Niraparib and Abiraterone (Monograph)

Brand name: Akeega
Drug class: Antineoplastic Agents

Introduction

Niraparib tosylate and abiraterone acetate (niraparib/abiraterone) is a fixed-combination preparation containing a poly (ADP-ribose) polymerase (PARP) inhibitor (niraparib) and a CYP17 inhibitor (abiraterone acetate); niraparib/abiraterone is an antineoplastic agent.

Uses for Niraparib and Abiraterone

Niraparib and abiraterone acetate has the following uses:

Niraparib/abiraterone is indicated with prednisone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved test for niraparib/abiraterone.

Niraparib and Abiraterone Dosage and Administration

General

Niraparib/abiraterone is available in the following dosage form(s) and strength(s):

Tablets:

• 50 mg niraparib/500 mg abiraterone acetate

• 100 mg niraparib/500 mg abiraterone acetate

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

The recommended dosage is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 10 mg prednisone daily until disease progression or unacceptable toxicity.

Patients receiving niraparib/abiraterone should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

Take niraparib/abiraterone on an empty stomach. Do not eat food two hours before and one hour after taking niraparib/abiraterone. Swallow tablets whole with water. Do not break, crush, or chew tablets.

For adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. See Full Prescribing Information for additional instructions.

Related/similar drugs

estradiol, Premarin, Xtandi, Zytiga, Casodex, Lynparza

Cautions for Niraparib and Abiraterone

Contraindications

None.

Warnings/Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia

Niraparib/abiraterone may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).

MDS/AML, including cases with fatal outcome, has been observed in patients treated with niraparib, a component of niraparib/abiraterone.

All patients treated with niraparib 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 niraparib/abiraterone if MDS/AML is confirmed.

Myelosuppression

Niraparib/abiraterone may cause myelosuppression (anemia, thrombocytopenia, or neutropenia).

In MAGNITUDE Cohort 1, Grade 3–4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving niraparib/abiraterone. Overall, 27% of patients required a red blood cell transfusion, including 11% who required multiple transfusions. Discontinuation due to anemia occurred in 3% of patients.

Monitor complete blood counts weekly during the first month of niraparib/abiraterone treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start niraparib/abiraterone until patients have adequately recovered from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following interruption, discontinue niraparib/abiraterone and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics.

Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions

Niraparib/abiraterone may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. In post-marketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate. Hypertension and hypertensive crisis have also been reported in patients treated with niraparib.

In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with niraparib/abiraterone, Grades 3–4 hypokalemia was detected in 2.7% of patients on the niraparib/abiraterone arm and Grades 3–4 hypertension were observed in 14% of patients on the niraparib/abiraterone arm.

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 MAGNITUDE.

Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. 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. Control hypertension and correct hypokalemia before and during treatment with niraparib/abiraterone.

Discontinue niraparib/abiraterone in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions.

Hepatotoxicity

Niraparib/abiraterone may cause hepatotoxicity.

Hepatotoxicity in patients receiving abiraterone acetate, a component of niraparib/abiraterone, has been reported in clinical trials. In post-marketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and deaths.

In MAGNITUDE Cohort 1, Grade 3–4 ALT or AST increases (at least 5 × ULN) were reported in 1.8% of patients. The safety of niraparib/abiraterone in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from MAGNITUDE.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with niraparib/abiraterone, every two weeks for the first three months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring and may require dosage modifications.

Permanently discontinue niraparib/abiraterone for patients who develop a concurrent elevation of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST ≥20 × ULN at any time after receiving niraparib/abiraterone.

Adrenocortical Insufficiency

Niraparib/abiraterone may cause adrenal insufficiency.

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 steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased doses of corticosteroids may be indicated before, during, and after stressful situations.

Hypoglycemia

Niraparib/abiraterone may cause hypoglycemia in patients being treated with other medications for diabetes.

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.

Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with niraparib/abiraterone. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

Increased Fractures and Mortality in Combination with Radium 223 Dichloride

Niraparib/abiraterone with prednisone is not recommended for use in combination with Ra-223 dichloride outside of clinical trials.

The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was 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. The study was unblinded early based on an Independent Data Monitoring Committee recommendation.

At the primary analysis, increased incidences of fractures (29% vs 11%) and deaths (39% vs 36%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone.

It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of niraparib/abiraterone, in combination with prednisone.

Posterior Reversible Encephalopathy Syndrome

Niraparib/abiraterone may cause Posterior Reversible Encephalopathy Syndrome (PRES).

PRES has been observed in patients treated with niraparib as a single agent at higher than the recommended dose included in niraparib/abiraterone.

Monitor all patients treated with niraparib/abiraterone for signs and symptoms of PRES. If PRES is suspected, promptly discontinue niraparib/abiraterone and administer appropriate treatment. The safety of reinitiating niraparib/abiraterone in patients previously experiencing PRES is not known.

Embryo-fetal Toxicity

The safety and efficacy of niraparib/abiraterone have not been established in females. 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.

