Niraparib tosylate monohydrate and abiraterone acetate, a fixed-combination preparation containing a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor (niraparib) and a 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor (abiraterone), is an antineoplastic agent.1
Metastatic Castration-resistant Prostate Cancer
Niraparib/abiraterone, in combination with prednisone, is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA -mutated ( BRCA m) metastatic castration-resistant prostate cancer (mCRPC).1 An FDA-approved companion diagnostic test is required to confirm the presence of specific biomarkers prior to initiation of niraparib/abiraterone.1
The efficacy of niraparib/abiraterone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) was evaluated in the randomized, double-blind, placebo-controlled, multicenter, phase 3, MAGNITUDE trial (NCT03748641).1, 2 A total of 423 patients with homologous recombination repair ( HRR ) gene-mutated mCRPC were randomized in a 1:1 manner to receive either niraparib 200 mg or placebo in combination with abiraterone acetate 1,000 mg.1, 2 All patients received prednisone 10 mg daily and a gonadotropin-releasing hormone (GnRH) analog unless they had a prior bilateral orchiectomy.1, 2 Treatment was continued until there was evidence of unequivocal clinical progression, unacceptable toxicity, or death.2 Adult patients (≥18 years of age) with mCRPC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were prescreened for HRR biomarker status; patients required confirmation of gene alteration in ≥1 assay to be included in the HRR-positive cohort (herein, cohort 1).2 HRR biomarkers were identified on either tissue or blood samples and included either monoallelic or biallelic pathogenic alterations in ≥1 of the following: ATM , BRCA 1, BRCA 2, BRIP 1, CDK 12, CHEK 2, FANCA , HDAC 2, or PALB 2.2 These genes were specifically evaluated on the basis of previous research showing PARP inhibitor activity in this setting.2 Patients could have received prior treatment (e.g., docetaxel, androgen receptor-targeted therapies) for either metastatic castration-sensitive prostate cancer or non-mCRPC prior to enrollment.1, 2 With the exception of up to 4 months of abiraterone with prednisone, prior treatments for mCRPC and use of other PARP inhibitors were not allowed.1, 2 The primary study endpoint was radiographic progression-free survival (rPFS), defined as the time from randomization to the first occurrence of radiographic progression as assessed by a blinded independent central review or death due to any cause.1, 2 Secondary endpoints, including time to initiation of cytotoxic chemotherapy, time to symptomatic progression, and treatment-emergent adverse events, were also evaluated.2
Of the 423 patients enrolled, 225 (53%) had BRCA gene mutations.1 Among the 225 patients with a BRCA gene mutation, the median age was 68 years (range: 43-100), of which 66% were 65 years or older; 72% were white, 17% were Asian, and 1% were Black.1 Baseline ECOG performance status was 0 in 66% and 1 in 34% of patients enrolled.1 A statistically significant improvement in rPFS was reported in the niraparib/abiraterone group compared to placebo/abiraterone in patients with a BRCA mutation and in the cohort 1 intention-to-treat population.1, 2 The investigators concluded that the benefit in the intention-to-treat population was largely driven by the positive results seen in the subgroup of patients with a BRCA mutation, which demonstrated the greatest benefit.1, 2 In the BRCA mutation subgroup, disease progression or death occurred in 40% of patients in the niraparib/abiraterone group compared to 57% of patients in the placebo/abiraterone group (hazard ratio 0.53, 95% confidence interval 0.36-0.79) at a median of 16.6 versus 10.9 months, respectively.1, 2 A preplanned futility analysis in patients with HRR-negative mCRPC showed no benefit and further enrollment was closed to this patient population.2, 3 In a pre-specified second interim analysis, a clinically meaningful treatment effect continued to be observed, lengthening the median rPFS by 8.6 months in patients that received niraparib/abiraterone (19.5 months) versus placebo/abiraterone (10.9 months).3 Patients with a BRCA mutation continued to demonstrate a greater treatment response to niraparib/abiraterone, extending the rPFS by 15.5 months compared to placebo/abiraterone (29.3 months versus 13.8 months, respectively).3
