Niraparib, a poly ADP ribose polymerase (PARP) inhibitor, was initially approved in March 2017 as maintenance therapy for adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a complete or partial response to platinum-based chemotherapy. PARP inhibitors are the only approved oral treatment options for patients with BRCA mutations in ovarian cancer. Patients must take the Myriad myChoice companion diagnostic test, which is approved by the FDA to determine HRD-positive status as either tBRCA and/or a genomic instability score (GIS) of at least 42.
This new indication is based on the QUADRA study, which is a phase 2, multicenter, open-label, single-arm study that evaluated the safety and activity of niraparib. The study included 463 patients with relapsed, high-grade, serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who were treated with three or more previous chemotherapy regimens.
Patients met inclusion criteria if they agreed to undergo homologous recombination deficiency (HRD) testing, had a negative pregnancy test, and had grade 2 or 3 serous epithelial ovarian, fallopian tube, or primary peritoneal cancer with recurrent disease. They also must have been previously treated with chemotherapy and experienced a response lasting at least 6 months to first-line platinum therapy, completed three or four chemotherapy regimens, and had a last-line chemotherapy regimen >4 weeks prior to treatment initiation. Patients had to have measurable disease according to RECIST (v 1.1), have formalin-fixed paraffin-embedded tumor samples available from the primary or recurrent cancer or agree to undergo flesh biopsy prior to the treatment initiation, and had to agree to blood samples during screening and at the end of treatment for cytogenetic analysis. Patients were excluded if they did not meet inclusion criteria and if they had a history of myelodysplastic syndromes (MDS) and acute myeloid leukemia.
The primary endpoint of the study was the proportion of patients with HRD-positive tumors sensitive to their last platinum-based therapy who achieved an overall response confirmed by the study investigator. Secondary endpoints included evaluating the efficacy of niraparib in the late-line ovarian cancer population and in subgroups of platinum-sensitive patients and BRCA-positive/HRD-status patients. Patients who met inclusion criteria received niraparib 300 mg orally once a day until disease progression. The objective response rate was clinically meaningful at 24% (95% CI 16-34%), and the median duration of response was 8.3 months (95% CI, 6.5 to not estimable).
The efficacy of niraparib in patients with deleterious or suspected deleterious somatic/germline BRCA mutations and a GIS was demonstrated. GIS is an algorithm that measures loss of heterozygosity, telomeric allelic imbalance, and large state transitions of about 42 patients. The most common grade 3 adverse events reported in 10% of patients were thrombocytopenia (28%), anemia (27%), neutropenia (13%), and nausea (10%). This side-effect profile is consistent with side effects of PARP inhibitors in general and with results from the phase 3 NOVA trial in the recurrent maintenance population. Patients who experienced toxicities had their dose reduced, and these adverse events resolved within the first 3 months. Niraparib showed superior anticancer activity, demonstrating durability in this heavily chemotherapy-treated patient population.
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