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      Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond

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          Abstract

          The androgen receptor drives the growth of metastatic castration-resistant prostate cancer. This has led to the development of multiple novel drugs targeting this hormone-regulated transcription factor, such as enzalutamide – a potent androgen receptor antagonist. Despite the plethora of possible treatment options, the absolute survival benefit of each treatment separately is limited to a few months. Therefore, current research efforts are directed to determine the optimal sequence of therapies, discover novel drugs effective in metastatic castration-resistant prostate cancer and define patient subpopulations that ultimately benefit from these treatments. Molecular studies provide evidence on which pathways mediate treatment resistance and may lead to improved treatment for metastatic castration-resistant prostate cancer. This review provides, firstly a concise overview of the clinical development, use and effectiveness of enzalutamide in the treatment of advanced prostate cancer, secondly it describes translational research addressing enzalutamide response vs resistance and lastly highlights novel potential treatment strategies in the enzalutamide-resistant setting.

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          Molecular determinants of resistance to antiandrogen therapy.

          Charlie D Chen, Derek S Welsbie, Chris Tran … (2004)
          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.
          Article 0 comments Cited 509 times – based on 0 reviews     Review now
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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.

            Karim Fizazi, Howard I Scher, Arturo Molina … (2012)
            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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              Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer

              Fred Saad, Neal Shore, Ubirajara Ferreira … (2018)
              Men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. We hypothesized that enzalutamide, which prolongs overall survival among patients with metastatic, castration-resistant prostate cancer, would delay metastasis in men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level.
              Article 0 comments Cited 379 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Endocr Relat Cancer
                Journal ID (iso-abbrev): Endocr. Relat. Cancer
                Journal ID (hwp): ERC
                Title: Endocrine-Related Cancer
                Publisher: Bioscientifica Ltd (Bristol )
                ISSN (Print): 1351-0088
                ISSN (Electronic): 1479-6821
                Publication date Collection: January 2019
                Publication date (Electronic): 14 September 2018
                Volume: 26
                Issue: 1
                Pages: R31-R52
                Affiliations
                [1 ]Division of Oncogenomics Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
                [2 ]Division of Urology The Netherlands Cancer Institute, Amsterdam, The Netherlands
                [3 ]Division of Medical Oncology The Netherlands Cancer Institute, Amsterdam, The Netherlands
                [4 ]Division of Oncogenomics The Netherlands Cancer Institute, Amsterdam, The Netherlands
                [5 ]Laboratory of Chemical Biology and Institute for Complex Molecular Systems Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
                Author notes
                Correspondence should be addressed to S Prekovic: s.prekovic@ 123456nki.nl
                Article
                Publisher ID: ERC180289
                DOI: 10.1530/ERC-18-0289
                PMC ID: 6215909
                PubMed ID: 30382692
                SO-VID: 0ceb7a5f-11a5-47db-96be-0463452d13b3
                Copyright © © 2018 The authors
                License:

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                Date received : 24 August 2018
                Date accepted : 14 September 2018
                Categories
                Subject: Review

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: enzalutamide,treatment resistance,biomarkers,androgen receptor,mutations,prostate cancer,mcrpc,androgen deprivation therapy,docetaxel
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: enzalutamide, treatment resistance, biomarkers, androgen receptor, mutations, prostate cancer, mcrpc, androgen deprivation therapy, docetaxel

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