Zejula Drug Information

Generic name: NIRAPARIB

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Uses of Zejula

is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:
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 and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: o a deleterious or suspected deleterious BRCA mutation, and/or o genomic instability. Select patients for therapy based on an FDA‑authorized companion diagnostic for ZEJULA. ( 1.1 , 2.1 )
for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA -mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Select patients for therapy based on an FDA‑authorized companion diagnostic for ZEJULA. ( 1.2 , 2.1 ) 1.1 First-Line Maintenance Treatment of HRD-Positive Advanced Ovarian Cancer ZEJULA is indicated 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 and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either:
a deleterious or suspected deleterious BRCA mutation, and/or
genomic instability. Select patients for therapy based on an FDA‑authorized companion diagnostic for ZEJULA [see Dosage and Administration ( 2.1 )] . 1.2 Maintenance Treatment of Recurrent Germline BRCA -Mutated Ovarian Cancer ZEJULA is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA -mutated (g BRCA mut) recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Select patients for therapy based on an FDA‑authorized companion diagnostic for ZEJULA [see Dosage and Administration ( 2.1 )] .

Dosage & Administration of Zejula

^a If further dose reduction below 100 mg/day is required, discontinue ZEJULA.
Starting Dose Level	200 mg
First dose reduction	100 mg/day^a
Second dose reduction	Discontinue ZEJULA.

