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On October 23, 2019, the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib was approved in the treatment of patients with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with at least three prior chemotherapy regimens and with homologous recombination deficiency (HRD)-positive status.^1,2 HRD is defined by a deleterious or suspected deleterious BRCA mutation or genomic instability in patients with disease progression more than 6 months after response to the last platinum-based chemotherapy.

The U.S. Food and Drug Administration (FDA) also approved the myChoice CDx test for determination of tumor HRD status to select patients for niraparib treatment.

Supporting Efficacy Data

Approval was based on findings in the subgroup of 98 patients with HRD-positive advanced ovarian cancer in the single-arm phase II QUADRA trial (ClinicalTrials.gov identifier NCT02354586), which evaluated niraparib in 463 women with advanced disease who had received at least three prior lines of chemotherapy.^2,3 Patients received niraparib at 300 mg once daily until disease progression or unacceptable toxicity. Patients with prior exposure to PARP inhibitors were excluded from the study. Patients without BRCA mutations must have experienced disease progression at least 6 months after the last dose of platinum-based therapy. HRD-positive status was determined using the myChoice CDx test, with patients either having a BRCA-mutated tumor (n = 63) or a genomic instability score (GIS) ≥ 42 (n = 35).

The objective response rate among all 98 patients on investigator assessment using Response Evaluation Criteria in Solid Tumors v1.1 was 24% (95% confidence interval = 16%–34%; all partial responses). The median duration of response was 8.3 months. Among patients with BRCA-mutated disease, responses were observed in 7 of 18 patients (39%) with platinum-sensitive disease, 6 of 21 patients (29%) with platinum-resistant disease, and 3 of 16 patients (19%) with platinum-refractory disease. The response rate was 20% among 35 patients with platinum-sensitive GIS-positive disease (without BRCA mutation).

How It Works

Niraparib inhibits the PARP enzymes PARP1 and PARP2, 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 HRD-positive xenograft tumor models that had either mutated or wild-type BRCA1/2.

How It Is Used

Patients must be selected for treatment in the current indication based on an FDA-approved companion diagnostic. The recommended dose of niraparib in the current indication is 300 mg once daily, with treatment being continued until disease progression or unacceptable toxicity. Bedtime administration may be a strategy to manage nausea.

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. Product labeling provides instructions for dose modification, including dose reduction, interruption, and discontinuation, for nonhematologic grade ≥ 3 adverse events for which prophylaxis is not considered feasible or that persist despite treatment of the adverse event. Product labeling provides instructions for dose modification for hematologic adverse events including platelet count < 100,000/μL, neutrophil count < 1,000/μL or hemoglobin < 8 g/dL, and adverse reactions requiring transfusion. Treatment should be discontinued if patients develop confirmed myelodysplastic syndrome or acute myeloid leukemia.

Safety Profile

The most common adverse events (incidence ≥ 10%) observed with niraparib treatment in clinical trials have been nausea, fatigue, thrombocytopenia, anemia, vomiting, constipation, abdominal pain, musculoskeletal pain, decreased appetite, neutropenia, insomnia, headache, dyspnea, diarrhea, hypertension, cough, dizziness, hypomagnesemia, urinary tract infection, acute kidney injury, and decreased white blood cell count.

Among all 463 patients receiving niraparib in the QUADRA trial, the most common adverse events of any grade were nausea (67%), fatigue (56%), thrombocytopenia (52%), anemia (51%), vomiting (44%), constipation (36%), abdominal pain (34%), musculoskeletal pain (29%), decreased appetite (27%), dyspnea (22%), insomnia (21%), and neutropenia (20%). Serious adverse events occurred in 43% of patients, with the most common being small intestinal obstruction, vomiting, nausea, and abdominal pain. Adverse events led to dose reduction or interruption in 73% of patients, with the most common causes being thrombocytopenia, anemia, neutropenia, nausea, vomiting, fatigue, and abdominal pain. Adverse events led to treatment discontinuation in 21% of patients. Fatal adverse events occurred in 2% of patients.

Niraparib has warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia (including fatalities), bone marrow suppression, cardiovascular effects, 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 at least weekly for the first 2 months, then monthly for the first year, and periodically thereafter during treatment. Hypertension should be managed with antihypertensive medication and with dose adjustment if necessary. Patients should not breastfeed during treatment and for 1 month after receiving the final dose of niraparib. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves niraparib for HRD-positive advanced ovarian cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-hrd-positive-advanced-ovarian-cancer. Accessed November 26, 2019.

2. Zejula (niraparib) capsules prescribing information, Tesaro, Inc, October 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208447s014lbl.pdf. Accessed November 26, 2019.

3. Moore KN, Secord AA, Geller MA, et al: Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): A multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 20:636-648, 2019.