Abstract and Introduction
Abstract
Androgen deprivation therapy is the standard of care for the initial treatment of metastatic prostate cancer. However, the majority of these patients live long enough to experience disease progression despite castration. This scenario is defined as castration-resistant prostate cancer (CRPC) and has a poor outcome and limited options for treatment. First-line treatment after hormonal therapy failure include secondary hormonal manipulation and docetaxel. Advances in the understanding of the molecular mechanisms underlying CRPC have translated into a recent increase in the number of effective systemic agents, and some of them have been already approved as first and second-line treatment. Despite these advances, the median survival in the first-line setting of metastatic CRPC is approximately 20 months and in the postdocetaxel setting is approximately 15 months. Promising and necessary new therapies in Phase III trials include hormonal agents, new cytotoxics agents, as well as other immunotherapeutics and antiprostate-specific membrane antigen therapies.
Introduction
Prostate cancer (PCa) is now recognized as one of the most important medical problems facing the male population. In Europe, PCa is the most common solid neoplasm, with an incidence rate of 214 cases per 1000 men. Furthermore, PCa is currently the second most common cause of cancer death in men in the Western world. The measurement of prostate-specific antigen (PSA) level has revolutionized the diagnosis of PCa, increasing the incidence, with a higher number of localized prostate cancer. However, patients still present with metastatic disease and 20–40% of the patients treated with localized prostate cancer will present a biochemical recurrence during the 10 years after the local treatment and 30–70% of them will develop metastatic disease. Since 1941, Huggins and Hodges demonstrated for the first time the responsiveness of PCa to androgen deprivation, androgen-suppressing strategies have become the mainstay of advanced PCa management. Hormonal therapy in the form of medical or surgical castration is the initial treatment for metastatic cancer and allows effective control of cancer-related symptoms in advanced stages. Although highly effectiveness, all men who live long enough will eventually experience disease progression and develop castration resistant. Patients with castration-resistant prostate cancer (CRPC) have a very poor outcome with a median survival of 1–3 years. The poor health-related quality of life and bad prognosis of these patients make necessary effective systemic treatments when hormonal therapy (HT) fails. Over the last decade, better knowledge of the mechanisms involved in androgen independence and the mechanisms common to all cancers underlying malignant proliferation (angiogenesis, metastases, immune surveillance), has been fundamental to identify new therapeutic targets in CPRC. Several new drugs have been approved, and others have reached advanced stages of clinical development.
The aim of the present review is focused on the current status of CRPC, and presents new and emerging drugs for the treatment of CRPC. A review of the literature searching Medline and oncological meetings for prospective trials and preclinical and retospective studies from the last 5 years was performed in March 2012 and updated in April 2013. The search strategy included the terms castration-resistant prostate cancer, treatment, targeted therapy, new therapies, biomarkers, new agents and immunotheraphy.