DOCSLIB.ORG

Gnrh Antagonists Have Direct Inhibitory Effects on Castration-Resistant Prostate

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Gnrh Antagonists Have Direct Inhibitory Effects on Castration-Resistant Prostate Author Manuscript Published OnlineFirst on July 24, 2019; DOI: 10.1158/1535-7163.MCT-18-1337 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. GnRH antagonists have direct inhibitory effects on castration-resistant prostate cancer via intracrine androgen and AR-V7 expression. Vito Cucchiara1*, Joy C. Yang1*, Chengfei Liu1, Hans H. Adomat2, Emma S. Tomlinson Guns2, Martin E. Gleave2, Allen C. Gao1,3, Christopher P. Evans1,3 1Department of Urologic Surgery, University of California at Davis, Sacramento, California. 2Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada 3UC Davis Comprehensive Cancer Center, University of California Davis, California. Running title: GnRH antagonist inhibits intracrine androgen and AR-V7 Keywords: Prostate Cancer, ADT, GnRH antagonist, intracrine androgen Financial Support: This work is supported in part by grants DOD PC150040P1 and Ferring Pharmaceuticals to CP Evans. Conflicts of Interest: Research support from Ferring to CPE and JCY. All other authors have no conflicts of interest. Corresponding Author: Christopher P. Evans, MD, FACS Professor and Chairman, Department of Urology Urologic Surgical Oncology University of California, Davis, School of Medicine 4860 Y St., Suite 3500 Sacramento, CA 95817 academic office tel # (916)734-7520 academic office fax # (916)734-8094 email: [email protected] *These authors contributed equally to this work Downloaded from mct.aacrjournals.org on October 6, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 24, 2019; DOI: 10.1158/1535-7163.MCT-18-1337 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer (PCa). Degarelix (Firmagon), a gonadotropin-releasing hormone (GnRH) receptor antagonist differs from luteinizing hormone–releasing hormone (LHRH) agonists by avoiding “testosterone flare” and lower follicle-stimulating hormone (FSH) levels. The direct effect of degarelix and leuprolide on human prostate cancer cells was evaluated. In LNCaP, C4-2BMDVR and CWR22Rv1 cells, degarelix significantly reduced cell viability compared to the controls (p≤0.01). Leuprolide was stimulatory in the same cell lines. In C4-2B MDVR cells, degarelix alone or combined with abiraterone or enzalutamide reduced the AR-V7 protein expression compared to the control group. SCID mice bearing VCaP xenograft tumors were divided into four groups and treated with surgical castration, degarelix, leuprolide or buffer alone for 4 weeks. Leuprolide slightly suppressed tumor growth compared to the vehicle control group (p>0.05). Tumors in degarelix-treated mice were 67% of those in the leuprolide-treatment group but 170% larger than in surgically castrated ones. Measurements of intratumoral steroids in serum, tumor samples or treated cell pellets by LC-MS confirmed that degarelix better decreased the levels of testosterone and steroidogenesis pathway intermediates, comparable to surgical castration; while leuprolide had no inhibitory effect. Collectively, our results suggested a selective mechanism of action of degarelix against androgen steroidogenesis and AR-variants. The present study provides additional molecular insights regarding the mechanism of degarelix compared to GnRH agonist therapy, which may have clincial implications. INTRODUCTION Prostate cancer (PCa) is the most common tumor and the second cause of cancer-death in men [1]. For advanced and metastatic PCa, androgen deprivation therapy (ADT) using luteinizing hormone– releasing hormone (LHRH) agonists or the gonadotropin-releasing hormone (GnRH) receptor Downloaded from mct.aacrjournals.org on October 6, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 24, 2019; DOI: 10.1158/1535-7163.MCT-18-1337 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. antagonist, alone or in combination with radiotherapy, is considered the best treatment option [2, 3]. A new generation of androgen receptor signaling inhibitors, such as abiraterone or enzalutamide, have been approved as treatment options in castration-resistant prostate cancer (CRPC) [2, 3]. Different ADT strategies have been tested to achieve castration levels of testosterone (<50 ng/dl). To date, long- acting depot formulations of GnRH agonists (in combination with antiandrogens for four weeks to avoid the “testosterone surge”) are the most commonly used agents. GnRH agonists, after a desensitization of the GnRH