Summary

• There are no published studies in humans describing the ability of AKEEGA to cross the blood-brain barrier.
• Patients with symptomatic brain metastases were excluded from the MAGNITUDE study, a phase 3 study evaluating the efficacy and safety of AKEEGA with prednisone as first line (L1) therapy in metastatic castration resistant prostate cancer (mCRPC) for patients with certain homologous recombination repair (HRR) mutations, including BRCA1/2.^1-4
• In preclinical models, after a single oral dose of niraparib, the area under the plasma concentration-time curve (AUC) brain:plasma ratio in rats was 0.85 while the AUC cerebrospinal fluid (CSF):plasma ratio in rhesus monkeys was 0.18. Relative to plasma, niraparib had a high tissue distribution (tissue:plasma [Kp] ratio was >1 in most organs), and the fraction unbound (Fu) of niraparib in tumor and brain homogenates was ~0.2 in mice (similar to human Fu of 0.16). The tumor:plasma ratio was ˃3.⁵
• Following oral administration, niraparib demonstrated no significant effects on the respiratory or central nervous system (CNS) at clinically relevant doses in rats and dogs. Niraparib did not result in behavioral or neurochemical effects consistent with enhanced dopamine availability in the CNS. In addition, there were no niraparib-related findings of CNS origin in safety pharmacology or in repeat-dose toxicity studies.⁵
• No secondary pharmacodynamic studies were performed for abiraterone acetate. After oral administration, abiraterone acetate had no effects on the CNS in rodents and telemetered monkeys in in vivo safety pharmacology studies.⁵

CLINICAL DATA

No clinical studies have been conducted in humans to evaluate the concentration of AKEEGA in the brain tissue or CNS.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 11 June 2024. Summarized in this response are relevant data pertaining to this topic in patients with prostate cancer.