The median duration of exposure to niraparib/abiraterone was 18 months (range: 0-37 months).1 Severe adverse reactions occurred in 41% of patients receiving niraparib/abiraterone; fatal adverse reactions, including COVID-19, cardiopulmonary arrest, dyspnea, pneumonia, and septic shock, occurred in 9% of patients.1 Permanent discontinuation of niraparib/abiraterone due to adverse events occurred in 15% of patients; discontinuation in >2% of patients occurred due to COVID-19 (4.4%), anemia (2.7%), asthenia (2.7%), and vomiting (2.7%).1 Dosage interruption was required due to an adverse event in 50% of patients; dosage reduction due to an adverse event was required in 28% of patients.1
Available guidelines from the American Urological Association (AUA) recommend offering a PARP inhibitor to patients with confirmed or suspected deleterious germline or somatic HRR gene-mutated (including BRCA -mutated) mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or taxane-based chemotherapy.4 For patients unable to take or obtain PARP inhibitors, platinum-based chemotherapy is an alternative.4 Use of PARP inhibitors in combination with abiraterone is not discussed in the guideline.4
Dispensing and Administration Precautions
Niraparib/abiraterone tablets should be taken orally on an empty stomach.1 Patients should not eat for 2 hours before and 1 hour after taking niraparib/abiraterone.1 Tablets should be swallowed whole with water.1 Do not break, crush, or chew tablets.1
If a patient misses a dose, instruct them to take the dose as soon as possible on the same day and resume their next dose at the normal schedule the following day.1
Store tablets at 20-25°C; excursions permitted to 15-30°C.1
The recommended dosage of niraparib/abiraterone for the treatment of deleterious or suspected deleterious BRCA -mutated ( BRCA m) metastatic castration-resistant prostate cancer (mCRPC) is 200 mg niraparib/1,000 mg abiraterone orally once daily in combination with prednisone 10 mg once daily until disease progression or unacceptable toxicity.1 Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently unless they have had a bilateral orchiectomy.1
Dosage Modifications for Toxicity
For adverse reactions, consider interruption of treatment, dosage reduction, or discontinuation.1 Treatment with niraparib/abiraterone should not be reinitiated until the toxicity has resolved to grade 1 or baseline.1 If the toxicity is attributed to one component of niraparib/abiraterone, the other component may be continued as a single agent at the current dose until the adverse reaction resolves and niraparib/abiraterone can be resumed.1
For hemoglobin <8 g/dL, withhold niraparib/abiraterone and monitor blood counts weekly.1 When hemoglobin returns to ≥9 g/dL, resume at a reduced dosage of niraparib 100 mg/abiraterone 1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated.1 Permanently discontinue niraparib/abiraterone if hemoglobin has not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to niraparib 100 mg/abiraterone 1,000 mg once daily.1
For platelet count <100,000/mm3, withhold niraparib/abiraterone for a maximum of 28 days.1 Consider platelet transfusion for patients with platelet count ≤10,000/mm3.1 If there are other risk factors such as coadministration of anticoagulation or antiplatelet drugs, consider interrupting these drugs and/or transfusion at a higher platelet count.1
For the first occurrence of platelet count <100,000/mm3, monitor blood counts weekly until platelet count returns to ≥100,000/mm3.1 Resume niraparib/abiraterone at the same or reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily.1 If the platelet count is <75,000/mm3, resume at the reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily.1 For the second occurrence of platelet count <100,000/mm3, monitor blood counts weekly until platelet count returns to ≥100,000/mm3.1 Resume at the reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily.1 Permanently discontinue niraparib/abiraterone if the platelet count has not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to niraparib 100 mg/abiraterone 1,000 mg once daily.1
For neutrophil count <1000/mm3, withhold niraparib/abiraterone and monitor blood counts weekly.1 When neutrophil count returns to ≥1,500/mm3, resume at the reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated.1 Permanently discontinue niraparib/abiraterone if neutrophils have not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to niraparib 100 mg/abiraterone 1,000 mg once daily.1