Side Effects of Zejula

The following clinically significant adverse reactions are described elsewhere in the labeling:
MDS/AML [see Warnings and Precautions ( 5.1 )]
Bone marrow suppression [see Warnings and Precautions ( 5.2 )]
Hypertension and cardiovascular effects [see Warnings and Precautions ( 5.3 )]
Posterior reversible encephalopathy syndrome [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (incidence ≥10%) in patients who received ZEJULA were 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a pooled safety population of patients (n = 1,314) with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with ZEJULA monotherapy including PRIMA (n = 484), NOVA (n = 367), and another clinical trial (n = 463), the most common adverse reactions >10% were nausea (65%), thrombocytopenia (60%), anemia (56%), fatigue (55%), constipation (39%), musculoskeletal pain (36%), abdominal pain (35%), vomiting (33%), neutropenia (31%), decreased appetite (24%), leukopenia (24%), insomnia (23%), headache (23%), dyspnea (22%), rash (21%), diarrhea (18%), hypertension (17%), cough (16%), dizziness (14%), acute kidney injury (13%), urinary tract infection (12%), and hypomagnesemia (11%). First-Line Maintenance Treatment of HRD-Positive Advanced Ovarian Cancer The safety of ZEJULA for the treatment of patients with advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was studied in the PRIMA trial, a placebo-controlled, double-blind study in which 484 patients received ZEJULA. Among this population, 245 patients were HRD-positive and their median duration of treatment was 13 months (range: 3 days to 29 months). HRD-Positive Patients Receiving ZEJULA in PRIMA: Serious adverse reactions occurred in 30% of patients receiving ZEJULA. Serious adverse reactions in >2% of patients were thrombocytopenia (11%) and anemia (5%). Fatal adverse reactions occurred in 1.6% of patients, including AML (0.4%), cardiac arrest (0.4%), intestinal perforation (0.4%), and sudden death (0.4%). Permanent discontinuation due to adverse reactions occurred in 11% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >1% of patients who received ZEJULA included thrombocytopenia (3.7%), nausea (1.6%), and anemia (1.2%). Adverse reactions led to dose reduction or interruption in 79% of patients, most frequently (>10%) from thrombocytopenia (53%), anemia (32%), and neutropenia (19%). Tables 4 and 5 summarize the common adverse reactions and abnormal laboratory findings observed in the PRIMA trial. Table 4. Adverse Reactions Reported in ≥10% of HRD-Positive Patients Receiving ZEJULA in PRIMA a AST/ALT = Aspartate aminotransferase/alanine aminotransferase. a All adverse reactions in the table consist of grouped preferred terms except for nausea, vomiting, decreased appetite, headache, and insomnia, which are single preferred terms. b Common Terminology Criteria for Adverse Events version 4.02. c Includes neutropenia, neutropenic infection, neutropenic sepsis, and febrile neutropenia. d Includes leukopenia, lymphocyte count decreased, lymphopenia, and white blood cell count decreased. e Includes blood creatinine increased, blood urea increased, acute kidney injury, and renal failure. Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 245) % Placebo (n = 125) % ZEJULA (n = 245) % Placebo (n = 125) % Blood and lymphatic system disorders Thrombocytopenia 66 4 38 0 Anemia 65 16 31 2 Neutropenia c 43 9 17 2 Leukopenia d 29 10 6 0.8 Gastrointestinal disorders Nausea 62 34 1 0 Constipation 40 26 1 0.8 Vomiting 23 14 2 0.8 General disorders and administration site conditions Fatigue 52 44 2 2 Musculoskeletal and connective tissue disorders Musculoskeletal pain 46 38 0.8 0 Nervous system disorders Headache 27 15 0.8 0 Dizziness 20 11 0 0 Psychiatric disorders Insomnia 25 16 0.4 0.8 Anxiety 12 6 0 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 21 15 0 0.8 Cough 20 14 0 0.8 Metabolism and nutrition disorders Decreased appetite 20 6 0.4 0 Vascular disorders Hypertension 20 8 7 2 Investigations AST/ALT elevation 14 8 3 0 Renal and urinary disorders Acute kidney injury e 13 3 0 0 Table 5. Abnormal Laboratory Findings in ≥25% of HRD-Positive Patients Receiving ZEJULA in PRIMA Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 245) % Placebo (n = 125) % ZEJULA (n = 245) % Placebo (n = 125) % Decreased hemoglobin 85 65 28 2 Decreased leukocytes 72 37 9 0 Decreased platelets 71 11 36 0 Decreased neutrophils 64 28 21 2 Increased glucose 62 57 3 4 Decreased lymphocytes 55 26 9 5 Increased alkaline phosphatase 48 19 2 0.8 Increased creatinine 40 24 0 0 Decreased magnesium 39 35 0.4 0 Increased aspartate aminotransferase 35 18 2 0.8 Increased alanine aminotransferase 32 19 2 2 Increased calcium 31 23 1 0 HRD-Positive Patients Receiving ZEJULA with Dose Based on Baseline Weight or Platelet Count in PRIMA: Among patients who received ZEJULA with the dose based on weight and platelet count (n = 86), the median duration of treatment was 12 months (range: 4 days to 16 months). Serious adverse reactions occurred in 24% of patients receiving ZEJULA. Serious adverse reactions in >2% of patients were anemia (9%) and thrombocytopenia (2%). Permanent discontinuation due to adverse reactions occurred in 11% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >2% of patients who received ZEJULA included nausea (3.5%). Adverse reactions led to dose reduction or interruption in 72% of patients, most frequently (>10%) from thrombocytopenia (35%), anemia (22%), and neutropenia (17%). Tables 6 and 7 summarize adverse reactions and abnormal laboratory findings observed in this group. Table 6. Adverse Reactions Reported in ≥10% of HRD-Positive Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA a a All adverse reactions in the table consist of grouped preferred terms except for nausea, vomiting, decreased appetite, headache, and insomnia, which are single preferred terms. b Common Terminology Criteria for Adverse Events version 4.02. c Includes neutropenia, neutropenic infection, neutropenic sepsis, and febrile neutropenia. d Includes leukopenia, lymphocyte count decreased, lymphopenia, and white blood cell count decreased. e Includes blood creatinine increased, blood urea increased, acute kidney injury, and renal failure. Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 86) % Placebo (n = 42) % ZEJULA (n = 86) % Placebo (n = 42) % Blood and lymphatic system disorders Thrombocytopenia 51 2 16 0 Anemia 49 21 22 0 Neutropenia c 35 7 13 0 Leukopenia d 26 7 6 0 Gastrointestinal disorders Nausea 55 21 0 0 Constipation 26 29 1 2 Vomiting 16 17 0 2.4 General disorders and administration site conditions Fatigue 47 41 0 0 Nervous system disorders Headache 24 19 1 0 Dizziness 15 7 0 0 Psychiatric disorders Insomnia 21 19 0 0 Metabolism and nutrition disorders Decreased appetite 19 7 1 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 20 12 0 2 Vascular disorders Hypertension 16 12 4 5 Renal and urinary disorders Acute kidney injury e 14 2 0 0 Table 7. Abnormal Laboratory Findings in ≥25% of HRD-Positive Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 86) % Placebo (n = 42) % ZEJULA (n = 86) % Placebo (n = 42) % Decreased hemoglobin 74 67 21 0 Decreased leukocytes 70 36 6 0 Decreased platelets 58 17 14 0 Increased glucose 57 62 4 2 Decreased neutrophils 57 31 13 0 Decreased lymphocytes 55 24 6 5 Decreased magnesium 51 41 0 0 Increased alkaline phosphatase 42 12 2 0 Increased creatinine 42 24 0 0 Increased aspartate aminotransferase 31 21 2 0 Increased alanine aminotransferase 30 17 2 2 Increased calcium 29 36 0 0 Maintenance Treatment of Recurrent Germline BRCA -Mutated Ovarian Cancer The safety of monotherapy with ZEJULA 300 mg once daily has been studied in 136 patients with platinum-sensitive recurrent g BRCA mut ovarian, fallopian tube, and primary peritoneal cancer in the NOVA trial. The percentages of patients who experienced adverse reactions in NOVA that led to dose reduction and dose interruption were 79% and 68%, respectively, most frequently from thrombocytopenia (41% and 35%, respectively) and anemia (23% and 20%, respectively). The permanent discontinuation rate due to adverse reactions in NOVA was 13%. The median exposure to ZEJULA in these patients was 367 days. Table 8 and Table 9 summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in patients treated with ZEJULA in the g BRCA mut cohort in NOVA. Table 8. Adverse Reactions Reported in ≥10% of Patients Receiving ZEJULA in NOVA gBRCAmut Cohort g BRCA mut = Germline BRCA -mutated. a Common Terminology Criteria for Adverse Events version 4.02. b Includes platelet count decreased. c Includes hemoglobin decreased. d Includes neutrophil count decreased. e Includes asthenia, malaise, and lethargy. Adverse Reaction Grades 1-4 a Grades 3-4 a ZEJULA (n = 136) % Placebo (n = 65) % ZEJULA (n = 136) % Placebo (n = 65) % Gastrointestinal disorders Nausea 77 34 5 3 Vomiting 40 15 4 0 Constipation 38 18 0.7 2 Dyspepsia 17 12 0 0 Dry mouth 13 3 0.7 0 Blood and lymphatic system disorders Thrombocytopenia b 71 5 38 2 Anemia c 52 8 33 0 Neutropenia d 31 9 21 3 General disorders and administration site conditions Fatigue e 61 35 8 2 Nervous system disorders Headache 35 8 0.7 0 Dizziness 18 9 0 0 Dysgeusia 13 2 0 0 Metabolism and nutrition disorders Decreased appetite 22 14 0 0 Vascular disorders Hypertension 21 8 8 5 Psychiatric disorders Insomnia 18 6 0.7 0 Anxiety 10 11 0.7 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 17 5 2 0 Cough 16 2 0 0 Nasopharyngitis 13 5 0 0 Musculoskeletal and connective tissue disorders Back pain 16 11 0.7 0 Infections and infestations Urinary tract infection 11 9 0 2 Skin and subcutaneous tissue disorders Rash 10 2 0 0 The following adverse reactions have been identified in ≥1 to <10% of the 136 patients receiving ZEJULA in the g BRCA mut cohort of the NOVA trial and not included in the table: palpitations (9%), mucositis/stomatitis (9%), MDS/AML (7%), tachycardia (7%), and bronchitis (4%). Table 9. Abnormal Laboratory Findings in ≥25% of Patients Receiving ZEJULA in NOVA gBRCAmut Cohort g BRCA mut = Germline BRCA- mutated. Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 136) % Placebo (n = 65) % ZEJULA (n = 136) % Placebo (n = 65) % Decrease in hemoglobin 85 62 32 0 Decrease in platelet count 81 25 38 2 Decrease in white blood cell count 71 37 9 2 Decrease in absolute neutrophil count 56 34 23 3 Increase in aspartate aminotransferase 35 25 0.7 0 Increase in alanine aminotransferase 25 15 0.7 2 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZEJULA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders Pancytopenia. Immune System Disorders Hypersensitivity (including anaphylaxis). Nervous System Disorders Posterior reversible encephalopathy syndrome (PRES). Psychiatric Disorders Confusional state/disorientation, hallucination, cognitive impairment (e.g., memory impairment, concentration impairment). Respiratory, Thoracic, and Mediastinal Disorders Non-infectious pneumonitis. Skin and Subcutaneous Tissue Disorders Photosensitivity. Vascular Disorders Hypertensive crisis.

