Profile
General Information
Akeega is a combination of niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and abiraterone acetate, a CYP17 inhibitor.
Akeega is specifically indicated with prednisone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).
Dosing/Administration
- Akeega is supplied as tablets for oral administration.
- The recommended dosage of Akeega 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 Akeega should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.
- Take Akeega on an empty stomach. Do not eat food two hours before and one hour after taking Akeega
- For adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation.
Mechanism of Action
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 17 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.
Side Effects
Adverse effects associated with the use of Akeega may include, but are not limited to, the following:
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
Clinical Trial Results
FDA approval of Akeega was based on results from the randomized, double-blind, placebo-controlled multi-center Phase 3 MAGNITUDE study. The study evaluated the safety and efficacy of the combination of Akeega plus prednisone for patients with mCRPC, with or without certain HRR gene alterations, and who have not received prior therapy for mCRPC except for up to four months of abiraterone acetate plus prednisone (AAP.)
The study included patients with (HRR biomarker [BM] positive; ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2) and without specified gene alterations (HRR BM negative), who were randomized 1:1 to receive niraparib 200 mg once daily plus AAP or placebo plus AAP. A total of 423 patients with HRR gene alterations were enrolled, 225 (53.2 percent) of whom had BRCA mutations. The primary endpoint of the MAGNITUDE trial was rPFS assessed by blinded independent central review.
In BRCA-positive patients treated with the combination Akeega plus prednisone, a statistically significant 47 percent risk reduction was observed for radiographic progression-free survival (rPFS). At the second interim analysis (IA2), with median follow-up at 24.8 months in the BRCA-positive subgroup, rPFS by central review demonstrated a consistent trend favoring Akeega plus prednisone, with a median rPFS of 19.5 months compared with 10.9 months for placebo and AAP. Additionally, there was an observed improvement in the secondary endpoints of time to symptomatic progression (TSP) and time to initiation of cytotoxic chemotherapy for Akeega plus prednisone compared with AAP alone, supported by a trend towards improvement in overall survival.