New immunotherapeutic paradigms for castration-resistant prostate cancer

Prostate cancer nowadays represents the first leading cause of cancer-related deaths among men in the UK, the second in US (after lung cancer) and the sixth worldwide. 1 The risk of developing prostate cancer (as well as several other malignancies) progressively increases with age, the average age of patients at diagnosis being 70. 2 According to current estimates, more than 80% of men will develop prostate cancer by the age of 80. However, the actual incidence of this malignancy cannot be precisely assessed, as several cases never become clinically manifest owing to the death of patients for cancer-unrelated causes. Indeed, malignant lesions of the prostate generally progress at a slow pace and early stage neoplasms are associated with few, if any, symptoms. 3,4 Many factors have been tentatively implicated in the etiology of prostate cancer, including genetic alterations as well as viral, alimentary and sexual determinants. However, while convincing evidence links some of these factors, such as BRCA1 and BRCA2 mutations (which also predispose to the development of breast and ovarian carcinoma), to an increased risk of developing prostate cancer, 5 other causal correlations, such as that with a xenotropic MuLV-related virus, have been officially discarded. 6,7 Upon diagnosis of prostate cancer, the first therapeutic decision relates to whether treatment is actually needed. As most of these neoplasms afflict the elderly (often exhibiting several co-morbidities) and progress very slowly, the risk of overtreatment is indeed relatively high. It has been suggested that in 50–75% of cases, prostate cancer does not cause any harm before death for other causes intervenes. 8 A reduced fraction of patients, however, present with aggressive lesions at a young age (50–60), calling for the delineation of a therapeutic strategy. The most appropriate therapeutic option for the management of prostate carcinoma obviously depends on several tumor-related parameters such as stage, Gleason score and prostate-specific antigen (PSA) circulating levels, as well as on the age and general health status of the patient. 3,4 Of note, a large fraction of patients is eligible for active surveillance, entailing the careful observation of the neoplasm over time until signs of progression (which may never manifest). Conversely, subjects bearing aggressive prostate cancers are generally treated with radical prostatectomy (if eligible) combined with cryotherapy or radiation therapy (in the case of localized lesions), or with chemotherapy and/or hormonal therapy (in the case of metastatic disease). 3,4 Unfortunately, most hormone-dependent cancers eventually become refractory …