Progress in the Treatment of Advanced Prostate Cancer

Abstract

The androgen receptor (AR) is the most significant target for patients with metastatic castration-resistant prostate cancer (mCRPC). There is now irrefutable evidence that the AR axis is functional in most patients throughout the history of prostate cancer, is crucial from diagnosis to death, even in patients who have received hormonal manipulation, and represents a relevant therapeutic target in all phases of the disease. The potential mechanisms of tumor escape after castration are multifold, with each mechanism today representing a therapeutic opportunity. Phase III trials have been able to demonstrate improved overall survival (OS), improved quality of life, decreased skeletal-related events, and other important clinical benefits in young and elderly patients. After the initial positive results with docetaxel chemotherapy in improving OS, further research has resulted in five new treatments in the past few years. Immunotherapy with sipuleucel-T, cabazitaxel chemotherapy, the androgen biosynthesis inhibitor abiraterone acetate, the antiandrogen enzalutamide, and the radioisotope radium-223 have all been shown to improve OS in large-scale, well-conducted clinical trials. Proper understanding of mechanisms of resistance and of cross-resistance among these agents, sequencing, and combinations is now a priority.KEY POINTSCastration-resistant prostate cancer (CRPC) will result in 29,000 deaths in the United States in 2014.Despite castrate levels of testosterone, the androgen receptor remains a target for therapy in these patients; this is achieved through inhibition intracrine steroid synthesis (abiratereone acetate) as well as disruption of androgen receptor translocation and activity (enzalutamide).Two chemotherapeutic agents are approved by the FDA and EMA for CRPC based upon improvement in survival as first-line therapy (docetaxel) or second-line therapy (cabazitaxel).Immune therapy with sipeuleucel in patients with asymptomatic or minimally symptomatic CRPC improves survival without significant post-treatment declines in PSA or improvement in time to progression.Treatment with the alpha particle-emitting isotope radium 223 improves survival in patients with symptomatic CRPC, both pre- and post-docetaxel.