Progress in the Treatment of Advanced Prostate Cancer Cora N. Sternberg, MD, Daniel P. Petrylak, MD, Ravi A. Madan, MD, and Chris Parker, MD OVERVIEW 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. P rostate cancer is the second most common cause of can- cer worldwide. 1 It is estimated that more than 29,000 men will die from metastatic prostate cancer in 2014. 2 For patients who relapse after treatment of organ-confıned dis- ease or those who present with metastatic disease, testoster- one suppression with hormone therapy is the foundation of therapy. Lowering testosterone and its precursors and alter- ing the AR axis was the fırst method discovered that could control this disease. The initial treatment for metastatic disease is androgen ab- lation, achieved either surgically or medically. Either modal- ity should result in reduction in testosterone to levels less than 50 ng/dL, resulting in prostate tumor regression. 3 Clin- ical response to androgen blockade is manifested by decline in serum prostate specifıc antigen (PSA), relief in pain from bone metastases, and improvement in neurologic symptoms from spinal cord compression when combined with high- dose steroids and radiation. Despite initial clinical and symp- tomatic improvement, nearly all men will progress to castration-resistant prostate cancer (CRPC). This state of disease is defıned as progression of disease, either biochemi- cally or objectively, despite castrate testosterone levels. The cutoff of testosterone less than 50 ng/dL has not been estab- lished for clinical utility, but rather for ease in clinical trial accrual. Before the advent of more effective chemotherapeu- tic, hormonal, immunotherapeutic, and radiological agents, CRPC historically had a dismal prognosis with median OS of 9 months to 12 months. Signifıcant morbidity from disease progression in CRPC may be caused by anemia, urinary tract obstruction, spinal cord compression, pathologic fractures, pain, and cachexia. Today, the AR still represents the most relevant target for patients with mCRPC. Although in the past prostate cancer has been referred to as “hormone refractory” or “androgen independent,” there is now irrefutable evidence that the AR axis is functional in most patients throughout the natural his- tory of prostate cancer from diagnosis to death, and repre- sents a therapeutic target that is relevant in all phases of the disease. The potential mechanisms of tumor escape after castration with luteinizing hormone-releasing hormone (LHRH) ana- logs, female hormones, and LHRH antagonists are multifold, with each mechanism today representing a therapeutic op- portunity. Phase III trials have been able to demonstrate im- proved survival, improved quality of life, decreased skeletal- related events, and other important clinical benefıts in young and elderly patients. mCRPC is a challenge; however, research has resulted in fıve 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 randomized phase III trials. 4-11 Bone-targeted therapy has From the San Camillo Forlanini Hospital, Rome, Italy; Yale University Cancer Center, New Haven, CT; Center for Cancer Research, National Cancer Institute, Bethesda, MD; The Royal Marsden Hospital, London, United Kingdom. Disclosures of potential conflicts of interest are found at the end of this article. Corresponding author: Cora N. Sternberg, MD, San Camillo Forlanini Hospital, Circonvallazione Gianicolense 87, 00152 Rome, Italy; email: cstern@mclink.it. © 2014 by American Society of Clinical Oncology. 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