If myelodysplastic syndrome or acute myeloid leukemia is confirmed, discontinue niraparib/abiraterone.1
In patients with ALT and/or AST >5 times the upper limit of normal (ULN) or total bilirubin >3 times the ULN, withhold niraparib/abiraterone and closely monitor liver function.1 When AST and ALT resolve to ≤2.5 times the ULN and total bilirubin to ≤1.5 times the ULN, niraparib/abiraterone may be resumed at the reduced dose of niraparib 100 mg/abiraterone 500 mg once daily.1 When resumed, monitor serum aminotransferases every 2 weeks for 3 months, monthly thereafter, and as clinically indicated.1
Permanently discontinue niraparib/abiraterone if ALT or AST is ≥20 times the ULN, if ALT is >3 times ULN and total bilirubin is >2 times the ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or if hepatotoxicity recurs at the reduced dose of niraparib 100 mg/abiraterone 500 mg once daily.1
Other Non-hematologic Adverse Reactions that Persist Despite Medical Management
Withhold niraparib/abiraterone until resolution of grade 3 or 4 adverse reactions or for a maximum of 28 days.1 If the adverse reaction resolves in 28 days or less, niraparib/abiraterone may be resumed at the reduced dose.1
Discontinue niraparib/abiraterone in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions.1
Permanently discontinue niraparib/abiraterone if the adverse reaction(s) have not resolved after 28 days or if a grade 3 or 4 adverse reaction reoccurs after dose reduction.1
Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Avoid concomitant use with strong CYP3A4 inducers.1
Avoid concomitant use with CYP2D6 substrates for which minimal changes in concentrations may lead to serious toxicities.1 If concomitant use is unavoidable, consider dose reduction of CYP2D6 substrate.1
No dosage modification is necessary for patients with mild hepatic impairment (Child-Pugh class A).1 Avoid use of niraparib/abiraterone in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1
No dosage modification is necessary for patients with mild to moderate renal impairment (creatinine clearance 30-90 mL/minute).1 Monitor patients with severe renal impairment (creatinine clearance 15-30 mL/minute) for increased adverse reactions and modify dosage as recommended for adverse reactions.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Myelodysplastic Syndrome/Acute Myeloid Leukemia
Niraparib/abiraterone may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).1 MDS/AML, including cases with a fatal outcome, has been observed in patients treated with niraparib, a component of niraparib/abiraterone.1 All patients treated with niraparib who developed secondary MDS/cancer therapy-related AML had received previous chemotherapy with platinum agents and/or DNA-damaging agents, including radiotherapy.1 For suspected MDS/AML or prolonged hematologic toxicities, refer the patient to a hematologist for further evaluation.1 Discontinue niraparib/abiraterone if MDS/AML is confirmed.1
Niraparib/abiraterone may cause myelosuppression, including anemia, thrombocytopenia, or neutropenia.1 In MAGNITUDE Cohort 1, grade 3-4 anemia, thrombocytopenia, and neutropenia were reported in 28, 8, and 7% of patients receiving niraparib/abiraterone, respectively.1, 2 Overall, 27% of patients required a red blood cell transfusion, including 11% who required multiple transfusions.1 Discontinuation due to anemia occurred in 3% of patients.1
Monitor complete blood counts (CBCs) weekly during the first month of niraparib/abiraterone treatment, every 2 weeks for the next 2 months, monthly for the remainder of the first year and then every other month, and as clinically indicated.1 Do not start niraparib/abiraterone until patients have adequately recovered from hematologic toxicity caused by previous therapy.1 If hematologic toxicities do not resolve within 28 days following therapy interruption, discontinue niraparib/abiraterone and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics.1
Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions
Niraparib/abiraterone may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from 17α-hydroxylase/C17,20-lyase (CYP17) inhibition.1 In post-marketing experience, QT prolongation and torsades de pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate, a component of niraparib/abiraterone.1 Hypertension and hypertensive crisis have also been reported in patients treated with niraparib, a component of niraparib/abiraterone.1
