Profile
General Information
Zejula (niraparib) is a poly(ADP-ribose) polymerase (PARP) inhibitor.
Zejula is specifically indicated for the following:
- the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
- the treatment of advanced ovarian, fallopian tube, or primary peritoneal cancer patients, who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:
- A deleterious or suspected deleterious BRCA mutation, or
- genomic instability and who have progressed more than six months after response to the last platinum-based chemotherapy
- as a monotherapy maintenance treatment for women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy, regardless of biomarker status.
Zejula is supplied as a capsule for oral administration. Each capsule should be swallowed whole and may be taken with or without food. Zejula treatment should be continued until disease progression or unacceptable toxicity. In the case of a missed dose, the next dose should be administered at its regularly scheduled time. If a patient vomits or misses a dose of Zejula, an additional dose should not be taken.
The recommended dosing is as follows:
First-line maintenance treatment of advanced ovarian cancer:
- For patients weighing <77 kg (<170 lbs) OR with a platelet count <150,000/mcL, the recommended dosage is 200 mg taken orally once daily.
- For patients weighing ≥77 kg (≥170 lbs) AND a platelet count ≥150,000/ mcL, the recommended dosage is 300 mg taken orally once daily.
Maintenance treatment of recurrent ovarian cancer and treatment of advanced ovarian cancer after 3 or more chemotherapies:
- The recommended dosage is 300 mg taken orally once daily.
Mechanism of Action
Zejula (niraparib) is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown 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 was 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 homologous recombination deficiency that had either mutated or wild type BRCA1/2.
Side Effects
Adverse effects associated with the use of Zejula may include, but are not limited to, the following:
- 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
- hypertension
Clinical Trial Results
The FDA approval of Zejula was based on NOVA, a double-blind, placebo-controlled trial in which 553 patients with platinum sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomized 2:1 to Zejula 300 mg orally daily or matched placebo within 8 weeks of the last therapy. All patients had received at least two prior platinum-containing regimens and were in response (complete or partial) to their most recent platinum-based regimen. The major efficacy outcome measure, PFS (progression-free survival), was determined primarily by central independent assessment per RECIST. Among patients who were germline BRCA mutation carriers, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS. The median PFS for patients treated with niraparib was 21.0 months, compared to 5.5 months for control (p < 0.0001). For patients who were not germline BRCA mutation carriers but whose tumors were determined to be HRD positive, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS. The median PFS for patients with HRD-positive tumors who were treated with niraparib was 12.9 months, compared to 3.8 months for control (p < 0.0001). Niraparib also showed statistical significance in the overall non-germline BRCA mutant cohort, which included patients with both HRD-positive and HRD-negative tumors. The niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS. The median PFS for patients treated with niraparib was 9.3 months, compared to 3.9 months for control (p < 0.0001).
The FDA approval of Zejula for the treatment of advanced ovarian, fallopian tube, or primary peritoneal cancer patients, who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a deleterious or suspected deleterious BRCA mutation or genomic instability and who have progressed more than six months after response to the last platinum-based chemotherapy was based on the QUADRA study, a Phase 2, multi-center, open label, single arm clinical study. The trial enrolled a broad patient population including women with BRCA+ platinum-sensitive, resistant and refractory disease as well as women with HRD+ platinum-sensitive disease. Clinically meaningful and durable benefit was demonstrated in the FDA-indicated patient population with an objective response rate (ORR) of 24%. A median duration of response (mDOR) of 8.3 months was observed.
The FDA approval of Zejula monotherapy maintenance treatment for women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy, regardless of biomarker status was based on the phase III PRIMA study (ENGOT-OV26/GOG-3012), which enrolled women who had higher risk of disease progression. The primary endpoint in the PRIMA study was progression-free survival (PFS) analyzed sequentially, first in the homologous recombination deficient (HRd) population, then in the overall population. The PRIMA study significantly improved PFS for patients treated with Zejula, regardless of biomarker status. In the HRd population, Zejula resulted in a 57% reduction in the risk of disease progression or death vs. placebo and a 38% reduction in the risk of disease progression or death vs. placebo in the overall population.