Antonio Gonzalez-Martin, MD
Frontline maintenance therapy with the PARP inhibitor niraparib (Zejula) improved median progression-free survival (PFS) by 5.6 months compared with placebo for patients with newly diagnosed, advanced ovarian cancer who responded to platinum-based chemotherapy, according to findings from the phase III PRIMA study presented at the ESMO Congress 2019 and simultaneously published in the New England Journal of Medicine
In the overall population of the PRIMA study, the median PFS in the niraparib arm was 13.8 months compared with 8.2 months in the placebo group, representing a 38% reduction in the risk of progression or death with the addition of the PARP inhibitor (HR, 0.62; 95% CI, 0.50-0.76; P
<.001). In patients with tumors that tested positive for homologous recombination deficiency (HRD), the median PFS was 21.9 months with niraparib compared with 10.4 months for placebo (HR, 0.43; 95% CI, 0.50-0.76; P
“Niraparib therapy in patients with advanced ovarian cancer provided a clinically significant improvement in PFS after response to first-line platinum-based chemotherapy in all patients," said study author Antonio Gonzalez-Martin, MD, from the Clinica Universidad de Navarra. "Niraparib is the first PARP inhibitor to demonstrate benefit in patients across biomarker subgroups after platinum-based chemotherapy in frontline, consistent with prior clinical studies of niraparib in recurrent ovarian cancer."
The study randomized 733 patients in a 2:1 ratio to receive niraparib (n = 487) or placebo (n = 246). Patients were randomized within 12 weeks of finishing the last cycle of chemotherapy. At the initiation of the study, niraparib was given at a fixed dose of 300 mg, which was adjusted to include a lower dose of 200 mg for those weighing less than 77 kg and for those with platelet counts below 150K/μL. The median relative dose intensity in the study was 63%. Gonzalez-Martin noted that future presentations would focus on the potential impact of this dose change.
Patient characteristics were similar across groups. The ECOG performance status was 1 for approximately 70% of patients, two-thirds had a FIGO stage of III, and a third had stage IV disease. The primary tumor locations were the ovary, fallopian tube, and peritoneum. The majority of patients had serous histology (~95%). Most patients had achieved a complete response to prior chemotherapy (70%). Two-thirds of patients received neoadjuvant chemotherapy, and none received bevacizumab, as the study was designed prior to approval of the VEGF inhibitor in the frontline setting.
At the interim analysis, median overall survival (OS) was not yet reached, at just 10.8% data maturity. At this early time point, however, the 24-month OS rate in the full population was 84% in the niraparib group and 77% in the placebo arm (HR, 0.70; 95% CI, 0.44-1.11). In the HRD-positive cohort, the 24-month OS rate was 91% with niraparib and 85% for placebo (HR, 0.61; 95% CI, 0.27-1.39).
Analysis of the HRD group was further broken down by BRCA
status. For those with a BRCA
mutation, the median PFS was 22.1 months with niraparib compared with 10.9 months for placebo (HR, 0.40; 95% CI, 0.27-0.62). In those with HRD-positive tumors who were negative for a BRCA
mutations, the median PFS was 19.6 versus 8.2 months, for niraparib and placebo, respectively (HR, 0.50; 95% CI, 0.31-0.83).
Niraparib outperformed placebo across several patient subgroups for PFS, including those with HRD-negative tumors. In this group, the median PFS was 8.1 months with niraparib and 5.4 months for placebo (HR, 0.68; 95% CI, 0.49-0.94). Interim OS data for HRD-negative patients showed an 81% 24-month OS rate for niraparib compared with 59% for placebo (HR, 0.51; 95% CI, 0.27-0.97).
More patients experienced treatment-related adverse event (AE) of any grade in the niraparib arm compared with placebo (96.3% vs 68.9%). Grade ≥3 treatment-related AEs were experienced by 65.3% of patients in the niraparib arm compared with 6.6% of those in the placebo group. The most common AEs of grade ≥3 severity in the niraparib and placebo groups, respectively, were anemia (31.0% vs 1.6%), thrombocytopenia (28.7% vs 0.4%), platelet count decrease (13.0% vs 0%), and neutropenia (12.8% vs 1.2%).
Overall, 70.9% of patients required a dose reduction in the niraparib arm, and 12% of patients discontinued therapy due to AEs. The main AEs relating to discontinuation were myelosuppressive in nature, with 4.3% from thrombocytopenia.
Niraparib monotherapy is approved as a maintenance therapy in the recurrent ovarian cancer setting. This approval was granted in March 2017. Additionally, an application is pending with the FDA for niraparib as a treatment for patients with BRCA
or HRD-positive ovarian cancer who have received 3 or more prior chemotherapy regimens and progressed more than 6 months after their last platinum-based chemotherapy. A decision on this application is expected by October 24, 2019.
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- Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). Presented at: ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. LBA
- Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. [published online September 28, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1910962.