On March 27, 2017, the oral poly ADP-ribose polymerase (PARP) inhibitor niraparib (Zejula) was approved for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.1,2
Supporting Efficacy Data
Approval was based on the finding of improved progression-free survival with niraparib treatment in a double-blind phase III trial (ENGOT-OV16/NOVA) in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received at least two prior treatments with platinum-based chemotherapy and were in complete or partial response to the most recent chemotherapy treatment.2,3 A total of 553 patients were randomized 2:1 within 8 weeks of the last therapy to receive either niraparib at 300 mg daily or placebo. Patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) on the basis of BRACAnalysis CDx testing. Among 203 patients in the gBRCA cohort, 138 were randomized to receive niraparib and 65, placebo; among the 350 patients in the non-gBRCA cohort, 234 were randomized to receive niraparib and 116, placebo. The primary endpoint was progression-free survival in the intent-to-treat population.
Niraparib carries warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia, bone marrow suppression, cardiovascular events, and embryofetal toxicity.
Median age of patients ranged from 57 to 67 years among groups, 86% of all patients were white, 40% were enrolled in the United States or Canada, 51% were in complete response to the most recent platinum-based regimen, 39% had an interval of 6 to 12 months since the penultimate platinum regimen, 26% to 31% had received prior bevacizumab (Avastin), and approximately 40% had ≥ 3 lines of treatment.
Median progression-free survival was 21 months in the niraparib group vs 5.5 months in the placebo group in the gBRCA cohort (hazard ratio [HR] = 0.26, P < .0001) and 9.3 months vs 3.9 months in the non-gBRCA cohort (HR = 0.45, P < .0001).
How It Works
Niraparib inhibits the PARP enzymes PARP-1 and PARP-2, which play a role in DNA repair. Studies in vitro indicate that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage, apoptosis, and cell death. Increased niraparib-induced cytotoxicity has been observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild-type BRCA1/2.
How It Is Used
The recommended dose of niraparib is 300 mg once daily. Bedtime administration is a potential strategy for managing nausea. Treatment should be started no later than 8 weeks after the patient’s most recent platinum-containing regimen and should be continued until disease progression or unacceptable toxicity.
Dose reductions for adverse events are to 200 mg/d and then to 100 mg/d, with discontinuation of treatment in case of further need for dose reduction. For nonhematologic grade ≥ 3 adverse events for which prophylaxis is not considered feasible or that persist despite treatment, niraparib treatment should be withheld for a maximum of 28 days or until resolution; treatment can then be resumed at a reduced dose, with up to 2 dose reductions permitted. Treatment should be discontinued for grade ≥ 3 treatment-related adverse events lasting more than 28 days while the patient is receiving 100 mg/d.
Dose reductions for hematologic adverse events follow. For the first occurrence of a platelet count < 100,000/L, treatment should be withheld for a maximum of 28 days, and blood cell counts should be monitored weekly until it returns to ≥ 100,000/L. Treatment can then be resumed at the same or a reduced dose; treatment should be resumed at a reduced dose if the platelet count is < 75,000/L. For a second occurrence, treatment should be withheld as previously stated and resumed at a reduced dose. Treatment should be discontinued if platelets have not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to 100 mg once daily.
For neutrophil counts < 1,000/L or hemoglobin < 8 g/dL, treatment should be withheld as mentioned until the return of neutrophil counts to ≥ 1,500/L or hemoglobin to ≥ 9 g/dL, with treatment resumed at a reduced dose. Treatment should be discontinued if neutrophils or hemoglobin have not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to 100 mg once daily. Treatment should be discontinued if myelodysplastic syndrome or acute myeloid leukemia is confirmed.
In the phase III trial, the most common adverse events of any grade in the niraparib group were thrombocytopenia (61% vs 5% with placebo), anemia (50% vs 7%), and neutropenia (30% vs 6%) among hematologic adverse events and nausea (74% vs 35%), fatigue/asthenia (57% vs 41%), constipation (40% vs 20%), vomiting (34% vs 16%), and abdominal pain/distension (33% vs 39%) among nonhematologic adverse events. The most common grade 3 or 4 adverse events were thrombocytopenia (29% vs 0.6%), anemia (25% vs 0%), and neutropenia (20% vs 2%) among hematologic adverse events and hypertension (9% vs 2%), fatigue/asthenia (8% vs 0.6%), and alanine transaminase/ aspartate transaminase elevation (4% vs 2%) among nonhematologic adverse events. Myelodysplastic syndrome or acute myeloid leukemia occurred in 5 niraparib patients (1.4%) vs 2 placebo patients (1.1%). The most common grade 3 or 4 laboratory abnormalities were thrombocytopenia (35% vs 0.5%), anemia (25% vs 0.5%), and neutropenia (21% vs 2%).
In the niraparib group, adverse events led to dose reduction or interruption in 69% of patients, most frequently due to thrombocytopenia (41%) and anemia (20%), and to permanent discontinuation in 15%.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Niraparib carries warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia (including fatalities), bone marrow suppression, cardiovascular events, and embryofetal toxicity. Patients should be monitored for hematologic toxicity. Complete blood cell counts should be monitored weekly for the first month, monthly for the next 11 months, and periodically thereafter for clinically significant changes. Blood pressure and heart rate should be monitored monthly for the first year and periodically thereafter. Hypertension should be managed with antihypertensive medication and with dose adjustment if necessary. Women of reproductive potential should be advised of the potential risk to a fetus and to use effective contraception. Women should not breastfeed during treatment and for 1 month after receiving the final dose. ■
1. U.S. Food and Drug Administration: Niraparib (Zejula). Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm548487.htm. Accessed April 25, 2017.
2. Zejula (niraparib) capsules prescribing information, Tesaro, Inc, March 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf. Accessed April 25, 2017.