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      Enzalutamide in European and North American men participating in the AFFIRM trial

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          Abstract

          Objective

          To explore any differences in efficacy and safety outcomes between European (EU) ( n = 684) and North American (NA) ( n = 395) patients in the AFFIRM trial (NCT00974311).

          Patients and Methods

          Phase III, double-blind, placebo-controlled, multinational AFFIRM trial in men with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel. Participants were randomly assigned in a 2:1 ratio to receive oral enzalutamide 160 mg/day or placebo. The primary end point was overall survival (OS) in a post hoc analysis.

          Results

          Enzalutamide significantly improved OS compared with placebo in both EU and NA patients. The median OS in EU patients was longer than NA patients in both treatment groups. However, the relative treatment effect, expressed as hazard ratio and 95% confidence interval, was similar in both regions: 0.64 (0.50, 0.82) for EU and 0.63 (0.47, 0.83) for NA. Significant improvements in other end points further confirmed the benefit of enzalutamide over placebo in patients from both regions. The tolerability profile of enzalutamide was comparable between EU and NA patients, with fatigue and nausea the most common adverse events. Four EU patients (4/461 enzalutamide-treated, 0.87%) and one NA patient (1/263 enzalutamide-treated, 0.38%) had seizures. The difference in median OS was related in part to the timing of development of mCRPC and baseline demographics on study entry.

          Conclusion

          This post hoc exploratory analysis of the AFFIRM trial showed a consistent OS benefit for enzalutamide in men with mCRPC who had previously progressed on docetaxel in both NA- and EU-treated patients, although the median OS was higher in EU relative to NA patients. Efficacy benefits were consistent across end points, with a comparable safety profile in both regions.

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          Most cited references20

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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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            EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer.

            Our aim is to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC). The working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and the levels of evidence (LEs) and/or grades of recommendation (GR) were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews. Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). Although LHRH antagonists decrease testosterone without any testosterone surge, their clinical benefit remains to be determined. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation (IAD) results in equivalent oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values >0.2 ng/ml following radical prostatectomy (RP) and >2 ng/ml above the nadir after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT at PSA levels 20 ng/ml. Follow-up after ADT should include screening for the metabolic syndrome and an analysis of PSA and testosterone levels. Treatment of castration-resistant prostate cancer (CRPC) includes second-line hormonal therapy, novel agents, and chemotherapy with docetaxel at 75 mg/m(2) every 3 wk. Cabazitaxel as a second-line therapy for relapse after docetaxel might become a future option. Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications. The knowledge in the field of advanced, metastatic, and CRPC is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or online at www.uroweb.org. Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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              Early detection of prostate cancer: European Association of Urology recommendation.

              The recommendations and the updated EAU guidelines consider early detection of PCa with the purpose of reducing PCa-related mortality and the development of advanced or metastatic disease. This paper presents the recommendations of the European Association of Urology (EAU) for early detection of prostate cancer (PCa) in men without evidence of PCa-related symptoms. The working panel conducted a systematic literature review and meta-analysis of prospective and retrospective clinical studies on baseline prostate-specific antigen (PSA) and early detection of PCa and on PCa screening published between 1990 and 2013 using Cochrane Reviews, Embase, and Medline search strategies. The level of evidence and grade of recommendation were analysed according to the principles of evidence-based medicine. The current strategy of the EAU recommends that (1) early detection of PCa reduces PCa-related mortality; (2) early detection of PCa reduces the risk of being diagnosed and developing advanced and metastatic PCa; (3) a baseline serum PSA level should be obtained at 40-45 yr of age; (4) intervals for early detection of PCa should be adapted to the baseline PSA serum concentration; (5) early detection should be offered to men with a life expectancy ≥ 10 yr; and (6) in the future, multivariable clinical risk-prediction tools need to be integrated into the decision-making process. A baseline serum PSA should be offered to all men 40-45 yr of age to initiate a risk-adapted follow-up approach with the purpose of reducing PCa mortality and the incidence of advanced and metastatic PCa. In the future, the development and application of multivariable risk-prediction tools will be necessary to prevent over diagnosis and over treatment. Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                BJU Int
                BJU Int
                bju
                Bju International
                John Wiley & Sons Ltd (Oxford, UK )
                1464-4096
                1464-410X
                January 2015
                23 October 2014
                : 115
                : 1
                : 41-49
                Affiliations
                Medizinische Hochschule Hannover Hannover, Germany
                [§ ]Charité – Universitätsmedizin Berlin Berlin, Germany
                [** ]Universitätsklinikum Tübingen Tübingen, Germany
                []Memorial Sloan-Kettering Cancer Center New York, NY, USA
                []Dana-Farber Cancer Institute, Harvard Medical School Boston, MA, USA
                [§§ ]Medivation, Inc. San Francisco, CA, USA
                [¶¶ ]Astellas Scientific and Medical Affairs, Inc. Northbrook, IL, USA
                []Radboud University Nijmegen Medical Centre Nijmegen, The Netherlands
                [††† ]Erasmus University Medical Center Rotterdam, The Netherlands
                [†† ]San Camillo – Forlanini Hospitals Rome, Italy
                [‡‡ ]Institut Gustave Roussy, University of Paris Sud Villejuif, France
                [*** ]Institute of Cancer Research and Royal Marsden NHS Foundation Trust Sutton, UK
                Author notes
                Correspondence: Axel S. Merseburger, Department of Urology and Urologic Oncology, Hannover Medical School (MHH), Carl Neuberg Str. 1, 30625 Hannover, Germany., e-mail: merseburger.axel@ 123456mh-hannover.de

                Trial registration: ClinicalTrials.gov NCT00974311.

                Article
                10.1111/bju.12898
                4312486
                25123978
                d02b7885-12f1-4d90-8d49-2edc368b30ad
                © 2014 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 14 August 2014
                Categories
                Urological Oncology

                Urology
                androgen receptor inhibitor,enzalutamide,metastatic castration-resistant prostate cancer

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