Abiraterone in the management of castration-resistant prostate cancer prior to chemotherapy

Abstract

The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has increased significantly over the past several years. Approved drugs associated with improved survival include androgen pathway-targeted agents (abiraterone acetate and enzalutamide), chemotherapeutics (docetaxel and cabazitaxel), an autologous vaccine (sipuleucel-T) and a radiopharmaceutical (radium-223). Abiraterone acetate, a prodrug of abiraterone, inhibits the CYP17A enzyme, a critical enzyme in androgen biosynthesis. Abiraterone has regulatory approval in mCRPC in both chemotherapy-naïve patients and in the post-docetaxel setting based on results from two randomized phase III studies. In the COU-AA-302 trial, abiraterone demonstrated significant improvement in the coprimary endpoints of radiographic progression-free survival and overall survival, as well as in a number of secondary endpoints including time until initiation of chemotherapy, time until opiate use for cancer-related pain, prostate-specific antigen progression-free survival and decline in performance status. Abiraterone is well-tolerated, although adverse events associated with this agent include abnormalities in liver function testing and mineralocorticoid-associated adverse events. This review evaluates the use of abiraterone in mCRPC prior to the use of chemotherapy.

Keywords: abiraterone; castration-resistant; chemotherapy-naïve; prostate cancer.

Figure 1.

Steroid biosynthesis pathways and mechanism of action of abiraterone acetate. CYP17 has two sequential enzymatic activities. The 17α-hydroxylase activity is critical to production of cortisol. The C_17,20-lyase activity is required for synthesis of testosterone and estradiol. Thus, inhibition of C_17,20-lyase function is the desired function of abiraterone as it is this enzymatic activity that is responsible for androgen production. Red arrows indicate the direction and degree of change in hormone levels from abiraterone. Blue arrows indicate the change in hormone levels when corticosteroids are administered with abiraterone. ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; Preg, pregnenolone.

Figure 2.

COU-AA-302 trial schema. AA, abiraterone acetate; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; Pl, placebo; Pr, prednisone; PSA, prostate specific antigen; rPFS, radiographic progression-free survival.