Warnings & Cautions for Zejula

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML occurred in patients exposed to ZEJULA, and some cases were fatal. Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed. ( 5.1 )
Bone Marrow Suppression: Test complete blood counts weekly for the first month, monthly for the next 11 months, and periodically thereafter for clinically significant changes. ( 5.2 )
Hypertension and Cardiovascular Effects: Monitor blood pressure and heart rate at least weekly for the first 2 months, then monthly for the first year and periodically thereafter during treatment with ZEJULA. Manage with antihypertensive medications and adjustment of the dose of ZEJULA, if necessary. ( 5.3 )
Posterior Reversible Encephalopathy Syndrome (PRES): PRES has occurred in patients treated with ZEJULA. Discontinue ZEJULA if PRES is confirmed. ( 5.4 )
Embryo-Fetal Toxicity: ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 ) 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), including cases with a fatal outcome, have been reported in patients who received ZEJULA. In PRIMA, of patients within the HRD-positive population, MDS/AML occurred in 8 out of 245 (3.3%) patients treated with ZEJULA and in 3 out of 125 (2.4%) patients treated with placebo with a follow-up of 6.1 years [see Adverse Reactions ( 6.1 )] . The duration of therapy with ZEJULA in patients who developed secondary MDS/cancer-therapy–related AML varied from 5.5 months to 5 years. In NOVA, of patients within the g BRCA mut cohort, MDS/AML occurred in 10 out of 136 (7%) patients treated with ZEJULA and in 2 out of 65 (3%) patients treated with placebo [see Adverse Reactions (6.1) ] . The duration of therapy with ZEJULA in patients who developed secondary MDS/cancer-therapy–related AML varied from 3.6 months to 5.9 years. All patients who developed secondary MDS/cancer-therapy–related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue ZEJULA if MDS/AML is confirmed. 5.2 Bone Marrow Suppression Hematologic adverse reactions, including thrombocytopenia, anemia, neutropenia, and/or pancytopenia have been reported in patients treated with ZEJULA [see Adverse Reactions (6) ] . In PRIMA, the overall incidences of ≥Grade 3 thrombocytopenia, anemia, and neutropenia were reported in 39%, 31%, and 21%, respectively, of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred in 4%, 2%, and 2%, respectively, of patients. In patients who were administered a starting dose of ZEJULA based on baseline weight or platelet count, ≥Grade 3 thrombocytopenia, anemia, and neutropenia were reported in 22%, 23%, and 15%, respectively, of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred in 3%, 3%, and 2%, respectively, of patients. In NOVA, ≥Grade 3 thrombocytopenia, anemia, and neutropenia were reported in 29%, 25%, and 20%, respectively, of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred in 3%, 1%, and 2%, respectively, of patients. Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time. If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics [see Dosage and Administration ( 2.3 )]. 5.3 Hypertension and Cardiovascular Effects Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA [see Adverse Reactions (6) ] . In PRIMA, Grade 3 to 4 hypertension occurred in 6% of patients treated with ZEJULA compared with 1% of placebo-treated patients with a median time from first dose to first onset of 43 days (range: 1 to 531 days) and with a median duration of 12 days (range: 1 to 61 days). There were no discontinuations due to hypertension. In NOVA, Grade 3 to 4 hypertension occurred in 9% of patients treated with ZEJULA compared with 2% of placebo-treated patients with a median time from first dose to first onset of 77 days (range: 4 to 504 days) and with a median duration of 15 days (range: 1 to 86 days). Discontinuation due to hypertension occurred in <1% of patients. Monitor blood pressure and heart rate at least weekly for the first 2 months, then monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Medically manage hypertension with antihypertensive medications and adjustment of the dose of ZEJULA, if necessary [see Dosage and Administration ( 2.3 ), Nonclinical Toxicology ( 13.2 )] . 5.4 Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) occurred in 0.1% of 2,165 patients treated with ZEJULA in clinical trials and has also been described in postmarketing reports [see Adverse Reactions ( 6.2 )]. Signs and symptoms of PRES include seizure, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging. Monitor all patients treated with ZEJULA for signs and symptoms of PRES. If PRES is suspected, promptly discontinue ZEJULA and administer appropriate treatment. The safety of reinitiating ZEJULA in patients previously experiencing PRES is not known. 5.5 Embryo-Fetal Toxicity Based on its mechanism of action, ZEJULA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . ZEJULA has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions ( 5.2 ), Nonclinical Toxicology ( 13.1 )] . Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of ZEJULA [see Use in Specific Populations ( 8.1 , 8.3 )] .