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).

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.

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. Females who are or may become pregnant should handle niraparib/abiraterone with protection (e.g., gloves).

Specific Populations

Pregnancy

The safety and efficacy of niraparib/abiraterone have not been established in females. Based on findings from animal studies and mechanism of action, niraparib/abiraterone can cause fetal harm and potential loss of pregnancy.

There are no human data on the use of niraparib/abiraterone in pregnant women.

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). 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.

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.

Lactation

The safety and efficacy of niraparib/abiraterone have not been established in females. There is no information available on the presence of niraparib or abiraterone in human milk, or on the effects on the breastfed child or milk production.

Females and Males of Reproductive Potential

Based on findings in animal reproduction studies and its 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.

Based on animal studies, niraparib/abiraterone may impair fertility in males of reproductive potential.

Pediatric Use

Safety and effectiveness of niraparib/abiraterone in pediatric patients have not been established.

Geriatric Use

Of the 113 patients with BRCA gene alteration(s) who received niraparib/abiraterone in MAGNITUDE, 34.5% of patients were less than 65 years, 38.9% of patients were 65 years to 74 years, and 26.5% were 75 years and over.

There was an insufficient number of patients with BRCA gene alteration(s) treated with niraparib/abiraterone in MAGNITUDE to accurately characterize efficacy or safety by age.

Hepatic Impairment

Avoid use of niraparib/abiraterone in patients with moderate or severe hepatic impairment.

No dosage modification is necessary for patients with mild hepatic impairment.

Renal Impairment

Monitor patients with severe renal impairment for increased adverse reactions and modify dosage as recommended for adverse reactions.

No dosage modification is recommended for patients with mild to moderate renal impairment.

Common Adverse Effects

The most common adverse reactions (≥10%), 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.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong CYP3A4 Inducers: Avoid coadministration.

• CYP2D6 Substrates: Avoid coadministration of niraparib/abiraterone with CYP2D6 substrates for which minimal changes in concentration may lead to serious toxicities. If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate.

Actions

Mechanism of Action

Niraparib is an inhibitor of poly (ADP-ribose) polymerase (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. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency (HRD) that had either mutated or wild-type BRCA1/2.

Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.

CYP17 catalyzes two 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 androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals.

Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor.

Abiraterone decreased serum testosterone and other androgens in patients in the placebo-controlled clinical trial. It is not necessary to monitor the effect of abiraterone on serum testosterone levels.

Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients.

In mouse xenograft models of prostate cancer, the combination of niraparib and abiraterone acetate increased anti-tumor activity when compared to either drug alone.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Advise patients that periodic monitoring of their blood counts is recommended. Advise patients to contact their healthcare provider for new onset of pallor, weakness, dyspnea, fatigue, bleeding, fever, or symptoms of infection.

• Inform patients that niraparib/abiraterone is associated with hypokalemia that may lead to QT prolongation. Advise patients that hypertension, hypokalemia, and fluid retention will be monitored at least weekly for the first two months, then once a month. Advise patients to adhere to corticosteroids and to report symptoms of hypokalemia or edema to their healthcare provider.

• Inform patients that niraparib/abiraterone is associated with severe hepatotoxicity. Inform patients that their liver function will be monitored using blood tests. Advise patients to immediately report symptoms of hepatotoxicity to their healthcare provider.

• Inform patients that niraparib/abiraterone with prednisone is associated with adrenal insufficiency. Advise patients to report symptoms of adrenocortical insufficiency to their healthcare provider.

• Inform patients that niraparib/abiraterone is associated with hypoglycemia. Advise patients with diabetes to monitor blood glucose during and after discontinuation of treatment with niraparib and abiraterone acetate.

• Inform patients that they are at risk of developing posterior reversible encephalopathy syndrome (PRES) that can present with signs and symptoms including seizure, headaches, altered mental status, or vision change. Advise patients to contact their healthcare provider if they develop any of these signs or symptoms.

• Inform patients that niraparib/abiraterone is taken orally once daily with prednisone daily (according to their healthcare provider's instructions) and to not interrupt or stop either of these medications without consulting their healthcare provider.

• Inform patients coadministered a gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with niraparib/abiraterone.

• Inform patients that in the event of a missed daily dose of niraparib/abiraterone, they should take their normal dose as soon as possible on the same day and resume their next dose at the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose.

• Instruct patients to take niraparib/abiraterone tablets as a single dose once daily on an empty stomach. Instruct patients to not eat food 2 hours before and 1 hour after taking niraparib/abiraterone. Niraparib/abiraterone taken with food causes increased exposure and may result in adverse reactions. Instruct patients to swallow tablets whole with water and not to break, crush, or chew the tablets.

• Inform patients that niraparib/abiraterone may harm a developing fetus and can cause loss of pregnancy.

• 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.

• Advise females who are pregnant or may become pregnant to handle niraparib/abiraterone tablets with protection (e.g., gloves).

• Advise male patients that niraparib/abiraterone may impair fertility.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

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.

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