FDA Approves ZEJULA (niraparib)

March 30, 2017

FDA Approves ZEJULA (Niraparib) for the Maintenance Treatment of Adult Patients With Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer who are in a Complete or Partial Response to Platinum-Based Chemotherapy

On March 27th, 2017, the U.S. Food and Drug Administration (FDA) approved ZEJULA (niraparib) for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The approved recommended dosage of ZEJULA is 300 mg (three 100 mg capsules) taken orally once daily with or without food. ZEJULA treatment should be continued until disease progression or unacceptable toxicity. Patients should start treatment with ZEJULA no later than 8 weeks after their most recent platinum-containing regimen. Do not start ZEJULA until patients have recovered (≤ Grade 1) from hematological toxicity caused by previous chemotherapy.

Test complete blood counts weekly for the first month, then monitor monthly for the next 11 months and periodically thereafter for clinically significant changes. Withhold or discontinue ZEJULA, as necessary, based upon parameters outlined in the prescribing information linked below. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with ZEJULA. Manage hypertension with antihypertensive medications as well as adjustment of the ZEJULA dose, if necessary.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)

• MOA: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor.
• Dose Proportionality: The systemic exposures (C_max and AUC) of niraparib increased in a dose proportional manner with daily doses ranging 30 mg (0.1 times the approved recommended dosage) to 400 mg (1.3 times the approved recommended dosage).
• Accumulation: Approximately 2-fold increase in niraparib exposure following 21 days of daily administration.
• Absorption: The absolute bioavailability of niraparib is approximately 73%. The peak niraparib concentration, C_max, is reached within 3 hours following administration of an oral niraparib formulation.
• Plasma Protein Binding: Niraparib is 83% bound to human plasma proteins.
• Elimination: The apparent total systemic clearance (CL/F) of niraparib was 16.2 L/h in cancer patients. The mean half-life (t_1/2) is 36 hours.
• Metabolism: Niraparib is metabolized primarily by carboxylesterases to form a major inactive metabolite, which subsequently undergoes glucuronidation.
• Excretion: Following administration of a single oral 300 mg dose of radiolabeled niraparib, the average percent recovery of the administered dose over 21 days was 47.5% (range 33.4% to 60.2%) in urine, and 38.8% (range 28.3% to 47.0%) in feces. Unchanged niraparib accounted for 11% and 19% of the administered dose recovered in pooled urine and feces collected over 6 days, respectively.

Use in Specific Populations

Age (18 to 65 years old), race/ethnicity, mild hepatic impairment, and mild to moderate renal impairment had no clinically significant effect on the PK of niraparib. The PK and safety of niraparib in patients with severe renal impairment, end stage renal disease undergoing hemodialysis, or moderate to severe hepatic impairment are unknown.

Efficacy and Safety

ZEJULA was studied at the approved dosage in a double-blind, placebo-controlled trial in which patients (n=553) with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomized in a 2:1 ratio to ZEJULA or matched placebo within 8 weeks of the last therapy. Eligible patients were subsequently assigned to two cohorts based on the results of the BRACAnalysis CDx companion diagnostic test. Patients with (n=203) and without (n=350) deleterious or suspected germline BRCA mutations were assigned to the gBRCAmut and non-gBRCAmut cohort, respectively. The major efficacy outcome measure was progression-free survival (PFS).

In the gBRCAmut cohort, an estimated median (95% CI) PFS of 21 months (12.9, Not Reached) was observed for patients treated with ZEJULA compared to 5.5 months (3.8, 7.2) for those on placebo (hazard ratio (HR) (95% CI): 0.26 (0.17, 0.41), p<0.0001). Similarly, in the non-gBRCAmut cohort, an estimated median (95% CI) PFS of 9.3 months (7.29, 11.2) was observed for patients treated with ZEJULA compared to 3.9 months (3.7, 5.5) for those on placebo (HR (95% CI) 0.45 (0.34, 0.61), p<0.0001). At the time of the efficacy analysis, limited overall survival data were available with 17% deaths reported across the two cohorts.

Based on a safety analysis of 367 patients treated with ZEJULA, the most commonly observed adverse reactions (incidence ≥ 10%) were thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain/distention, mucositis/stomatitis, diarrhea, dyspepsia, dry mouth, fatigue/asthenia, decreased appetite, urinary tract infection, AST/ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, and hypertension. Serious adverse reactions included myelodysplastic syndrome/acute myeloid leukemia, bone marrow suppression, and cardiovascular effects.

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This burst was prepared by the Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.