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      Advanced prostate cancer – patient survival and potential impact of enzalutamide and other emerging therapies

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          Abstract

          The advent of exponential growth of novel agents tested and approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) has brought about a need for understanding of the mechanism of action, side-effects, and clinical efficacy of these drugs as they relate to these patients. This review will provide a synopsis of the treatment landscape in mCRPC as varying agents such as abiraterone acetate, cabazitaxel, sipuleucel-T, radium, and selected emerging agents are presented. A distinct focus on the utilization of enzalutamide, its mechanism of action, key pivotal trials that brought about its US Food and Drug Administration approval, as well as patient-focused perspectives and clinical implications are discussed herein.

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          Most cited references 71

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          Molecular determinants of resistance to antiandrogen therapy.

          Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.
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            Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth.

            Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.
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              Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study.

              Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events). Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00091442. Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4-22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8-17·0] vs 11·2 months [10·4-13·1]; hazard ratio [HR] 0·74, 95% CI 0·64-0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3-11·1, in the abiraterone group vs 6·6 months, 5·6-8·3, in the placebo group; HR 0·63, 0·52-0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6-6·5, vs 3·6 months, 2·9-5·5; HR 0·66, 0·58-0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]). This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2014
                16 August 2014
                : 10
                : 651-664
                Affiliations
                Department of Medicine, Division of Hematology and Oncology, George Washington University Medical Center, Washington, DC, USA
                Author notes
                Correspondence: Jeanny B Aragon-Ching, Division of Hematology and Oncology, George Washington University Medical Center, 2150 Pennsylvania Avenue, NW, Suite 1-205, Washington, DC 20037, USA, Tel +1 202 741 2478, Fax +1 202 741 2487, Email jaragonching@ 123456mfa.gwu.edu
                Article
                tcrm-10-651
                10.2147/TCRM.S57509
                4144843
                © 2014 Patel et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Medicine

                systemic therapies, enzalutamide, metastatic castration-resistant prostate cancer

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