April 29, 2020–Niraparib (ZEJULA, GlaxoSmithKline) for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.
March 27, 2017–niraparib (ZEJULA™, Tesaro, Inc.), for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.(With Pharmacist's Applications to Practice)
April 29, 2020
On April 29, 2020, the Food and Drug Administration approved niraparib (ZEJULA, GlaxoSmithKline) for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.
Efficacy was investigated in PRIMA (NCT02655016), a double-blind, placebo-controlled trial that randomized 733 patients to niraparib or matched placebo. Patients were in a complete or partial response to first-line platinum-based chemotherapy.
The main efficacy outcome measure, progression-free survival (PFS), was first tested in the homologous recombination deficient population, then in the overall population and was determined by blinded independent central review per RECIST 1.1. Tumor samples were tested for homologous recombination deficiency status; homologous recombination deficient was defined by either presence of tumor breast cancer susceptibility gene (tBRCA) mutation or genomic instability score (GIS) ≥42. An FDA-approved companion diagnostic is not required to initiate treatment with ZEJULA for this indication.
The trial demonstrated a statistically significant improvement in PFS for patients randomized to niraparib compared with placebo in the homologous recombination deficient and overall population. Median PFS in the homologous recombination deficient population was 21.9 months (19.3, NE) for patients receiving niraparib compared with 10.4 months (8.1, 12.1) for those receiving placebo (HR 0.43; 95% CI: 0.31, 0.59; p<0.0001). Median PFS in the overall population was 13.8 months (11.5, 14.9) for patients receiving niraparib compared with 8.2 months (7.3, 8.5) for those receiving placebo (HR 0.62; 95% CI: 0.50, 0.76; p<0.0001).
The most common adverse reactions in ≥10% of all patients receiving niraparib in the PRIMA trial were thrombocytopenia, anemia, nausea, fatigue, neutropenia, constipation, musculoskeletal pain, leukopenia, headache, insomnia, vomiting, dyspnea, decreased appetite, dizziness, cough, hypertension, AST/ALT elevation, and acute kidney injury.
The recommended niraparib dose for first-line maintenance treatment of advanced ovarian cancer is based on body weight or platelet count. For patients weighing less than 77 kg (170 lbs) OR with a platelet count of less than 150,000/μL, the recommended dose is 200 mg taken orally once daily. For patients weighing greater than or equal to 77 kg (170 lbs) AND who have a platelet count greater than or equal to 150,000/μL, the recommended dose is 300 mg taken orally once daily.
This review used the Real-Time Oncology Review (RTOR), which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was approved 2 months prior to the FDA goal date.
This application was granted priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
For information on the COVID-19 pandemic, see the following resources:
- FDA: Coronavirus Disease 2019 (COVID-19)
- NCI: Coronavirus: What People With Cancer Should Know
- CDC: Coronavirus (COVID-19)
March 27, 2017 with PAP
On March 27, 2017, the U.S. Food and Drug Administration approved niraparib (ZEJULA™, Tesaro, Inc.), a poly ADP-ribose polymerase (PARP) inhibitor, for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
Approval was based on a randomized trial (NOVA) of 553 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received at least two prior treatments of platinum-based chemotherapy and were in a complete or partial response to the most recent chemotherapy treatment. Patients were randomized (2:1) within 8 weeks of the last therapy to either niraparib (300 mg orally daily) or matched placebo. Patients were assigned to one of two cohorts based on the BRACAnalysis CDx. Patients with deleterious or suspected deleterious germline BRCA mutations (gBRCAm) were assigned to the germline BRCA-mutated (gBRCAmut) cohort (n=203), and those without germline BRCA mutations were assigned to the non-gBRCAmut cohort (n=350).
The trial demonstrated a statistically significant improvement in progression-free survival (PFS) for patients randomized to niraparib compared with placebo in both cohorts. The estimated median PFS for those taking niraparib who had a germline BRCA mutation was 21 months compared with 5.5 months for those in the gBRCAmut cohort receiving placebo (HR=0.26; 95% CI: 0.17, 0.41; p<0.0001). The estimated median PFS for those taking niraparib who did not have a germline BRCA mutation was 9.3 months compared with 3.9 months for those patients in the non-gBRCAmut cohort receiving placebo (HR=0.45; 95% CI: 0.34, 0.61; p<0.0001).
The FDA approved niraparib with the complementary diagnostic BRACAnalysis CDx that detects the presence of gBRCAm in blood samples from ovarian cancer patients. BRACAnalysis CDx was originally approved in 2014 as a companion diagnostic test for use with Lynparza (olaparib). The FDA’s approval of the expanded indications for the use of BRACAnalysis CDx with niraparib was based on data from the NOVA trial.
