ZEJULA- niraparib_tablet, film coated

Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that 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 BRCA1/2 BRCA1/2 The pharmacodynamic response of niraparib has not been characterized. Hypertension and Cardiovascular Effects Niraparib has the potential to cause effects on pulse rate and blood pressure in patients receiving the recommended dose, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) [see Nonclinical Toxicology 13. 2 In the PRIMA study, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at most on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 22. 0 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24. 6 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 15. 9 mmHg in the niraparib and placebo arms, respectively. In the NOVA study, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at all on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 24. 8 beats/min in the niraparib and placebo arms, respectively. 3 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 16. Cardiac Electrophysiology The potential for QTc prolongation with niraparib was evaluated in a randomized, placebo‑controlled trial in patients with cancer (367 patients on niraparib and 179 patients on placebo). No large changes in the mean QTc interval (>20 ms) were detected in the trial following the treatment of niraparib 300 mg once daily. Following a single-dose administration of 300 mg niraparib, the mean (+/-SD) peak plasma concentration (C max max Absorption The absolute bioavailability of niraparib is approximately 73%. Following oral administration of niraparib, peak plasma concentration, C max Food Effect: max inf Distribution Niraparib is 83. 0% bound to human plasma proteins. The average (+/-SD) apparent volume of distribution (Vd/F) was 1,220 (+/-1,114) L. In a population pharmacokinetic analysis, the Vd/F of niraparib was 1,074 L in patients with cancer. Elimination Following multiple daily doses of 300 mg of niraparib, the mean half-life (t 1/2 Metabolism: Excretion: Specific Populations Age (18 to 65 years), race/ethnicity, and mild to moderate renal impairment (CLcr >=30 to 90 mL/min) had no clinically significant effect on the pharmacokinetics of niraparib. The effect of severe renal impairment (CLcr <30 mL/min) or end-stage renal disease undergoing hemodialysis on the pharmacokinetics of niraparib is unknown. Patients with Hepatic Impairment: In a trial of patients with moderate hepatic impairment (total bilirubin >=1. 5 x ULN to 3. 0 x ULN and any AST level) (n = 8), niraparib AUC inf [see Dosage and Administration 2. 4 max The effect of severe hepatic impairment (total bilirubin >3. 0 x ULN and any AST level) on the pharmacokinetics of niraparib is unknown. Drug Interaction Studies No clinical drug interaction studies have been performed with ZEJULA. In Vitro Studies: Inhibition of Cytochrome P450 CYP) Enzymes: Induction of CYP Enzymes: Substrate of CYP Enzymes: Inhibition of Uridine 5'-Diphospho-Glucuronosyltransferases (UGTs): Inhibition of Transporter Systems: Niraparib is an inhibitor of multidrug and toxin extrusion (MATE) 1 and 2 with IC 50 The M1 metabolite is not an inhibitor of P-gp, BCRP, BSEP, MRP2, or MATE1 or 2. Neither niraparib nor M1 is an inhibitor of organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT1)1, organic anion transporter (OAT)1, OAT3, or OCT2. Substrate of Transporter Systems:.

ZEJULA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: 1. 1 BRCA 1. 1 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. ZEJULA is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAmut) 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-approved companion diagnostic for ZEJULA [see Dosage and Administration (2.

First-line maintenance treatment of advanced ovarian cancer: o 2. 2 Maintenance treatment of recurrent germline BRCA-mutated ovarian cancer: 2. 4 Maintenance Treatment of Recurrent Germline BRCA Select patients for the maintenance treatment of recurrent ovarian cancer with ZEJULA based on the presence of deleterious or suspected deleterious germline BRCA mutations [see Clinical Studies (14. 2) Information on FDA-approved tests for the detection of deleterious or suspected deleterious germline BRCA mutations for this indication is available at https://www. gov/companiondiagnostics Continue treatment with ZEJULA until disease progression or unacceptable toxicity. Instruct patients to take their dose of ZEJULA at approximately the same time each day. Advise patients to swallow each tablet whole and not to chew, crush, or split ZEJULA prior to swallowing. ZEJULA may be taken with or without food. Bedtime administration may be a potential method for managing nausea. In the case of a missed dose of ZEJULA, instruct patients to take their next dose at its regularly scheduled time. If a patient vomits or misses a dose of ZEJULA, an additional dose should not be taken. First-Line Maintenance Treatment of Advanced Ovarian Cancer For the maintenance treatment of advanced ovarian cancer, patients should start treatment with ZEJULA no later than 12 weeks after their most recent platinum-containing regimen. Maintenance Treatment of Recurrent Germline BRCA The recommended dosage of ZEJULA is 300 mg taken orally once daily. For the maintenance treatment of recurrent ovarian cancer, patients should start treatment with ZEJULA no later than 8 weeks after their most recent platinum-containing regimen. To manage adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. The recommended dose modifications for adverse reactions are listed in Tables 1, 2, and 3. Recommended Dose Modifications for Adverse Reactions a Starting Dose Level 200 mg 300 mg First dose reduction 100 mg/day a 200 mg/day Second dose reduction Discontinue ZEJULA. 100 mg/day a Table 2. Dose Modifications for Non-Hematologic Adverse Reactions CTCAE = Common Terminology Criteria for Adverse Events. Non-hematologic CTCAE >=Grade 3 adverse reaction that persists despite medical management Table 1 CTCAE >=Grade 3 treatment-related adverse reaction lasting more than 28 days while patient is administered ZEJULA 100 mg/day Discontinue ZEJULA. Dose Modifications for Hematologic Adverse Reactions a [see Warnings and Precautions 5. 2 Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time [see Warnings and Precautions 5. 1 Platelet count <100,000/mcL First occurrence: Table 1 Second occurrence: Table 1 a Neutrophil <1,000/mcL or hemoglobin <8 g/dL Table 1 a Hematologic adverse reaction requiring transfusion Moderate Hepatic Impairment For patients with moderate hepatic impairment, reduce the starting dosage of ZEJULA to 200 mg once daily. Monitor patients for hematologic toxicity and reduce the dose further, if needed [see Dosage and Administration 2. 3 Use in Specific Populations 8. 7 Clinical Pharmacology 12.