receptor response, determine a reduction in luteinising hormone (LH), follicle-stimulating hormone (FSH), and testosterone production [2, 3]. GnRH antagonists, like degarelix, are also an approved form of ADT [4]. GnRH antagonists, by blocking GnRH receptors, produce a more rapid suppression of testosterone without testosterone surge or micro-surge [4]. Presently, international prostate cancer guidelines recommend the use of either GnRH agonists or antagonists as treatment options for ADT in PCa patients [2, 3]. While some studies have suggested differences in efficacy and disease-related outcomes (musculoskeletal and urinary events) with degarelix compared to LHRH agonists [4], a systematic review of the literature did not support the superiority of antagonists over agonists [5]. All the available phase III studies included in the analysis have treatment bias, short-term follow-up and heterogeneous populations [5]. GnRH agonists and antagonists both induce castrate levels of testosterone by altering the intracellular signaling of pituitary cells, but several attempts have been made to elucidate the effect of these agents on other cells that express GNRH receptor (GnRH-R) [6, 7]. These studies revealed that extra-pituitary tissues are affected by compounds directed toward GnRH-R [8-11]. In prostate cells, GnRH-R manipulation may influence several biological processes such as cell growth, apoptosis, angiogenesis and cell adhesion [8-11]. We hypothesized that, unlike agonists, GnRH antagonists may have a direct mechanism of action on PCa cells growth, by affecting the AR signaling pathway. Specifically, we investigated the Downloaded from mct.aacrjournals.org on October 6, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 24, 2019; DOI: 10.1158/1535-7163.MCT-18-1337 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. role of GnRH agonists and antagonists in castration sensitive and castration resistant PCa cell lines and xenograft models and their possible interaction with AR and AR splice variants (AR-Vs such as AR- V7). It is already know that aberrant AR signaling and AR-Vs are able to promote the development of CRPC and may drive drug resistance [8-11]. Preclinical and clinical trials have described a direct correlation between AR-V7 expression, one of the most intensively studied AR-variant, and resistance to enzalutamide and abiraterone. Moreover, AR-V7 detection has been independently associated with poor prognosis in CRPC [12, 13]. AR-V7 has been proposed as a prognostic marker of prostate specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) among CRPC patients treated with AR-targeted agents (abiraterone and enzalutamide) or chemotherapy [14, 15], but there are no studies that have investigated the relationship between the type of ADT (GnRH agonist or antagonist) and the expression of AR-V7. In this study, we showed that different PCa cell lines are sensitive to the antiproliferative effect of the GnRH antagonist degarelix. Furthermore, the use of degarelix, alone or in combination with enzalutamide or abiraterone, affected the expression of AR-V7. In particular, we observed a reduction of AR-V7 at both the protein and transcription levels. These insights suggest extra-pituitary activity of GnRH-R in PCa tumors and may have implications regarding resistance to second generation AR pathway inhibitors. Downloaded from mct.aacrjournals.org on October 6, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 24, 2019; DOI: 10.1158/1535-7163.MCT-18-1337 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Materials and Methods Reagents and Cell Culture LNCaP, VCaP, and CWR22Rv1 cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA). All experiments with cell lines were performed within 6 months of receipt from ATCC or resuscitation after cryopreservation. The cells were maintained in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), 100 units/ml penicillin and 0.1 mg/ml streptomycin. VCaP cells were maintained in DMEM supplemented with 10% fetal bovine serum (FBS), 100 units/ml penicillin and 0.1 mg/ml streptomycin. C4-2B MDVR (C4-2B enzalutamide resistant) [16] cells were maintained in 20 μM enzalutamide containing medium. All cells were maintained at 37°C in a humidified incubator with 5% carbon dioxide. Western blot analysis Total protein was extracted from cultured cells and/or xenograft tumors and the concentrations were estimated using the BCA Protein Assay Reagent (Pierce, Rockford, IL). Equal amounts of denatured protein samples were loaded on a 10% SDS-polyacrylamide gel.