Pregnancy Safety for Zejula

Pregnancy Risk Summary Based on its mechanism of action, ZEJULA can cause fetal harm when administered to pregnant women . There are no data regarding the use of ZEJULA in pregnant women to inform the drug-associated risk. ZEJULA has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) . Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. Apprise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Pediatric Use of Zejula

Pediatric Use The safety and effectiveness of ZEJULA have not been established in pediatric patients.

Clinical Studies of Zejula

First-Line Maintenance Treatment of

HRD-Positive Advanced Ovarian Cancer PRIMA (NCT02655016) was a double-blind, placebo-controlled trial in which patients (N = 733) in complete or partial response to first-line platinum-based chemotherapy were randomized 2:1 to ZEJULA or matched placebo. Initially, the patients received a starting dosage of 300 mg once daily regardless of body weight or platelet count. The study was amended to include a starting dose of 200 mg for patients weighing <77 kg (<170 lbs) OR with a platelet count of <150,000/mcL or 300 mg for patients weighing ≥77 kg (≥170 lbs) AND who had a platelet count ≥150,000/mcL. Patients were randomized post‑completion of first‑line platinum‑based chemotherapy plus surgery.

Randomization was stratified by best response during the front‑line platinum regimen (complete response vs. partial response), neoadjuvant chemotherapy (NACT) (yes vs. no), and HRD status (positive vs. negative or not determined). HRD status was determined using Myriad MyChoice CDx assay. HRD‑positive status included either tumor BRCA mutant (t BRCA m) or a genomic instability score (GIS) ≥42. The major efficacy outcome measure, progression-free survival (PFS), was determined by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In some cases, criteria other than RECIST, such as clinical signs and symptoms and increasing CA-125, were also applied. Overall survival (OS) was an additional efficacy outcome measure.

Efficacy was evaluated in 373 patients in the HRD-positive population. The median age was 58 years (range 32 to 83 years). Eighty-seven percent of patients were White, 4.8% were Asian, 1.6% were Black or African American, 0.3% were Native Hawaiian or Other Pacific Islander, and 0.3% were American Indian or Alaska Native. Six percent of patients were Hispanic or Latino.

Seventy-five percent of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 at trial baseline. Approximately 47% of patients were enrolled in the U.S. or Canada. Sixty-four percent of patients had Stage III disease and 36% had Stage IV disease.

Sixty-three percent of the patients received NACT. Seventy-five percent of the patients had a complete response to the first-line platinum-based chemotherapy. Approximately 35% (n = 130) of patients received a starting dose of 200 or 300 mg depending on baseline body weight and platelet count. PRIMA demonstrated a statistically significant improvement in PFS for patients randomized to ZEJULA as compared with placebo in the HRD-positive population ( Table 10 and Figure 1 ). Table 10. Efficacy Results – PRIMA HRD-Positive Population Progression-Free Survival (PFS) a HRD = Homologous Recombination Deficient; NE = Not Estimable. a Efficacy analysis was based on blinded independent central review. b Based on a stratified Cox proportional hazards model. c Based on a stratified log-rank test.

