Prostate cancer is the most common non-dermatological malignant disease in men in western countries. According to the American Cancer Society in 2010, the incidence of prostate cancer was 217,730 cases with 32,050 deaths from the disease [1]. Overall, the actuarial 10 and 15 years survival are 93% and 77% respectively [1]. The rise in incidence and improved survival of prostate cancer over the past decades have often been attributed to prostate cancer screening and early detection. Definite evidence supporting this relationship is, however, still pending. There are also alternative explanations such as improved treatment at advanced stages that could lower prostate cancer mortality. Because of earlier detection, up to 90% of new cases in the post prostate-specific antigen (PSA) era present with clinically localized disease, the majority of which do well regardless of treatment regimen undertaken. Overall, those with advanced prostate cancer at time of diagnosis remains essentially incurable, and do poorly after androgen withdrawal therapy developing progressive disease that is resistant to further hormone manipulation. For these patients with castration-resistent prostate cancer (CRPC), and particularly patients with metastatic disease, options till few years ago have been limited. However, as newer agents become available, higher rate of biochemical and clinical response are being achieved, providing a new hope for the management of these patients [2].

CRPC is defined as patients with serum castration levels of testosterone (< 50 ng/dL or < 1.7 nmol/L), PSA and/or clinical progression to castration, and progression despite anti-andro-

gen withdrawal for at least 4-6 weeks. PSA progression is defined as three consecutive rises of PSA, 1 week apart, resulting in two 25% increases over the nadir, with a PSA level > 2 ng/dL above the nadir. Clinical progression includes progression of bone lesions (two or more lesions on bone scan) or soft tissue progression using Respond Evaluation Criteria In Solid Tumors (RECIST) criteria [3].

Although patients with CRPC have, by definition, castrate levels of circulating testosterone, most tumors continue to remain dependent on androgen and on signaling from the androgen receptor (AR). This may occur through constitutive activation of the AR (gene amplification, alternative splicing, AR-activating gene mutations), intratumoral production of androgen, promiscuity of the AR (and binding of other hormones), activation of downstream targets by dysregulation of transcription factors (eg, binding of the frequently rearranged and overexpressed ETS oncogenic factors to androgen-regulated promoters), and alternative yet unidentified mechanisms [1, 2].

CRPC status includes patient cohorts with significantly different median survival times and different sensitivity to second hormonal manipulations. However, the vast majority of patients eventually develop progressive disease that is resistant to further hormone manipulation. We now know that although this group of patients progress to androgen deprivation, they might still be hormone-sensitive. Until 2004, cytotoxic chemotherapy was considered to be relatively ineffective in men with CRPC. In 2004, 2 landmark trials, TAX 327 and Southwest Oncology Group (SWOG) 99-16, showed for the first time a survival benefit in men with metastatic HRPC. Specifically, docetaxel-based chemotherapy demonstrated a median improvement in survival of 2.5 months as compared with mitoxantrone and prednisone in metastatic HRPC [4, 5]. Regimens that include docetaxel, have demonstrated higher rates of objective and biochemical PSA response, as well as longer survival durations. In contrast, metastatic CRPC has become a more complicated disease to be properly treated. Since then, newer treatments in this stage of the disease have been approved optimizing survival and quality of life.

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