On April 29, 2020, niraparib was approved for maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy.1,2
Supporting Efficacy Data
Approval was based on findings in the phase III, double-blind PRIMA trial (ClinicalTrials.gov identifier NCT02655016).2,3 In the trial, 733 patients in complete or partial response to first-line platinum-based chemotherapy were randomly assigned 2:1 to oral niraparib (n = 487) or placebo (n = 286). Initially, all patients received a starting dose of 300 mg once daily. The study was amended to include a starting dose of 200 mg for patients weighing less than 77 kg (170 lb) or with a platelet count of less than 150,000/μL.
The main efficacy measure was progression-free survival on blinded independent central review per Response Evaluation Criteria in Solid Tumors, version 1.1, tested first in the subgroup of patients who were homologous recombination deficient (HRD) and then in the overall population. HRD was defined as either the presence of tumor BRCA mutation or a genomic instability score ≥ 42. The HRD population consisted of 247 patients in the niraparib group and 126 in the placebo group.
The median age of study patients was 62 years, 89% were white, and approximately 70% had an Eastern Cooperative Oncology Group performance status of 0. Furthermore, 65% had stage III disease, 35% had stage IV disease, 67% had received neoadjuvant chemotherapy, and 69% demonstrated a complete response to first-line platinum-based chemotherapy.
Median progression-free survival in the HRD population was 21.9 months in the niraparib group vs 10.4 months in the placebo group (hazard ratio [HR] = 0.43, P < .0001). Median progression-free survival in the entire population was 13.8 months vs 8.2 months (HR = 0.62, P < .0001). In an exploratory subgroup analysis of patients who received treatment based on weight or platelet count, the hazard ratio for progression-free survival was 0.39 (95% confidence interval [CI] = 0.22–0.72) in the HRD subgroup (n = 130) and 0.68 (95% CI = 0.48–0.97) in the overall population (n = 258).
How It Works
Niraparib inhibits the poly (ADP-ribose) polymerase (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 xenograft tumor models with HRD that had either mutated or wild-type BRCA1/2.
How It Is Used
A U.S. Food and Drug administration–approved companion diagnostic is not required to initiate treatment for the current indication. The recommended niraparib dose is based on body weight or platelet count. For patients weighing less than 77 kg or with a platelet count < 150,000/μL, the recommended dose is 200 mg once daily. For patients weighing ≥ 77 kg and who have a platelet count ≥ 150,000/μL, the recommended dose is 300 mg once daily.
Patients should start treatment no later than 12 weeks after their most recent platinum-containing regimen. Treatment should continue until disease progression or unacceptable toxicity.
Recommended dose reductions for adverse events are to 100 mg/d in patients with a starting dose of 200 mg/d and sequentially to 200 mg, and to 100 mg/d in those with a starting dose of 300 mg/d. Treatment should be discontinued if a further need for dose reduction arises.
Product labeling provides instructions for dose modification for nonhematologic grade ≥ 3 adverse reactions for which prophylaxis is not considered feasible or that persist despite treatment. Other developments necessitating dose modification include 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 observed in patients receiving niraparib in clinical trials have been nausea, thrombocytopenia, anemia, fatigue, constipation, musculoskeletal pain, abdominal pain, vomiting, neutropenia, decreased appetite, leukopenia, insomnia, headache, dyspnea, rash, diarrhea, hypertension, cough, dizziness, acute kidney injury, urinary tract infection, and hypomagnesemia.
In the PRIMA trial, the most common adverse events of any grade in those receiving niraparib were thrombocytopenia, anemia, nausea, fatigue, neutropenia, constipation, musculoskeletal pain, leukopenia, headache, insomnia, vomiting, and dyspnea. Hypertension occurred in 18% of patients who received niraparib.
The most common grade 3 or 4 adverse events included thrombocytopenia, anemia, neutropenia, hypertension, and leukopenia. The most common grade 3 or 4 laboratory abnormalities were decreased platelets, decreased hemoglobin, and decreased neutrophils. Serious adverse events occurred in 32% of patients receiving niraparib, with the most common being thrombocytopenia, anemia, and small intestinal obstruction. Adverse events led to dose reduction or interruption in 80% of patients and led to death in two patients (0.4%).
Niraparib has warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia, 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 with niraparib and for 1 month after receiving the final dose.
REFERENCES
1. U.S. Food and Drug Administration: FDA approves niraparib for first-line maintenance of advanced ovarian cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-niraparib-first-line-maintenance-advanced-ovarian-cancer. Accessed May 7, 2020.
2. U.S. Food and Drug Administration: Highlights of prescribing information for Zejula (niraparib) capsules. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf. Accessed May 7, 2020.
3. González-Martín A, Pothuri B, Vergote I, et al: Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 381:2391-2402, 2019.
