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Prostate Cancer Current and Emerging Therapies in Metastatic Prostate Cancer Hema Vankayala, MD 1 and Ulka Vaishampayan, MD, GU 2 1. Medical Oncologist, John D Dingell VA Medical Center; 2. Professor of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, US Abstract The face of metastatic prostate cancer (PC) has been remarkably reshaped with the current advances in its management. Kudos to the cutting- edge research that has pinpointed new targets and agents. The main stumbling block in this disease is progression on androgen deprivation therapy (ADT) and the development of castrate resistance. Despite this phenomenon, the majority of patients with PC continue to rely on androgen receptors (ARs) for disease growth and progression. Several of these newer agents directly or indirectly target ARs. Many drugs have earned US Food and Drug Administration (FDA) approval in the past decade by showing survival benefit, which is the gold standard endpoint in all the pivotal PC trials. An array of new targets and agents are being explored currently. The future of metastatic castration-resistant prostate cancer (mCRPC) appears exciting with the expanding armamentarium; however, the challenges of affordability and sequencing of the agents remain. Keywords Metastatic prostate cancer, castrate resistant, androgen sensitive, immune therapy Disclosure: Hema Vankayala, MD, and Ulka Vaishampayan, MD, GU, have no conflicts of interest to declare. No funding was received in the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: 21 January, 2015 Accepted: 4 March, 2015 Citation: Oncology & Hematology Review, 2015;11(1):58–66 Correspondence: Ulka Vaishampayan, MD, GU, Professor of Oncology, Karmanos Cancer Institute/Wayne State University, 4100 John R, 4233 HWCRC, Detroit MI 48201. E: vaishamu@karmanos.org Knowledge regarding the mechanisms driving progression of prostate cancer (PC) has improved dramatically in the past few years. This has allowed the accelerated development and approval of multiple drugs with different targets. The wide spectrum of rapid developments in this field warrants a comprehensive review. In this paper we aim to summarize the current standard of care incorporating recent advances, and placing emphasis on novel developments. PC is the second most common malignancy in American men, and the second leading cause of cancer-related death in men in the US. It is estimated that in 2014 nearly 233,000 men will be diagnosed with PC, and 29,480 will die from the disease. 1,2 The majority of them are diagnosed as a result of screening, so symptomatic presentation is unusual. Median age at diagnosis is 66 years. In the Surveillance Epidemiology End Results (SEER) 18 data, only 4  % have distant disease at presentation and the 5-year survival rate is 25–30 %. 3 Over 95  % of PCs are adenocarcinomas. With the advent of multiple therapies, the incidence of variant histologies such as neuroendocrine PC appears to be increasing. The therapeutic management of these histologies is an area of active clinical and research interest. The therapies chosen in every setting of PC should demonstrate improved survival, but also factor in the patient characteristics of a predominantly elderly population with numerous comorbidities and the impact on quality of life (QoL). 58 Androgen-sensitive Metastatic Prostate Cancer (see Figure 1) PC is predominantly driven by androgen-induced activation of androgen receptors (ARs) for its growth and survival. Disruption of this pathway ceases PC proliferation and induces apoptosis. The role of androgen ablation or androgen deprivation therapy (ADT) to suppress the testosterone to castrate levels, a Nobel Prize-winning discovery, was clearly established decades ago and continues to be the standard of care. Recent data (in the era of prostate-specific antigen [PSA] use) indicate that the current median survival for this group of patients is 5 years, but contemporary overall survival (OS) is likely to be longer given the multiple therapies that are now available for clinical use. 4,5 The question of whether intermittent ADT should be the standard was put to rest with the results of Southwest Oncology Group (SWOG) 9346 (INT-0162). This was an intergroup phase III noninferiority trial in which men with androgen-sensitive metastatic disease were randomized to either intermittent or continuous ADT, if they achieved a PSA of 4 or below after 7 months of ADT. Over 3,000 patients were registered, and 1,535 patients were randomized. Median survival was 5.8 years in the continuous arm and 5.1 years in the intermittent arm (hazard ratio [HR] 1.09; 95  % confidence interval [CI] 0.95–1.24). This difference did not meet prespecified criteria for noninferiority for the study population. QoL analyses demonstrated modest but short-lived improvements in sexual Touch ME d ica l ME d ia