The following clinically significant adverse reactions are described elsewhere in the labeling: [see Warnings and Precautions 5. 1 [see Warnings and Precautions 5. 2 [see Warnings and Precautions 5. 3 [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. 1 To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 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 728 patients received niraparib or placebo. Among patients who received ZEJULA, the median duration of treatment was 11. 1 months (range: 0. 03 to 29 months). All Patients Receiving ZEJULA in PRIMA: Permanent discontinuation due to adverse reactions occurred in 12% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >1% of patients who received ZEJULA included thrombocytopenia (3. 7%), anemia (1. 9%), and nausea and neutropenia (1. Adverse reactions led to dose reduction or interruption in 80% of patients, most frequently from thrombocytopenia (56%), anemia (33%), and neutropenia (20%). Table 4 Table 5 Table 4. Adverse Reactions Reported in >=10% of All Patients Receiving ZEJULA in PRIMA a AST/ALT = Aspartate transaminase/alanine aminotransferase. a b c d e Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 484) % Placebo (n = 244) % ZEJULA (n = 484) % Placebo (n = 244) % Blood and lymphatic system disorders Thrombocytopenia 66 5 39 0. 4 Anemia 64 18 31 2 Neutropenia c 42 8 21 1 Leukopenia d 28 9 5 0. 4 Gastrointestinal disorders Nausea 57 28 1 1 Constipation 40 20 1 0. 4 Vomiting 22 12 1 1 General disorders and administration site conditions Fatigue 51 41 3 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain 39 38 1 0 Nervous system disorders Headache 26 15 0. 4 0 Dizziness 19 13 0 0. 4 Psychiatric disorders Insomnia 25 15 1 0. 4 Respiratory, thoracic, and mediastinal disorders Dyspnea 22 13 0. 4 1 Cough 18 15 0 0. 4 Metabolism and nutrition disorders Decreased appetite 19 8 1 0 Vascular disorders Hypertension 18 7 6 1 Investigations AST/ALT elevation 14 7 3 0. 8 Renal and urinary disorders Acute kidney injury e 12 5 0. 2 0 Table 5. Abnormal Laboratory Findings in >=25% of All Patients Receiving ZEJULA in PRIMA Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 484) % Placebo (n = 244) % ZEJULA (n = 484) % Placebo (n = 244) % Decreased hemoglobin 87 66 29 1 Decreased platelets 74 13 37 0 Decreased leukocytes 71 36 9 0 Increased glucose 66 57 3 3 Decreased neutrophils 66 25 23 1 Decreased lymphocytes 51 29 7 3 Increased alkaline phosphatase 46 21 1 0 Increased creatinine 40 23 0 0 Decreased magnesium 36 34 1 0 Increased aspartate aminotransferase 35 17 1 0. 4 Increased alanine aminotransferase 29 17 2 1 Patients Receiving ZEJULA with Dose Based on Baseline Weight or Platelet Count in PRIMA: Serious adverse reactions occurred in 27% of patients receiving ZEJULA. Serious adverse reactions in >2% of patients were anemia (8%), and thrombocytopenia (7%). No fatal adverse reactions occurred. Permanent discontinuation due to adverse reactions occurred in 14% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >2% of patients who received ZEJULA included thrombocytopenia and anemia (3% each) and nausea (2. Adverse reactions led to dose reduction or interruption in 72% of patients, most frequently from thrombocytopenia (40%), anemia (23%), and neutropenia (15%). Table 6 Table 7 Table 6. Adverse Reactions Reported in >=10% of Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA a a b c d e Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 169) % Placebo (n = 86) % ZEJULA (n = 169) % Placebo (n = 86) % Blood and lymphatic system disorders Thrombocytopenia 54 5 21 1 Anemia 50 28 23 1 Neutropenia c 36 8 15 1 Leukopenia d 28 11 5 0 Gastrointestinal disorders Nausea 53 21 1 0 Constipation 31 15 1 1 Vomiting 17 9 0 1 General disorders and administration site conditions Fatigue 48 36 3 0 Nervous system disorders Headache 22 17 1 0 Dizziness 14 13 0 0 Psychiatric disorders Insomnia 21 14 0 0 Metabolism and nutrition disorders Decreased appetite 19 5 1 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 18 10 0 1 Vascular disorders Hypertension 17 9 5 2 Renal and urinary disorders Acute kidney injury e 12 5 1 0 Table 7. Abnormal Laboratory Findings in >=25% of All Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 169) % Placebo (n = 86) % ZEJULA (n = 169) % Placebo (n = 86) % Decreased hemoglobin 81 70 21 0 Decreased leukocytes 70 36 6 0 Decreased platelets 63 15 18 0 Increased glucose 63 56 2 1 Decreased neutrophils 60 27 15 0 Decreased lymphocytes 52 30 5 4 Decreased magnesium 44 30 0 0 Increased alkaline phosphatase 43 17 1 0 Increased creatinine 41 22 0 0 Increased aspartate aminotransferase 31 19 1 0 Increased alanine aminotransferase 28 15 2 2 Maintenance Treatment of Recurrent Germline BRCA The safety of monotherapy with ZEJULA 300 mg once daily has been studied in 136 patients with platinum-sensitive recurrent g BRCA Table 8 Table 9 BRCA Table 8. Adverse Reactions Reported in >=10% of Patients Receiving ZEJULA in NOVA gBRCAmut Cohort a b c d e 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 Table 9. Abnormal Laboratory Findings in >=25% of Patients Receiving ZEJULA in NOVA gBRCAmut Cohort 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 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. , memory impairment, concentration impairment). Respiratory, Thoracic, and Mediastinal Disorders Non-infectious pneumonitis. Skin and Subcutaneous Tissue Disorders Photosensitivity. Vascular Disorders Hypertensive crisis.

