What is niraparib?
Niraparib is an oral inhibitor of PARP (poly (ADP-ribose) polymerase) enzymes.
How does niraparib work?
PARP enzymes work to repair DNA. Inhibition of PARP-1 and PARP-2 enzymes with inhibitors like niraparib cause increased formation of PARP-DNA complexes that ultimately lead to DNA damage, apoptosis, and cellular death.
What is this approved for?
Niraparib is approved for maintenance therapy of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have achieved either a complete or partial response to platinum-based chemotherapy. A companion diagnostic test, BRAC Analysis CDx, was approved with niraparib to identify patients with germline BRCA mutations who are most likely to benefit from niraparib maintenance therapy.
What is the basis for this approval?
Niraparib was approved based on the results of the NOVA trial, which was a randomized, double-blind, phase III trial. A total of 553 patients with ovarian, fallopian tube, or primary peritoneal cancer and platinum-sensitive disease were enrolled in the trial and randomized in a 2:1 fashion to niraparib 300 mg daily or placebo until disease progression. Platinum-sensitive disease was defined as having a complete or partial response to the most recent platinum-based regimen and randomized within 8 weeks of the last treatment. Patients were assigned to two cohorts based on the presence or absence of BRCA (detected by BRACAnalysis CDx) germline mutations.
The primary endpoint was progression-free survival (PFS). For patients with a BRCA germline mutation, the median PFS was 21 months with niraparib and 5.5 months with placebo (HR 0.27, p < 0.0001). The cohort without a germline BRCA mutation demonstrated a median PFS of 9.3 months with niraparib and 3.9 months with placebo (HR 0.45, p < 0.0001) (N Engl J Med 2016;375:2154-2164).
How do you administer this drug?
Niraparib is administered as three 100 mg capsules for a total daily dose of 300 mg orally daily. It can be given with or without food.
Are there any premedications needed for niraparib?
While there are no required premedications for niraparib, if patients have nausea or vomiting from the medication, an oral anti-nausea medication may be necessary prior to the dose or consider switching administration time to bedtime.
What are the common side effects associated with niraparib (> or =10%)?
* Hematologic: thrombocytopenia, anemia, neutropenia, leukopenia
* Cardiovascular: palpitations, hypertension
* GI: nausea, vomiting, constipation, abdominal pain, mucositis, diarrhea, dry mouth, decreased appetite
* General: fatigue, cough, dyspnea, rash
* Infections: urinary tract infections
* Laboratory: elevated liver enzymes
* Neurology: headache, dizziness, insomnia, anxiety
What are the uncommon side effects associated with niraparib (less than 10%)?
About 1 percent of patients who have taken niraparib have subsequently developed either myelodysplastic syndrome or acute myeloid leukemia. Additional side effects include tachycardia, peripheral edema, hypokalemia, bronchitis, conjunctivitis, depression, and epistaxis.
Are there any important drug interactions?
There are no known clinically significant drug interactions with niraparib.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
There are no known renal or hepatic dose adjustments for niraparib; however, it has not been studied in severe renal or hepatic dysfunction. About 50 percent of niraparib is excreted in the urine, but no studies have been conducted in patients with a creatinine clearance less than 30 mL/minute.
Practical tips
* If a patient is suffering from nausea with niraparib, it may be helpful to have them take it at bedtime instead of in the morning.
* If a dose reduction is needed for niraparib, it should be done in 100 mg increments. Since niraparib is supplied in 100 mg capsules, the dose reduction will be a reduction in the number of daily capsules the patient takes.
* While patients with germline BRCA mutations will have the most benefit from niraparib, a BRCA mutation is not required for treatment.
What should my patients know about niraparib?
Patients should contact their health care provider if they experience fevers, unusual bruising or bleeding, hypertension, and/or mouth sores.
What else should I know about niraparib?
* Patients should have their blood pressure and heart rate monitored monthly for the first year and periodically thereafter while receiving niraparib. Grade 3/4 hypertension occurred in 9 percent of patients in the clinical trials.
* Patients should have recovered from their previously hematologic toxicity with prior chemotherapy prior to starting niraparib. Patients should have their blood counts monitored weekly for the first month of therapy, monthly for the next 11 months, and then periodically thereafter. Dose adjustment may be necessary for hematologic toxicity. If the hematologic toxicity does not resolve with either dose reduction or holding medication, further investigation from a hematologist would be necessary.
What useful links are available regarding niraparib?
* https://www.tesarobio.com/en/products/zejula-niraparib
* https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm548487.htm
Any ongoing clinical trials related to niraparib?
Clinical trials with niraparib are being conducted in several settings, including as a single agent in prostate cancer and pancreatic cancer, and in combination with trastuzumab for breast cancer, everolimus in ovarian cancer, and carboplatin for solid tumors. More information is available about the clinical trials at https://clinicaltrials.gov.
SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as a Pharmacy Forum column co-editor.