Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy

Abstract

Background Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) post-chemotherapy. Many mCRPC patients never receive chemotherapy and thus cannot benefit from abiraterone acetate; we evaluated this agent in mCRPC patients who had not received chemotherapy. Methods In this double-blind study, 1088 patients were randomized 1:1 to abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. Co-primary end points were radiographic progression-free survival (rPFS) and OS. Secondary end points measured clinically relevant landmarks of mCRPC progression. Patient-reported outcomes included pain progression and quality of life. Results The study was unblinded after a planned interim analysis (IA) at 43% of OS events. Treatment with abiraterone acetate-prednisone resulted in a 57% reduction in the risk of radiographic progression or death (hazard ratio [HR], 0.43; 95% confidence interval [CI]: 0.35 to 0.52; P<0.001; 13% OS events IA) and an estimated 25% decrease in the risk of death (HR, 0.75; 95% CI: 0.61 to 0.93; P=0.009; 43% OS events IA). Secondary end points supported superiority of abiraterone acetate-prednisone: time to cytotoxic chemotherapy initiation, opiate use for cancer-related pain, prostate-specific antigen progression (all P<0.001) and performance status deterioration (P=0.005). Self-reported time to pain progression and patient functional status degradation favored abiraterone acetate-prednisone (P=0.05 and P=0.003). Grade 3/4 mineralocorticoid-related adverse events and liver function test abnormalities were more common with abiraterone acetate-prednisone. Conclusions Abiraterone acetate produces OS and rPFS benefits, as well as significant delays in clinical deterioration and initiation of chemotherapy, in mCRPC.

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

“…More recently, discovery campaigns have focused on the development of specific CYP17 inhibitors to reduce androgen biosynthesis. The first drug of this class to be approved, abiraterone, was shown to significantly impact disease progression in patients with CRPC in 2 phase III clinical trials (COU-AA-301 and COU-AA-302) (3,9). Importantly, appropriate drug exposure for abiraterone to directly impact WT or mutant AR activity is attainable in patients.…”

“…Although the majority of patients with prostate cancer initially respond to hormone therapy, relapse invariably occurs, and the disease progresses to a state defined as castration-resistant prostate cancer (CRPC). CRPC is associated with poor survival rates, with patients usually succumbing to metastatic disease within 24 to 48 months (3).…”

“…Therefore, even in CRPC, the AR and the AR-signaling axis remain important therapeutic targets. This is evidenced by the clinical efficacy of the approved hormone therapeutics enzalutamide and abiraterone in both chemotherapynaive and prior chemotherapy-treated CRPC patients (3,(8)(9)(10). Enzalutamide is a second-generation antiandrogen that, unlike first-generation antiandrogens (e.g., flutamide and bicalutamide), prevents the recruitment of the AR to target gene promoters and functions as an antagonist, even in the presence of AR overexpression (11).…”

Impact of skeletal-related events on survival in patients with metastatic prostate cancer prescribed androgen deprivation therapy

“…Various treatments have been proven to improve OS in patients with metastatic prostate cancer, including docetaxel, 19 cabazitaxel, 20 abiraterone, [21][22][23] sipuleucel-T, 24 and enzalutamide. 25,26 Various bonemodulating agents have also been studied for patients with bone metastasis.…”

Second-line hormonal therapy with the enzalutamid in patients with castrate-resistant prostate cancer

“…Одним из первых гормональных препаратов 2-й линии терапии явился препарат абиратерона ацетат, продемонстрировавший свою эффективность в иссле-дованиях III фазы у пациентов как до, так и после про-веденной химиотерапии доцетакселом [10,11]. Абира-терон -препарат, направленный на ингибирование фермента CYP17, являющегося одним из коэнзимов цитохрома P450.…”