Lactation: Advise not to breastfeed. 2 Risk Summary Based on its mechanism of action, ZEJULA can cause fetal harm when administered to pregnant women [see Clinical Pharmacology 12. 1 [see Warnings and Precautions 5. 2 Nonclinical Toxicology 13. 1 The background risk of major birth defects and miscarriage for the indicated population is unknown. 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. Risk Summary No data are available regarding the presence of niraparib or its metabolites in human milk, or on its effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during treatment with ZEJULA and for 1 month after receiving the last dose. ZEJULA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations 8. 1 Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating treatment with ZEJULA. Contraception Females: Infertility Males: [see Nonclinical Toxicology 13. 1 The safety and effectiveness of ZEJULA have not been established in pediatric patients. In PRIMA, 39% of patients were aged 65 years or older and 10% were aged 75 years or older. In NOVA, 35% of patients were aged 65 years or older and 8% were aged 75 years or older. No overall differences in safety and effectiveness of ZEJULA were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is necessary for patients with mild (CLcr: 60 to 89 mL/min) to moderate (CLcr: 30 to 59 mL/min) renal impairment. The degree of renal impairment was determined by creatinine clearance as estimated by the Cockcroft-Gault equation. The safety of ZEJULA in patients with severe renal impairment or end-stage renal disease undergoing hemodialysis is unknown. For patients with moderate hepatic impairment, reduce the starting dosage of niraparib to 200 mg once daily [see Dosage and Administration 2. 4 [see Dosage and Administration 2. 3 For patients with mild hepatic impairment (total bilirubin ULN), no dose adjustment is needed. The recommended dose of ZEJULA has not been established for patients with severe hepatic impairment (total bilirubin >3. 0 x ULN and any AST level) [see Clinical Pharmacology 12.

