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Niraparib: Mechanism of Action, Adverse Effects, and Contraindications

Mechanism of Action of PARP Inhibitors:

The poly(ADP-ribose) polymerase (PARP) enzyme participates in cellular DNA repair. Another mechanism for DNA repair is homologous recombination repair (HRR); well-known HRR genes include BRCA1 and BRCA2. Inhibition of PARP with niraparib prevents DNA repair. Tumor cells, which divide frequently and exhibit high DNA turnover, are particularly susceptible to damage and undergo apoptosis. Niraparib is especially effective when HRR is also compromised by mutations.

Indications for Niraparib plus Abiraterone

The fixed-dose combination of niraparib plus abiraterone (Akeega) plus prednisone is approved as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC) in patients with BRCA1/2 mutations when chemotherapy with docetaxel is not indicated or feasible (Chi et al., 2023). It demonstrated an improvement in radiographic progression-free survival (20 vs. 11 months). This benefit was also observed in patients with other HRR gene mutations (17 vs. 14 months). The overall survival analysis has, to date, shown no significant difference.

Pharmacokinetics of Niraparib plus Abiraterone

Administration of abiraterone with food leads to a marked increase in absorption, with up to a 17-fold rise in peak concentration; therefore, it should not be taken with meals (see dosage). Abiraterone exhibits a large volume of distribution and high plasma protein binding. The half-life of abiraterone is approximately 20 hours, and that of niraparib is approximately 62 hours. Both agents undergo hepatic metabolism. Metabolites of niraparib are excreted in roughly equal proportions via urine and feces.

Adverse Effects of Niraparib plus Abiraterone

The most common adverse events (all grades) are anemia, neutropenia, thrombocytopenia, and nausea. The frequencies of grade 3 and 4 adverse events are listed below (very common >10%, common 1–10%, rare <1%):

• Hematologic: anemia (30%), thrombocytopenia (7%), and neutropenia (7%).
• Hepatic: elevation of transaminases (2%).
• Cardiac: hypertension (16%) and common cardiac arrhythmias.
• Gastrointestinal: common nausea and vomiting; less frequently, stomatitis, diarrhea, or abdominal pain.
• Respiratory tract: rare dyspnea or cough; very rarely, severe pneumonitis.
• Skin: rare rash; very rare dermatitis.
• Other adverse events: common fatigue; risk of adrenal insufficiency; hypokalemia due to mineralocorticoid effects.

Drug Interactions of Niraparib plus Abiraterone

Avoid concomitant use of CYP3A4 inhibitors (e.g., ketoconazole, azithromycin) or CYP3A4 inducers (e.g., rifampin). Abiraterone inhibits CYP2D6; therefore, reduce the dose or exercise caution when co-administered with metoprolol, propranolol, desipramine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone, and tramadol.

Contraindications of Niraparib plus Abiraterone

• Allergy
• Women and children
• Severe hepatic impairment (Child-Pugh class C)
• Severely reduced kidney function (glomerular filtration rate < 30 mL/min)
• Persistent grade 3 or 4 adverse events despite dose reduction
• Concomitant therapy with radium-223

Dosage of Niraparib plus Abiraterone

One 100 mg niraparib/500 mg abiraterone tablet taken 2-0-0 orally, one hour before or two hours after breakfast; this corresponds to a total daily dose of 200 mg niraparib and 1000 mg abiraterone. The combination is prescribed with prednisolone 10 mg 1-0-0. A 50 mg niraparib/500 mg abiraterone tablet taken 2-0-0 orally is available for dose reduction.

For grade 2 adverse events, interrupt therapy and, after improvement, re-initiate treatment at the standard dose with weekly laboratory monitoring. For grade ≥3 adverse events, interrupt therapy and, after improvement, re-initiate treatment at a reduced dose with weekly laboratory monitoring. If grade 3 or higher adverse events recur, discontinue the drug permanently.

Monitoring During Therapy:

During the first month, monitor the differential blood count weekly, then monthly thereafter. Perform monthly assessments of liver function tests (bilirubin, AST, ALT) and blood pressure. Assess electrolytes, creatinine, skin, and the oral cavity monthly.

Trade Names

Akeega

References

K. N. Chi, D. Rathkopf, M. R. Smith, and E. Efstathiou, “Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer.,” J Clin Oncol., vol. 41, no. 18, pp. 3339–3351, 2023.

  Deutsche Version: Mechanismus, Nebenwirkungen, Kontraindikationen und Dosierung von Niraparib

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