In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with niraparib/abiraterone, grade 3-4 hypokalemia was detected in 2.7% of patients in the niraparib/abiraterone arm and grade 3-4 hypertension was observed in 14% of patients in the niraparib/abiraterone arm.1, 2 The safety of niraparib/abiraterone in patients with New York Heart Association (NYHA) class II to IV heart failure has not been established because these patients were excluded from the MAGNITUDE trial.1
Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first 2 months, then once a month.1 Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia.1 Control hypertension and correct hypokalemia before and during treatment with niraparib/abiraterone.1 Discontinue niraparib/abiraterone in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions.1
Niraparib/abiraterone may cause hepatotoxicity.1 Hepatotoxicity in patients receiving abiraterone acetate, a component of niraparib/abiraterone, has been reported in clinical trials.1 In post-marketing experience, there has been abiraterone acetate-associated severe hepatotoxicity, including fulminant hepatitis, acute liver failure, and deaths.1 In MAGNITUDE Cohort 1, grade 3-4 ALT or AST increases (at least 5 times the upper limit of normal [ULN]) were reported in 1.8% of patients.1, 2 The safety of niraparib/abiraterone in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from the MAGNITUDE trial.1, 2
Measure serum aminotransferases (ALT and AST) and bilirubin levels prior to starting treatment with niraparib/abiraterone, every 2 weeks for the first 3 months of treatment, and monthly thereafter.1 Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.1 Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring and may require dosage modifications.1 Permanently discontinue niraparib/abiraterone for patients who develop a concurrent elevation of ALT greater than 3 times the ULN and total bilirubin greater than 2 times the ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST ≥20 times the ULN at any time after receiving niraparib/abiraterone.1
Niraparib/abiraterone may cause adrenal insufficiency.1 Adrenocortical insufficiency has been reported in clinical trials in patients receiving abiraterone acetate, a component of niraparib/abiraterone, in combination with prednisone, following interruption of daily corticosteroids and/or with concurrent infection or stress.1 Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress.1 Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate.1 If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency.1 Increased doses of corticosteroids may be indicated before, during, and after stressful situations.1
Niraparib/abiraterone may cause hypoglycemia in patients being treated with other medications for diabetes.1 Severe hypoglycemia has been reported when abiraterone acetate, a component of niraparib/abiraterone, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide.1 Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with niraparib/abiraterone.1 Assess if antihyperglycemic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.1
Increased Fractures and Mortality in Combination with Radium-223 Dichloride
Niraparib/abiraterone with prednisone is not recommended for use in combination with radium-223 dichloride outside of clinical trials.1 The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium-223 dichloride were assessed in a randomized, placebo-controlled, multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases.1, 5 The study was unblinded early based on an Independent Data Monitoring Committee recommendation.1, 5 At the primary analysis, an increased incidence of fractures (29% versus 11%, respectively) and deaths (39% versus 36%, respectively) was observed in patients who received radium-223 dichloride in combination with abiraterone acetate plus prednisone/prednisolone compared to those who received placebo in combination with abiraterone acetate plus prednisone.1, 5 It is recommended that subsequent treatment with radium-223 not be initiated for at least 5 days after the last administration of niraparib/abiraterone in combination with prednisone.1
Posterior Reversible Encephalopathy Syndrome