NONCLINICAL TOXICOLOGY
Carcinogenicity studies have not been conducted with niraparib. Niraparib was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans. Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test. Fertility studies in animals have not been conducted with niraparib. In repeat-dose oral toxicity studies, niraparib was administered daily for up to 3 months’ duration in rats and dogs. Reduced sperm, spermatids, and germ cells in epididymides and testes were observed at doses >=10 mg/kg and >=1. 5 mg/kg in rats and dogs, respectively. These dose levels resulted in systemic exposures approximately 0. 012 times, respectively, the human exposure (AUC 0-24h In vitro, niraparib bound to DAT, NET, and SERT and inhibited uptake of norepinephrine and dopamine in cells with IC 50 min Intravenous administration of niraparib to vagotomized dogs over 30 minutes at 1, 3, and 10 mg/kg resulted in an increased range of arterial pressures of 13% to 20%, 18% to 27%, and 19% to 25%, respectively, and increased range of heart rates of 2% to 11%, 4% to 17%, and 12% to 21%, respectively, above pre-dose levels. The unbound plasma concentrations of niraparib in dogs at these dose levels were approximately 0. 8 times the unbound C max In addition, niraparib crossed the blood-brain barrier in rats and monkeys following oral administration. The cerebrospinal fluid:plasma C max.
CLINICAL STUDIES
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 the FDA-approved Myriad myChoice CDx assay. HRD positive status included either tumor BRCA BRCA 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. In some cases, criteria other than RECIST, such as clinical signs and symptoms and increasing CA-125, were also applied. Overall survival was an additional efficacy outcome measure. PFS testing was performed hierarchically: first in the homologous recombination (HR)-deficient (HRD positive) population, then in the overall population. The median age of 62 ranged from 32 to 85 years among patients randomized with ZEJULA and 33 to 88 years among patients randomized with placebo. Eighty-nine percent of all patients were White. Sixty-nine percent of patients randomized with ZEJULA and 71% of patients randomized with placebo had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 at study baseline. Approximately 45% of patients were enrolled in the U. In the overall population, 65% of patients had stage III disease and 35% had stage IV disease. Sixty‑seven percent of the patients received NACT. Sixty-nine percent of the patients had a complete response to the first-line platinum-based chemotherapy. Approximately 35% (n = 258) of patients received a starting dose of 200 or 300 mg depending on baseline body weight and platelet count. Among those patients, 186 patients received a starting dose of 200 mg. PRIMA demonstrated a statistically significant improvement in PFS for patients randomized to ZEJULA as compared with placebo in the HR-deficient and overall population ( Table 1 Table 10. Efficacy Results en dash PRIMA (determined by BICR a BICR = Blinded Independent Central Review, HR = Homologous Recombination, NE = not estimable. a b c HR-Deficient Population Overall Population ZEJULA (n = 247) Placebo (n = 126) ZEJULA (n = 487) Placebo (n = 246) Progression-free survival events, n (%) 81 (33) 73 (58) 232 (48) 155 (63) Progression-free survival median in months (95% CI) 21. 5) Hazard ratio b 0. 0001 In exploratory subgroup analyses of patients who were administered a starting dose of ZEJULA or matched placebo based on baseline weight or platelet count, the hazard ratio for PFS was 0. 39 (95% CI: 0. 72) in the HR-deficient subgroup (n = 130) and 0. 68 (95% CI: 0. 97) in the overall population (n = 258). Progression-Free Survival en dash PRIMA Patients with HR-Deficient Tumors (Intent-to-Treat Population, N = 373) Figure 2. Progression-Free Survival en dash PRIMA Overall Population (Intent-to-Treat Population, N = 733) At the time of the PFS analysis, overall survival data were immature, with 11% deaths in the overall population. Progression-Free Survival in Patients with HR-Deficient Tumors (Intent-to-Treat Population, n = 373) Figure 2. Progression-Free Surivival in the Overall Population (Intent-to-Treat Population, n=733) 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 BRCA BRCA BRCA BRCA BRCA BRCA BRCA The major efficacy outcome measure, PFS, was determined primarily by central independent assessment per RECIST version 1. Overall survival (OS) was an additional outcome measure. For the g BRCA The trial demonstrated a statistically significant improvement in PFS for patients randomized to ZEJULA as compared with placebo in the g BRCA Table 1 Table 11. Efficacy Results en dash NOVA gBRCAmut Cohort (IRC Assessment a IRC = Independent Review Committee, g BRCA BRCA- a b c ZEJULA (n = 138) Placebo (n = 65) Progression-free survival median in months (95% CI) 21. 2) Hazard ratio b 0. 0001 Figure 3. Progression-Free Survival en dash NOVA gBRCAmut Cohort Based on IRC Assessment (N = 203) g BRCA BRCA A final OS analysis was conducted after 154 events were observed. Exploratory OS results showed a HR of 0. 85 (95% CI: 0. 20) in the g BRCA Figure 3. Progression-Free Survival in the gBRCAmut Cohort Based on IRC Assessment (Intent-to-Treat Population, n = 203).

GlaxoSmithKline LLC

ZEJULA- niraparib_tablet, film coated Product manual source documgent