ZEJULA (n = 247) Placebo (n = 126) PFS events, n (%) 81 73 PFS median in months (95% CI) 21.9 (19.3, NE)

Hazard ratio b (95% CI) 0.43 P value c <0.0001

In an exploratory subgroup analysis of patients in the HRD-positive population who were administered a starting dose of ZEJULA or matched placebo based on baseline weight or platelet count (n = 130), the hazard ratio (HR) for PFS was 0.39 (95% CI: 0.22, 0.72). Figure 1. PRIMA Progression-Free Survival – HRD-Positive Population HRD = Homologous Recombination Deficient. A final OS analysis was conducted in the HRD-positive population after 185 events were observed; the HR was 0.95 (95% CI: 0.71, 1.29) with a median OS of 71.9 months (95% CI: 55.5, NE) for patients treated with ZEJULA and 69.8 months (95% CI: 51.6, NE) for patients on placebo. Figure 1

Maintenance Treatment of Recurrent Germline

BRCA -Mutated Ovarian Cancer NOVA (NCT01847274) was 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 2:1 to ZEJULA 300 mg orally daily or matched placebo within 8 weeks of the last therapy. Treatment was continued until disease progression or unacceptable toxicity. All patients had received at least 2 prior platinum-containing regimens and were in response (complete or partial) to their most recent platinum-based regimen.

Randomization was stratified by time to progression after the penultimate platinum therapy (6 to <12 months and ≥12 months), use of bevacizumab in conjunction with the penultimate or last platinum regimen (yes/no), and best response during the most recent platinum regimen (complete response and partial response). Eligible patients were assigned to 1 of 2 cohorts based on the results of germline BRCA testing with Myriad BRACAnalysis CDx. Patients with deleterious or suspected deleterious germline BRCA mutations (g BRCA mut) were assigned to the germline BRCA -mutated (g BRCA mut) cohort (n = 203), and those without germline BRCA mutations were assigned to the non-g BRCA mut cohort (n = 350). The efficacy results are based on the g BRCA mut cohort only. The major efficacy outcome measure, PFS, was determined primarily by central independent assessment per RECIST version 1.1. In some cases, criteria other than RECIST, such as clinical signs and symptoms and increasing CA-125, were also applied.

Overall survival (OS) was an additional outcome measure. For the g BRCA mut cohort, the median age of patients was 57 years among patients treated with ZEJULA and 58 years among patients treated with placebo. Eighty-eight percent of all patients were White.

Sixty-six percent of patients receiving ZEJULA and 74% of patients receiving placebo had an ECOG PS of 0 at study baseline. Approximately 40% of patients were enrolled in the U.S. or Canada, and 51% of all patients were in complete response to most recent platinum‑based regimen, with 39% on both arms with an interval of 6 to 12 months since the penultimate platinum regimen. Twenty-four percent of those treated with ZEJULA and 26% treated with placebo had received prior bevacizumab therapy.

Approximately 50% of patients had 3 or more lines of treatment. The trial demonstrated a statistically significant improvement in PFS for patients randomized to ZEJULA as compared with placebo in the g BRCA mut cohort ( Table 11 and Figure 2 ). Table 11. Efficacy Results – NOVA gBRCAmut Cohort (IRC Assessment a ) g BRCA mut = germline BRCA -mutated; IRC = Independent Review Committee; NR = Not Reached. a Efficacy analysis was based on blinded central independent radiologic and clinical oncology review committee. b Based on a stratified Cox proportional hazards model. c Based on a stratified log-rank test. ZEJULA (n = 138) Placebo (n = 65) Progression-free survival median in months (95% CI) 21.0 (12.9, NR)

Hazard ratio b (95% CI) 0.26 P value c <0.0001 Figure 2.

Progression-Free Survival – NOVA g BRCA mut Cohort Based on IRC Assessment (N = 203) g BRCA mut = germline BRCA -mutated; IRC = Independent Review Committee. A final OS analysis was conducted after 154 events were observed. Exploratory OS results showed a HR of 0.85 (95% CI: 0.61, 1.20) in the g BRCA mut cohort with a median OS of 40.9 months (95% CI: 34.9, 52.9) for patients treated with ZEJULA and 38.1 months (95% CI: 27.6, 47.3) for patients on placebo.

Figure 2

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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