Niraparib/abiraterone may cause Posterior Reversible Encephalopathy Syndrome (PRES).1 PRES has been observed in patients treated with niraparib as a single agent at higher than the recommended dose included in the niraparib/abiraterone combination preparation.1 Monitor all patients treated with niraparib/abiraterone for signs and symptoms of PRES.1 If PRES is suspected, promptly discontinue niraparib/abiraterone and administer appropriate treatment.1 The safety of reinitiating niraparib/abiraterone in patients previously experiencing PRES is not known.1
The safety and efficacy of niraparib/abiraterone have not been established in females.1 Based on animal reproductive studies and mechanism of action, niraparib/abiraterone can cause fetal harm and loss of pregnancy when administered to a pregnant female.1 Niraparib 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).1 In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥0.03 times the human exposure (AUC) at the recommended dose.1 Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of niraparib/abiraterone.1 Females who are or may become pregnant should handle niraparib/abiraterone with protection (e.g., gloves).1
The safety and efficacy of niraparib/abiraterone have not been established in females.1 There are no human data on the use of niraparib/abiraterone in pregnant women.1 Based on findings from animal studies and the mechanism of action, niraparib/abiraterone can cause fetal harm and potential loss of pregnancy.1 Niraparib 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).1 In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis (gestational days 6-17) caused adverse developmental effects at maternal exposures approximately ≥0.03 times the human exposure (AUC) at the recommended dose.1 Findings included embryo-fetal lethality (increased postimplantation loss and resorptions and decreased number of live fetuses), fetal developmental delay, and urogenital effects (bilateral ureter dilation) at dosages ≥10 mg/kg/day, decreased fetal anogenital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day, which represents approximately 0.03, 0.1, and 0.3 times the AUC of patients receiving 1,000 mg of abiraterone acetate, respectively.1
The safety and efficacy of niraparib/abiraterone have not been established in females.1 There is no information available on the presence of niraparib or abiraterone in human milk, or on the effects of these drugs on the breast-fed child or milk production.1
Females and Males of Reproductive Potential
Based on findings in animal reproduction studies and the mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of niraparib/abiraterone.1 Based on animal studies, niraparib/abiraterone may impair fertility in males of reproductive potential.1
Safety and effectiveness of niraparib/abiraterone in pediatric patients have not been established.1
Of the 113 patients with BRCA gene alteration(s) who received niraparib/abiraterone in the MAGNITUDE trial, 34.5% of patients were less than 65 years of age, 38.9% of patients were 65 to 74 years, and 26.5% were 75 years and older.1, 2 There was an insufficient number of patients with BRCA gene alteration(s) treated with niraparib/abiraterone in the MAGNITUDE trial to accurately characterize efficacy or safety by age.1
Mild hepatic impairment (Child-Pugh class A) does not affect the exposure to niraparib but increases abiraterone AUC by 1.1-fold compared to normal hepatic function.1 Moderate hepatic impairment (total bilirubin >1.5 to 3 times the upper limit of normal and any AST value) increased niraparib AUC by 56%.1 Moderate hepatic impairment (Child-Pugh class B) increases abiraterone AUC 3.6-fold compared to normal hepatic function.1 Severe hepatic impairment (Child-Pugh class C) increases abiraterone AUC by 7-fold and increases the fraction of free drug by 2-fold compared to normal hepatic function.1
No dosage modification is necessary for patients with mild hepatic impairment (Child-Pugh class A).1 Avoid use of niraparib/abiraterone in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1
There are no clinically significant effects on the pharmacokinetics of niraparib/abiraterone in patients with mild to moderate renal impairment (creatinine clearance 30-90 mL/minute).1 No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance 30-90 mL/minute).1 Niraparib/abiraterone has not been studied in patients with severe renal impairment (creatinine clearance 15-30 mL/minute).1 Monitor patients with severe renal impairment for increased adverse reactions and modify dosage as recommended for adverse reactions.1