Niraparib’s safety was evaluated in 367 patients with platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancer in the NOVA trial. The most common adverse reactions occurring in at least 10% of patients receiving niraparib were thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain/distention, mucositis/stomatitis, diarrhea, dyspepsia, dry mouth, fatigue, decreased appetite, urinary tract infection, AST/ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, and hypertension. Myelodysplastic syndrome and/or acute myeloid leukemia occurred in 5 of 367 (1.4%) patients receiving niraparib and in 2 of 179 (1.1%) patients assigned to placebo. Grade 3-4 hypertension occurred in 9% of niraparib- treated patients compared with 2% of patients assigned to placebo.
The recommended dose and schedule of niraparib is 300 mg taken once daily with or without food.
Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf.
The FDA granted this application Fast Track, Priority Review, and Breakthrough Therapy designation, as well as Orphan Drug designation specifically for treating recurrent epithelial ovarian cancer. FDA approved this application approximately three months ahead of the goal date. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and 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) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Pharmacist’s Applications to Practice
Niraparib (Zejula) for Maintenance Therapy in Patients with Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Malignancy
Author: Jill M. Comeau, PharmD BCOP
Assistant Professor of Clinical Sciences
University of Louisiana at Monroe School of Pharmacy
Gratis Assistant Professor of Internal Medicine
Feist-Weiller Cancer Center
What is the potential role for niraparib in the management of platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer?1,2,4,7
- Niraparib is the only therapy approved by the Food and Drug Administration (FDA) specifically for maintenance in the treatment of platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer after at least a partial response to a platinum-based regimen. Because the majority of patients will relapse after first-line treatment, with around 40% having platinum-sensitive disease upon recurrence, niraparib plays an important role in maintaining a response after the second line of treatment.
- Per the National Comprehensive Cancer Network guidelines, niraparib and bevacizumab are the only treatments that are recommended for maintenance therapy in patients with platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer.4
- In the OCEANS phase 3 trial, bevacizumab or placebo was given with carboplatin and gemcitabine, with bevacizumab or placebo continued until disease progression. The patients in the bevacizumab group had a median progression-free survival (PFS) of 12.4 months compared to 8.4 months in the placebo group.5
- In the NOVA phase 3 niraparib trial, patients were divided into three subgroups based on BRCA mutation: germline BRCA (gBRCA) mutation, non-gBRCA mutation with homologous recombination deficiency (HRD), and non-gBRCA HRD-negative. The median PFS in the gBRCA cohort was 21 months and 5.5 months in the niraparib and placebo groups, respectively. In the non-gBRCA cohort, the median PFS was 9.3 months in the niraparib group and 3.9 months in the placebo group. Patients in the non-gBRCA group that were HRD-positive had a median PFS of 12.9 months in the niraparib group compared to 3.8 months in the placebo group. The HRD-negative subgroup had a median PFS of 6.9 months versus 3.8 months. All PFS outcomes were statistically significant. Overall, patients in the gBRCA group had the longest median PFS benefit of 15.5 months; the patients in the HRD-negative, non-gBRCA group had the smallest but statically significant median PFS benefit of 3.1 months.2
- It is very difficult to compare the outcomes of the OCEANS trial to those of the NOVA trial because the NOVA cohorts with gBRCA and non-gBRCA HRD had a drastically higher PFS benefit. On the other hand, the other two groups studied, non-gBRCA overall and non-gBRCA HRD-negative, had similar PFS outcomes to bevacizumab in the OCEANS trial.
- Two other poly (ADP-ribose) polymerase (PARP) inhibitors, olaparib and rucaparib, are indicated only in patients with a BRCA-associated ovarian cancer. Olaparib is FDA approved after three lines of treatment and rucaparib after two lines of therapy for recurrent ovarian, fallopian tube, or primary peritoneal cancer. Niraparib is the only FDA-approved PARP inhibitor that can be used in patients regardless of BRCA mutations and as part of first-line recurrent ovarian cancer as maintenance treatment.6,7
- Olaparib was FDA approved based on a phase 2 clinical trial involving patients with a gBRCA1/2 mutation, including 193 patients with relapsed or recurrent ovarian cancer, fallopian tube, and primary peritoneal malignancies. Thirty-one percent of the 193 patients had a tumor response, with 3% having a complete response and 28% having a partial response. For the ovarian cancer cohort, the median PFS was 7 months, and the median overall survival (OS) was 16.6 months.8 Even though olaparib has not been FDA approved as maintenance therapy, olaparib was studied in a phase 2 placebo-controlled trial as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer. Overall, the median PFS was 8.4 months in the olaparib group and 4.8 months in the placebo group. According to the article, comparisons between gBRCA mutation and non-gBRCA mutation patients were not performed because of the low incidence of progression or death among the non-gBRCA population.9
- Rucaparib is being studied in the ARIEL2 trial as treatment for relapsed platinum-sensitive ovarian cancer. In the ARIEL2 Part 1 publication, patients were divided into three groups: BRCA mutant, BRCA wild-type with high genomic loss of heterozygosity (LOH), and BRCA wild-type with low LOH. The largest benefit was seen in the BRCA mutant group, with a median PFS of 12.8 months, followed by the wild-type BRCA high-LOH group at 5.7 months and 5.2 months in the wild-type BRCA low-LOH group.10
- Niraparib is currently being studied in the PRIMA trial as maintenance therapy in patients with treatment-naive stage 3 or stage 4 ovarian cancer who have obtained at least a partial response after completion of platinum-based chemotherapy.11
What role can the pharmacist play in the management of patients on niraparib?
