Prostate cancer is the most common cancer, and the second leading cause of death from cancer, in males in most Western countries. Prostate cancer has an exquisite sensitivity to androgen deprivation therapy, although the disease may eventually progress to the castration-resistant status (CRPC). However, recent evidence was provided that the cancer progression at the CRPC stage is often mediated by androgen receptor signalling, so that subsequent androgen receptor targeting may further contribute to disease control and eventually survival improvement.
Abiraterone acetate is an irreversible inhibitor of cytochrome P450-17 (CYP17), with 17α–hydroxylase and C17,20-lyase properties. Since CYP17 is a key enzyme in the production of androgens and oestrogens in the adrenal glands and tumour tissue, abiraterone inhibits both adrenal androgen and intratumoral androgen synthesis.
Recently, an international, multi-centre randomized Phase III double-blind placebo-controlled was published in the NEJM. This trial was performed in 1195 patients with metastatic CRPC who had failed docetaxel-based chemotherapy to compare the efficacy and safety of abiraterone acetate plus prednisone (AP) with those of placebo plus prednisone (PP). After a median follow up of 12.8 months, median overall survival in the AP group was 14.8 months versus 10.9 months in the PP group (P<0.0001; HR=0.65). Time to PSA progression, radiographic progression-free survival and PSA response rate were also significantly improved in the AR arm. Mineralocorticoid-related AEs were more common in the AP arm: fluid retention 30.5% vs 22.3%, and hypokaliemia 17.1% versus 8.4%. However Grade 3/4 hypokaliemia (3.8% versus 0.8%), and Grade 3/4 hypertension (1.3% versus 0.3%) were infrequent. This trial showed for the first time that targeting the AR pathway can prolong overall survival in patients with metastatic CRPC.
Another placebo-controlled randomized Phase III study in the pre-docetaxel setting is closed to accrual after more than 1000 patients have been randomized 1:1 for abiraterone acetate plus prednisolone versus prednisolone plus placebo. The results of this second trial are awaited.
With the recent development of new therapies (hormonal manipulations, chemotherapy, immunotherapy, bone-targeting agents), a more rationale use of therapeutic agents is urgently required in patients with CRPC. Molecular characterization is likely to lead to the identification of different subsets of prostate cancers with a different sensitivity to available treatments.
References: De Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators: "Abiraterone and increased survival in metastatic prostate cancer", N Engl J Med., 2011 May 26;364(21):1995-2005.