The most common adverse reactions of niraparib/abiraterone (≥10% of patients) reported in clinical studies, including laboratory abnormalities, are decreased hemoglobin, decreased lymphocytes, decreased white blood cells, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, increased AST, increased ALT, edema, dyspnea, decreased appetite, vomiting, dizziness, COVID-19, headache, abdominal pain, hemorrhage, urinary tract infection, cough, insomnia, increased bilirubin, weight decreased, arrhythmia, fall, and pyrexia.1
Niraparib is metabolized by carboxylesterases.1 In vitro, niraparib is not an inhibitor of cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4.1 Niraparib is not an inducer of CYP3A4 but is an in vitro inducer of CYP1A2.1 Niraparib does not inhibit uridine-diphosphate glucuronosyltransferases (UGT) 1A1, 1A4, 1A9, or 2B7.1 Niraparib is a substrate of breast cancer resistance protein (BRCP) and P-glycoprotein (P-gp).1 In vitro, niraparib inhibits BRCP and multidrug and toxic compound extrusion (MATE) 1 and 2.1 Niraparib does not inhibit P-gp, bile salt export pump (BSEP), or multidrug resistance-associated protein (MRP) 2.1
Abiraterone acetate is rapidly converted to abiraterone and is subsequently metabolized by CYP3A4 and sulfotransferase family 2A member 1 (SULT2A1).1 In vitro, abiraterone is a substrate of CYP3A4 and has the potential to inhibit CYP1A2, 2D6, 2C8, and to a lesser extent CYP2C9, 2C19, 3A4/5.1 Abiraterone acetate and abiraterone are not substrates of P-gp.1 Abiraterone acetate is a P-gp inhibitor in vitro.1 In vitro, abiraterone and its major metabolites are inhibitors of organic anion transporter polypeptide (OATP) 1B1.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Abiraterone increases the concentration of CYP2D6 substrates, which may increase the risk of adverse events related to these substrates.1 Concomitant use of abiraterone (1,000 mg daily in combination with prednisone) with dextromethorphan, a CYP2D6 substrate, increased dextromethorphan maximum concentration (Cmax) and AUC by 2.8- and 2.9-fold, respectively.1 The AUC of the active metabolite of dextromethorphan, dextrorphan, was increased approximately 1.3-fold.1 Avoid coadministration with CYP2D6 substrates unless otherwise recommended in the prescribing information for CYP2D6 substrates for which minimal changes in concentration may lead to serious toxicities.1 If alternate treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate.1
Abiraterone increases the concentration of CYP2C8 substrates, which may increase the risk of adverse events related to these substrates.1 Coadministration of abiraterone with pioglitazone, a CYP2C8 substrate, increased the AUC of pioglitazone by 46%.1 Monitor patients for signs of toxicity related to a CYP2C8 substrate for which a minimal change in plasma concentration may lead to serious or life-threatening adverse reactions.1
Concomitant use of abiraterone with a single dose of theophylline, a CYP1A2 substrate, did not affect systemic exposure to theophylline.1
Concomitant use of the strong CYP3A4 inhibitor ketoconazole has no clinically meaningful effect on the pharmacokinetics of abiraterone.1
Strong CYP3A4 inducers may decrease abiraterone concentrations, which may reduce the effectiveness of abiraterone.1 When the strong CYP3A4 inducer rifampin was administered concomitantly with abiraterone, the mean AUC of abiraterone was decreased by 55%.1 Avoid concomitant use of strong CYP3A4 inducers.1
Anticoagulants and Antiplatelet Drugs
There is a potential for increased risk of adverse hematologic reactions and hemorrhagic events in patients concurrently receiving niraparib/abiraterone and anticoagulants or antiplatelet agents.1 Interruption of therapy with anticoagulants and/or antiplatelet drugs may be required in the setting of hematologic adverse reactions (see Myelosuppression under Dosage Modifications for Toxicity).1
Hypoglycemia may occur when niraparib/abiraterone is used concurrently with antidiabetic agents.1 Blood glucose should be monitored in patients with diabetes during and following discontinuance of niraparib/abiraterone.1 Evaluate patients to determine if dosage adjustment is necessary to reduce the risk of hypoglycemia.1
Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, including PARP-1 and PARP-2, that play a role in DNA repair.1 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.1 Increased niraparib-induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA 1/2.1 Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA 1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild-type BRCA 1/2.1
Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels.1 Androgen deprivation therapies, such as treatment with gondatropin-releasing-hormone (GnRH) agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor.1 Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17α-hydroxylase/C17,20-lyase (CYP17).1 This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.1 CYP17 catalyzes 2 sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and, 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17,20-lyase activity (DHEA and androstenedione are androgen precursors of testosterone).1 Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals.1 Abiraterone decreased serum testosterone and other androgens in patients in the placebo-controlled clinical trial.1 It is not necessary to monitor the effect of abiraterone on serum testosterone levels.1 Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients.1 In mouse xenograft models of prostate cancer, the combination of niraparib and abiraterone acetate increased anti-tumor activity when compared to either drug alone.1
Niraparib exhibits a dose-proportional increase in Cmax and AUC in the dose range of 30-400 mg.1 Abiraterone demonstrates no major deviation for dose proportionality observed in the dose range of 250-1,000 mg.1 The bioavailability of niraparib is approximately 73%, reaching maximum concentration at 3 hours.1 Abiraterone reaches maximum concentration at 1.5 hours.1 Administration of abiraterone with food results in up to a 10-fold increase in AUC and up to a 17-fold increase in systemic exposure compared to the fasted state depending on fat content of the meal; administration with food has the potential to result in increased and highly variable exposure.1 Niraparib is 83% bound to human plasma proteins.1
Abiraterone is >99% bound to human plasma proteins (primarily albumin and alpha-1 acid glycoprotein).1 Niraparib is metabolized by carboxylesterases and has a half-life of approximately 62 hours, after which 48% (range: 33-60%) is recovered in urine and 39% (range: 28-47%) in feces; unchanged niraparib accounts for 11% and 19% of the administered dose recovered in urine and feces, respectively.1 Abiraterone acetate is rapidly converted to abiraterone and is subsequently metabolized by cytochrome P450 (CYP) 3A4 and sulfotransferase family 2A member 1 (SULT2A1).1 Abiraterone has a half-life of approximately 20 hours.1 Abiraterone is recovered in feces (88%) and in urine (5%); unchanged abiraterone acetate and abiraterone account for 55% and 22% of administered dose recovered in the feces, respectively.1 No clinically significant effects on the pharmacokinetics of niraparib or abiraterone are observed based on body weight, age, race/ethnicity, and mild to moderate renal impairment (creatinine clearance 30-90 mL/minute).1 Severe renal impairment (creatinine clearance 15-30 mL/minute) has not been studied.1 Mild hepatic impairment (Child-Pugh class A) has no effect on niraparib exposure but increases abiraterone AUC by 1.1-fold.1 Moderate hepatic impairment (Child-Pugh class B) increases niraparib AUC by 56% and increases abiraterone AUC by 3.6-fold.1 Severe hepatic impairment (Child-Pugh class C) increases abiraterone AUC by 7-fold and fraction of free drug by 2-fold.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Niraparib/abiraterone is obtained through designated specialty distributors. Contact manufacturer or consult the niraparib/abiraterone website ( [Web]) for specific availability information.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 50 mg niraparib and 500 mg abiraterone acetate | Akeega® | Janssen Biotech |
100 mg niraparib and 500 mg abiraterone acetate | Akeega® | Janssen Biotech |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Janssen Biotech, Inc. Akeega® (niraparib tosylate monohydrate and abiraterone acetate) oral tablets prescribing information. Horsham, PA; 2023 Aug.
2. Chi KN, Rathkopf D, Smith MR et al; MAGNITUDE Principal Investigators. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023; 41(18): 3339-3351.
3. Chi KN, Sandhu S, Smith MR et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol. 2023; 34(9): 772-782.
4. Lowrance W, Dreicer R, Jarrad DF, et al. Updates to advanced prostate cancer: AUA/SUO guideline (2023). J Urol. 2023; 209(6): 1082-1090.
5. Smith M, Parker C, Saad F et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; 20(3): 408-419. [published correction appears in Lancet Oncol. 2019; 20(10): e559.]