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      Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations

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          Abstract

          Background

          Androgen deprivation therapy (ADT) is foundational in the management of advanced prostate cancer (PCa) and has benefitted from a recent explosion in scientific advances. These include approval of new therapies that suppress testosterone (T) levels or inactivate its function, improvements in diagnostic and assay technologies, identification of lower therapeutic targets for T, discovery of the relevance of germline genetic mutations and identification of the benefits of sequential and combination therapies.

          Methods

          This review discusses the clinical profiles of the most up-to-date options for ADT, best practices for managing patients with advanced PCa and future directions in therapy.

          Results and conclusions

          Modern assay technologies reveal that bilateral orchiectomy results in a serum T level of approximately 15 ng/dL as compared to the historical definition of castration of T < 50 ng/dL. Evidence shows that lowering T levels to <20 ng/dL improves patient survival and delays disease progression. Routine monitoring of T in addition to prostate-specific antigen throughout treatment is important to ensure continuing efficacy of T suppression. New drugs that inhibit androgen signaling in combination with traditional ADT suppress T activity to near zero and have significantly improved patient survival. When personalizing ADT regimens physicians should consider a number of factors including initiation and duration of ADT, monitoring of T levels and PSA, the possibility of switching monotherapies if a patient does not achieve adequate T suppression, and consideration of intermittent vs. continuous ADT according to patients’ lifestyles, comorbidities, risk factors and tolerance to treatment.

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          Most cited references94

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          Patient adherence and persistence with oral anticancer treatment.

          Given the recent significant increase in the use of oral therapies in cancer management, an understanding of patients' adherence to and persistence with oral therapy is crucial. Nonadherence and early cessation may be substantial barriers to the delivery of valuable therapies, and may impair health. Potential obstacles to adherence and persistence include personal characteristics, treatment features, and system factors. Techniques for measuring adherence and persistence include self-report, pill counts, microelectronic monitoring systems (MEMS), prescription database analysis, and the assessment of serum or urine drug levels. This review article describes available data regarding adherence and persistence among patients with cancer, as well as studies of interventions to improve adherence. All reports of studies of adherence with oral cancer therapy that the authors could find on PubMed or in the reference sections of these PubMed-located articles were included. Adherence and persistence rates ranged from 16% to 100% with different therapies and different methods of measurement. Studies that included educational, behavioral, and multidimensional interventions to improve adherence were also described. (c) 2009 American Cancer Society.
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            The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer.

            To evaluate the efficacy and safety of degarelix, a new gonadotrophin-releasing hormone (GnRH) antagonist (blocker), vs leuprolide for achieving and maintaining testosterone suppression in a 1-year phase III trial involving patients with prostate cancer. In all, 610 patients with adenocarcinoma of the prostate (any stage; median age 72 years; median testosterone 3.93 ng/mL, median prostate-specific antigen, PSA, level 19.0 ng/mL) were randomized and received study treatment. Androgen-deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator's assessment. Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (s.c.) for 1 month, followed by s.c. maintenance doses of 80 mg or 160 mg monthly, or intramuscular (i.m.) leuprolide doses of 7.5 mg monthly. Therapy was maintained for the 12-month study. Both the intent-to-treat (ITT) and per protocol populations were analysed. The primary endpoint of the trial was suppression of testosterone to
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              Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer

              While programmed cell death 1 (PD-1) inhibitors have shown clear anti-tumor efficacy in several solid tumors, prior results in men with metastatic castration resistant prostate cancer (mCRPC) showed no evidence of activity. Here we report unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1 antibody pembrolizumab. Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses; pembrolizumab was added to standard dose enzalutamide. Three of the first ten patients enrolled in this ongoing phase II trial experienced rapid prostate specific antigen (PSA) reductions to ≤ 0.2 ng/ml. Two of these three patients had measurable disease upon study entry; both achieved a partial response. There were three patients with significant immune-related adverse events. One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response. Two of the three responders had a baseline tumor biopsy. Immunohistochemistry from those biopsies showed the presence of CD3+, CD8+, and CD163+ leukocyte infiltrates and PD-L1 expression. Genetic analysis of the two responders revealed markers of microsatellite instability in one. The surprising and robust responses seen in this study should lead to re-examination of PD-1 inhibition in prostate cancer.
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                Author and article information

                Contributors
                +1 720 848 0195 , David.Crawford@UCDenver.edu
                Journal
                Prostate Cancer Prostatic Dis
                Prostate Cancer Prostatic Dis
                Prostate Cancer and Prostatic Diseases
                Nature Publishing Group UK (London )
                1365-7852
                1476-5608
                21 August 2018
                21 August 2018
                2019
                : 22
                : 1
                : 24-38
                Affiliations
                [1 ]ISNI 0000000107903411, GRID grid.241116.1, University of Colorado School of Medicine, ; Denver, CO USA
                [2 ]ISNI 0000 0000 8580 3777, GRID grid.6190.e, University of Cologne, ; Cologne, Germany
                [3 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Medical University of Vienna, ; Vienna, Austria
                [4 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, University of Melbourne, ; Melbourne, Australia
                [5 ]ISNI 0000 0004 0461 6320, GRID grid.48769.34, Cliniques Universitaires Saint-Luc, ; Brussels, Belgium
                [6 ]ISNI 0000 0004 0413 8963, GRID grid.419034.b, Faculdade de Medicina do ABC, ; São Paulo, Brazil
                [7 ]GRID grid.414741.3, Hospital Médica Sur, ; Ciudad de México, Mexico
                [8 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Charité Universitätsmedizin Berlin, ; Berlin, Germany
                [9 ]GRID grid.491676.b, Andros Mannenkliniek, ; Arnhem, Netherlands
                [10 ]ISNI 0000 0000 9743 1587, GRID grid.413104.3, Sunnybrook Health Sciences Centre, ; Toronto, Canada
                Article
                79
                10.1038/s41391-018-0079-0
                6370592
                30131604
                aa049e73-367a-4888-ad44-09583b90971f
                © Springer Nature Limited 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 May 2018
                : 12 July 2018
                : 20 July 2018
                Categories
                Review Article
                Custom metadata
                © Springer Nature America, Inc. 2019

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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