Mary Lynne Hedley, PhD
Niraparib (Zejula) met the primary endpoint of overall response as a fourth-line or later treatment in patients with ovarian cancer, regardless of BRCA
status, according to top-line results from the QUADRA study announced by TESARO, the manufacturer of the PARP inhibitor.
In the phase II open-label, single-arm study, niraparib induced an overall response rate (ORR) of 29% and a duration of response (DOR) of 9.2 months among homologous recombination deficiency (HRD)–positive, PARP inhibitor–naive, platinum-sensitive patients receiving treatment in the fourth- or fifth-line setting (n = 45).
The ORR was 31% and the median DOR was 9.4 months among 55 BRCA
-positive patients who were either platinum sensitive or resistant/refractory and being treated in the fourth-line setting and beyond.
In a statement, TESARO reported its plan to communicate with the FDA regarding a biomarker-focused label expansion for niraparib, with the potential for submitting a new application by the end of this year. The company also noted that data from QUADRA will be presented at the 2018 ASCO Annual Meeting.
“These results demonstrated that Zejula is active as a late-line treatment for patients beyond those with BRCA
mutations, which is the only treatment setting in which PARP inhibitors are approved today. In addition, the QUADRA data describe Zejula monotherapy activity in platinum-resistant/refractory patients, providing important context for our TOPACIO study of Zejula in combination with an anti-PD-1 inhibitor,” said Mary Lynne Hedley, PhD, president and COO of Tesaro, said in a statement.
QUADRA evaluated niraparib monotherapy in 461 patients with advanced, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer previous treated with 3 or 4 lines of chemotherapy. Among patients with no prior PARP therapy (92%), 63% had prior bevacizumab (Avastin), 15% had a BRCA
mutation, and more than two-thirds were platinum resistant/refractory.
The primary endpoint was ORR in HRD-positive, platinum sensitive patients who had received 3 or 4 lines of prior chemotherapy. Secondary endpoints included overall survival (OS), progression-free survival (PFS), durability of response, disease control rate, and safety/tolerability.
In March 2017, the FDA approved niraparib for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
The approval was based on the phase III NOVA trial, in which niraparib reduced the risk of progression or death by 74% compared with placebo for patients with germline BRCA-positive platinum-sensitive, recurrent ovarian cancer.1,2
The median PFS with maintenance niraparib was 21 months compared with 5.5 months for placebo in patients with germline BRCA
mutations (HR, 0.26; 95% CI, 0.17-0.41; P
<.0001). These findings remained consistent across subgroups of patients, including those without BRCA
The phase III NOVA study randomized patients in a 2:1 ratio across 2 independent cohorts. In the first cohort, 201 patients with germline BRCA
mutations received niraparib at 300 mg daily (n = 138) or placebo (n = 65). In the second cohort, 345 patients with non-germline BRCA-mutant tumors received the PARP Inhibitor (n = 231) or placebo (n = 114). Patients in this group were tested for homologous recombination deficiency (HRD), and could be either positive (n = 162) or negative (n = 134). Of those who tested positive, 47 had somatic BRCA
mutations and 115 were wild-type.
Patient demographics were well balanced between the arms for each cohort. In the germline BRCA
group, the median age was 57 years and 65.9% had an ECOG performance status (PS) of 0. In the placebo group, the median age was 58 years and 73.8% of patients had an ECOG PS of 0. Overall, 48.6% and 53.8% of patients had received ≥3 prior therapies, in the niraparib and placebo arms, respectively.
Across both cohorts, the majority of patients had stage III cancer (68.8% to 74.1%). Approximately half of patients had achieved a complete response to prior platinum-based therapy and a quarter had received prior bevacizumab. In the non-BRCA
-mutant arm, 33.8% and 32.8% of patients had received ≥3 prior therapies.
In the germline BRCA
mutation group, the chemotherapy-free interval was 22.8 months with niraparib compared with 9.4 months for placebo (HR, 0.26; 95% CI, 0.17-0.41; P
<.001). The median time to subsequent therapy was 21 months with niraparib versus 8.4 months with placebo (HR, 0.31; 95% CI, 0.21-0.48).
The median time to progression or death during the first subsequent therapy following the study (PFS2) was 25.8 months for those who received maintenance niraparib versus 19.5 months for placebo (HR, 0.48; 95% CI, 0.28-0.82; P
= .006). Findings for OS were not yet mature.
In patients with HRD-positive, BRCA
wild-type tumors, median PFS was 9.3 versus 3.7 months for niraparib and placebo, respectively (HR, 0.38; 95% CI, 0.23-0.63; P
<.001). In those with HRD-positive, somatic BRCA-
mutated tumors, the median PFS was 20.9 months with niraparib versus 11.0 months for placebo (HR, 0.27; 95% CI, 0.08-0.90; P = .02). In patients with HRD-negative, non-germline BRCA
-mutated tumors, median PFS was 6.9 versus 3.8 months for niraparib and placebo, respectively (HR, 0.58; 95% CI, 0.36-0.92; P
In those with non-germline BRCA
mutations regardless of HRD status, the median chemotherapy-free interval was 12.7 versus 8.6 months for niraparib and placebo, respectively (HR, 0.50; 95% CI, 0.37-0.67; P
<.001). The median time to subsequent therapy was 11.8 versus 7.2 months (HR, 0.55; 95% CI, 0.41-0.72; P
<.001) and the median PFS2 was 18.6 and 15.6 months for the niraparib and placebo arms, respectively (HR, 0.69; 95% CI, 0.49-0.96; P
- Mirza MR, Monk BJ, Oza A, et al. A randomized, double-blind phase 3 trial of maintenance therapy with niraparib vs placebo in patients with platinum-sensitive recurrent ovarian cancer (ENGOT-OV16/NOVA trial). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA3_PR.
- Mirza MR, Monk B, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer [published online October 8, 2016]. N Engl J Med. DOI: 10.1056/NEJMoa1611310.