. As clinicians know, you follow blood counts very carefully, and especially with niraparib. The package insert says patients need to have weekly blood counts checked, looking specifically neutrophil count, red blood cell counts, their hemoglobin hematocrit and then platelets and then adjust accordingly. There's also a weight in platelet-based dosing as well. Once that first year comes and goes, patients are typically on a very stable dose of the drug and the toxicities are well mitigated. In terms of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) , there was a higher rate in the patients who have an underlying germline BRCA mutation compared to the non-germline BRCA group. And that's regardless of whether they received the PARP inhibitor or not.
TARGETED ONCOLOGY: For those cases of thrombocytopenia, anemia and neutropenia, were there any other strategies used to minimize these toxicities in 1 to 2 years? Or was it just dose reduction?
MATULONIS: In the NOVA study, there was not a predesigned criterion for tailoring the dose of either 300 versus 200. It was in the radar analysis that was published, subsequently to the primary results, showing that if patients were less than 77 kilos, or have a platelet count of 150 or less, then they should probably be started at 200 milligrams, versus the alternative for patients who were more than 77 kilos and had a platelet count of 150 or greater than they could go on and 300. That individualized dosing was eventually brought into the PRIMA trial (NCT02655016), not initially, but as an amendment. And that's actually written into the FDA package insert for niraparib, especially around upfront dosing. But I do think that for patients who are recurrent, and these patients are going to be more heavily pretreated, that it's really important for clinicians to understand they need to take to pay attention to the weight-based and the platelet-based dosing.
TARGETED ONCOLOGY: What is your key takeaway from this analysis?
MATULONIS: I think for the NOVA study, the initial PFS results do show impressive data for both the germline BRCA-mutated patients as well as a non-germline BRCA-mutated patients. What I showed at SGO is PFS2 continues to show that improvement in both cohorts. For OS, we showed that there's no benefit for for patients in the non-germline BRCA-mutated group for receiving niraparib. In the germline BRCA-mutated group, there was a trend towards OS improvement for the germline BRCA-mutated patients of about 9.7 months. And with regards to safety, I think that it's really important to use the weight and platelet-based dosing. Then for patients who have underlying germline BRCA-mutated ovarian cancer, there's a higher risk of AML and MDS that approached around 3.5% here. That higher risk is irrespective of whether patients receive a PARP inhibitor or not. So, there's an intrinsic increase in susceptibility of women who have germline BRCA mutations to developing AML and MDS, and that's acquired because of prior chemotherapy, as well as the use of PARP inhibitors.
Mirza M, Bradley M, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016; 375(22):2154-2164. doi: 10.1056/NEJMoa1611310