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Review Prostate Cancer The Changing Therapeutic Landscape in Metastatic Prostate Cancer Alan J Koletsky Lynn Cancer Institute, Boca Raton, FL, US O ver the past several years a number of novel and diverse agents have provided a significant clinical benefit for patients with metastatic castration-resistant prostate cancer including abiraterone, enzalutamide, sipuleucel-T, cabazitaxel, and radium-223. The early use of docetaxel or abiraterone at initiation of standard androgen deprivation therapy in patients with metastatic hormone-sensitive prostate cancer has also led to substantial improvements in overall survival. The identification of a truncating mutation in the androgen receptor (AR- V7), a biomarker of resistance, may help clarify a more optimal sequencing of hormonal and chemotherapy-based therapies for patients with metastatic disease. The genomic landscape of both primary and metastatic prostate cancer has been an important focal point of translational research. The most widely studied pathways that affect tumorigenesis are the phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) and poly ADP ribose polymerase (PARP) and DNA repair pathways. This review will highlight recent clinical trials which have had a major impact on the management of patients with metastatic disease with an emphasis on treatments driven by common genomic aberrations present in advanced prostate cancer. Keywords Metastatic hormone-sensitive prostate cancer (mHSPC), metastatic castration- resistant prostate cancer (mCRPC), androgen receptor (AR), androgen deprivation therapy (ADT), radiographic progression-free survival (rPFS), failure-free survival (FFS), prostate- specific antigen (PSA), prostrate specific membrane antigen (PSMA), granulocyte- macrophage colony stimulating factor (GM-CSF), radiographic skeletal-related events (rSRE) Disclosure: Alan J Koletsky serves on speaker’s bureaus for Bristol Myers Squibb, Exelixis, and Astellas. No funding was received for the publication of this article. Compliance with Ethics: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. 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: August 21, 2017 Accepted: September 25, 2017 Citation: Oncology & Hematology Review, 2017;13(2):112–6 Corresponding Author: Alan J Koletsky, MD, Lynn Cancer Institute, 701 NW 13th Street, Boca Raton, FL 33486, US. Androgen ablation therapy (ADT) alone has long been the standard of care (SOC) for patients with metastatic prostate cancer initiating systemic therapy. Although most patients treated with standard ADT achieve a substantial prostate specific antigen (PSA) decline, transition to a castration-resistant state invariably occurs. In a large retrospective review of 659 patients with primary advanced prostate cancer and bone metastasis, the median duration of response to initial ADT was 22.4 months. 1 Risk factors associated with a shorter overall survival (OS) in men treated with ADT alone included pre- treatment PSA level, Gleason score, and extent of bone involvement at diagnosis. Chemo-hormonal therapy in metastatic hormone-sensitive prostate cancer—the CHAARTED and STAMPEDE trials Early studies which sought to examine a potential efficacy of concurrent ADT and chemotherapy were limited by the small numbers of patients enrolled, many of whom had a low tumor burden at study entry. 2,3 In the CHAARTED trial, 790 metastatic hormone-sensitive patients (mHSPC) were randomized to receive ADT alone or ADT plus docetaxel. Patients were prospectively stratified into high volume disease (defined as four or more bone metastases with at least one outside the vertebral column and pelvis and/or visceral metastases) and low-volume disease. 4 Long-term results from the CHAARTED trial were presented at ESMO 2016. Patients receiving ADT plus docetaxel had a significant improvement in median OS compared with ADT alone (57.6 months versus 42 months; hazard ratio [HR] 0.73; p=0.0018). A subgroup analysis continued to show benefit from the addition of docetaxel only in the high volume group. The median OS in this group was 51.2 months for ADT plus docetaxel versus 34.4 months for ADT alone (HR 0.61; p<0.0001). Secondary end-points including time to clinical progression and quality of life (Functional Assessment of Cancer Therapy-Prostate [FACT-P] questionnaire) also benefited the group with high-volume disease. An OS benefit with earlier use of docetaxel and ADT in patients with low volume disease has yet to be demonstrated with longer follow-up; although, these patients had a longer time to onset of CRPC, PSA progression, and clinical progression. The STAMPEDE trial included both non-metastatic (M0) and metastatic hormone-naïve (M1) patients in two of the comparator arms each randomized to ADT plus chemotherapy (with or without zoledronic acid) and compared to a control group receiving ADT alone. 5,6 A total of 592 men with newly diagnosed M1 disease were accrued to the ADT plus docetaxel arm of STAMPEDE. Docetaxel was started within 2 weeks of randomization, and approximately 9 weeks after initiation of ADT, similar to the time used 112 TOUCH ME D ICA L ME D IA