- This medication has a high incidence of grade 3 and 4 myelosuppression occurring most commonly in the first three cycles. Specifically, 29% of patients had thrombocytopenia, 29% developed anemia, and 20% had neutropenia.2 Patients need to be monitored closely with a complete blood count and differential weekly for the first month, monthly for 11 months, and then periodically. Dose reductions may be necessary. After patients are dose reduced appropriately, myelosuppression past cycle 3 is rare.1
- Niraparib has a 19.3% incidence of hypertension, with 8.2% being grade 3 or 4.2 It is recommended that patients be monitored at baseline and monthly for a significant increase in blood pressure. If hypertension is present, patients need to be treated with antihypertensives or may need a dose reduction of niraparib. No specific recommendation has been made for which antihypertensive to use in this population.1
- Because of the high incidence of nausea and vomiting, it is recommended that niraparib be given at bedtime with or without food.1 Nausea occurred in 73.6% of patients receiving niraparib and vomiting in 34.3%. Three percent of patients who had nausea and 1.9% of patients who had vomiting were considered documented as a grade 3 or 4.2
- Niraparib has a very specific place in therapy for the treatment of patients with recurrent ovarian, fallopian, or primary peritoneal cancer. The patients receiving it must have platinum-sensitive disease, defined as having a partial response or remission of greater than 6 months from the last dose during the first-line chemotherapy treatment. Upon progression or relapse from the first chemotherapy regimen, patients in the NOVA trial then received a second round of platinum-based chemotherapy for at least 4 cycles. Patients had to have at least a partial response after their second line of chemotherapy to be enrolled in this study.1,2
- Secondary primary neoplasms have been reported in clinical trials for niraparib as well as olaparib and rucaparib.
- In the NOVA trial, 1.4% (5 patients) in the niraparib arm developed myelodysplastic syndrome (MDS), compared to 1.1% of patients in the placebo arm. One patient who received the placebo treatment developed MDS, and 1 patient developed acute myeloid leukemia (AML).2
- In the study by Kaufman et al., 3 patients developed a hematologic malignancy, which made up 1.6% of the ovarian cancer cohort. Two patients developed leukemia, and one patient developed MDS. These diagnoses occurred at a range of 155-296 days from initiation of olaparib therapy. The patient who developed MDS died from this complication.8
- A combination of two trials showed an incidence of 0.5% of patients who were treated with rucaparib for ovarian cancer. The patients developed these malignancies after receiving 57 days and 539 days of treatment, respectively.7
- Most of the patients included in the trials received multiple lines of chemotherapy treatment with agents known to increase the risk for MDS or AML. Another theory is that the development of these malignancies is caused by genomic instability due to PARP inhibitors altering DNA repair.2,7,8,12
- Niraparib is considered a hazardous agent by the National Institute for Occupational Safety and Health. Anyone handling this medication in any way should wear gloves. People who are pregnant should not handle this medication.1
- Niraparib is considered teratogenic on the basis of its mechanism of action, even though embryo-fetal studies have not been conducted. With olaparib, studies in rats have shown a risk for postimplantation loss and major malformations if the drug is given during the first trimester of pregnancy or in the period of organogenesis.1,6
- Two Together with Tesasro programs help patients get access to niraparib. They provide assistance with prior authorizations, co-pay assistance, and patient assistance programs.13 A quick start and bridge program assists in providing a 15-day supply for patients who have an insurance delay with either starting or continuing the medication. This can be used up to five times.13
- Zejula [package insert]. Waltham, MA: Tesaro, Inc.; 2017.
- Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. New Engl J Med. 2016;37(22)5:2154-64.
- Hanker LC, Loibl S, Burchardi N, et al. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol. 2012;23(10):2605-12.
- Ovarian Cancer including fallopian tube cancer and primary peritoneal cancer. Version 2.2017. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed July 17, 2017.
- Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial overian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039-45.
- Lynparza [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
- Rubraca [package insert]. Boulder, CO: Clovis Oncology, Inc.; 2017.
- Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33:244-50.
- Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382-92.
- Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Onc. 2017;18:75-87.
- Clinicaltrials.gov Registry. National Institutes of Health. Available at: www.clinicaltrials.gov. Accessed July 17, 2017.
- Bhatia S. Therapy-related myelodysplasia and acute myeloid leukemia. Semin Oncol. 2013;40:666-75.
- Together with Tesaro Patient Resource Program. Zejula website. Available at: https://www.togetherwithtesaro.com/zejula_niraparib/solutions. 2017. Accessed July 17, 2017.