Castration-Resistant Prostate Cancer: Current Status and Future Directions

OBJECTIVES

Prostate cancer is the most common cancer in men and the second leading cause of cancer related deaths in the Western World 1. After the introduction of a prostate specific antigen (PSA), it has become a standard method of prostate cancer screening and although the incidence of prostate cancer has increased, many patients are diagnosed with the localized disease and have excellent survival and high cure rates with standard treatments 2. However, approximately 30%–50% of treated patients will have a local or distant recurrence despite definitive local therapy 3. Androgen deprivation therapy (ADT) via surgical castration or hormonal manipulation using luteinizing hormone releasing hormone (LHRH), antiandrogens, or both has become the standard treatment of patients with the metastatic disease. Although the disease initially responds to ADT, most of the patients eventually progress to a state of castration-resistant prostate cancer (CRPC). CRPC refers to prostate cancer that has progressed despite castrate levels of testosterone (<50 ng/dL or <1.7 nmol/L), has three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA>2 ng/mL and the patient on antiandrogen withdrawal (AAW) for at least 4 weeks 4. The PSA concentration increases in almost 90% of the patients and bone metastasis, substantive pain and soft tissue/lymph node metastasis are observed in 90%, 35%, and 20% of the patients, respectively 5. Unfortunately, the majority of the patients progress to an androgen independent stage that is also termed CRPC, mostly unresponsive to further hormonal manipulations 6.

An earlier publication by Yagoda and Petrylak 7 revealed that among 1001 men with CRPC who had received chemotherapy in 26 trials, the overall response rate was only 8.7%. Prostate cancer thereby was considered resistant to chemotherapy until the mid-1990s. However, the entry criteria for these trials included the presence of the measurable disease, which usually means late stage or metastatic disease in prostate cancer. Subsequently, after the introduction of surrogate end points for the prostate cancer clinical trials including a >50% PSA response, pain response, and quality of life measures, more patients with a less extensive disease, fewer symptoms, and better performance status were included in later trials demonstrating far better results 8.

This review highlights the current approaches and recent developments, particularly focusing on the most encouraging results with new agents that might be candidates for the routine clinical practice in the management of CRPC ().