Load more

Recommended publications
  • Personalized ADT
    Personalized ADT Thomas Keane MD Conflicts • Ferring • Tolemar • Bayer • Astellas • myriad Personalized ADT for the Specific Paent • Cardiac • OBesity and testosterone • Fsh • High volume metastac disease • Docetaxol • Significant LUTS Cardiovascular risk profile and ADT Is there a difference? Degarelix Belongs to a class of synthe@c drug, GnRH antagonist (Blocker) GnRH pGlu His Trp Ser Tyr Gly Leu Arg Pro Gly NH2 Leuprolide D-Leu NEt Goserelin D-Ser NH2 LHRH agonists Triptorelin D-Trp NH2 Buserelin D-Ser NEt Degarelix D-NaI D-Cpa D-PaI Aph D-Aph D-Ala NH2 N-Me ABarelix D-NaI D-Cpa D-PaI D-Asn Lys D-Ala NH2 Tyr GnRH antagonists Cetrorelix D-NaI D-Cpa D-PaI D-Cit D-Ala NH2 Ganirelix D-NaI D-CPa D-PaI D-hArg D-hArg D-Ala NH2 Millar RP, et al. Endocr Rev 2004;25:235–75 Most acute CVD events are caused By rupture of a vulnerable atherosclero@c plaque The vulnerable plaque – thin cap with inflammaon Inflammation Plaque instability is at the heart of cardiovascular disease Stable plaque Vulnerable plaque Lumen Lumen Lipid core Lipid core FiBrous cap FiBrous cap Thick Cap Thin Rich in SMC and matrix Composion Rich in inflammatory cells: proteoly@c ac@vity Poor Lipid Rich Inflammatory Inflammatory state Highly inflammatory LiBBy P. Circulaon 1995;91:2844-2850 Incidence of Both prostate cancer and CV events is highest in older men Prostate cancer CV events 3500 3500 Prostate cancer All CV disease Major CV events 3000 3000 2827.1 2500 2500 2338.9 2000 2000 1719.7 1500 1500 1152.6 1008.7 1038.7 1000 1000 641.2 545.2 571.1 Age-specific incidence per 100,000 person-years 500 500 246.9 133.7 4.3 0 0 40-49 50-59 60-69 70-79 80-89 90-99 40-49 50-59 60-69 70-79 80-89 90-99 CV, cardiovascular Major CV events = myocardial infarc@on, stroke, or death due to CV disease All CV disease = major CV events + self-reported angina or revascularisaon procedures Driver, et al.
    [Show full text]
  • Degarelix for Treating Advanced Hormone- Dependent Prostate Cancer
    CONFIDENTIAL UNTIL PUBLISHED NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE Final appraisal determination Degarelix for treating advanced hormone- dependent prostate cancer This guidance was developed using the single technology appraisal (STA) process 1 Guidance 1.1 Degarelix is recommended as an option for treating advanced hormone-dependent prostate cancer, only in adults with spinal metastases who present with signs or symptoms of spinal cord compression. 1.2 People currently receiving treatment initiated within the NHS with degarelix that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop. 2 The technology 2.1 Degarelix (Firmagon, Ferring Pharmaceuticals) is a selective gonadotrophin-releasing hormone antagonist that reduces the release of gonadotrophins by the pituitary, which in turn reduces the secretion of testosterone by the testes. Gonadotrophin- releasing hormone is also known as luteinising hormone-releasing hormone (LHRH). Because gonadotrophin-releasing hormone antagonists do not produce a rise in hormone levels at the start of treatment, there is no initial testosterone surge or tumour stimulation, and therefore no potential for symptomatic flares. National Institute for Health and Care Excellence Page 1 of 71 Final appraisal determination – Degarelix for treating advanced hormone-dependent prostate cancer Issue date: April 2014 CONFIDENTIAL UNTIL PUBLISHED Degarelix has a UK marketing authorisation for the ‘treatment of adult male patients with advanced hormone-dependent prostate cancer’. It is administered as a subcutaneous injection. 2.2 The most common adverse reactions with degarelix are related to the effects of testosterone suppression, including hot flushes and weight increase, or injection site reactions (such as pain and erythema).
    [Show full text]
  • Degarelix Acetate (Firmagon) Reference Number: PA.CP.PHAR.170 Effective Date: 01/18 Last Review Date: 10/18 Revision Log
    Clinical Policy: Degarelix Acetate (Firmagon) Reference Number: PA.CP.PHAR.170 Effective Date: 01/18 Last Review Date: 10/18 Revision Log Description The intent of the criteria is to ensure that patients follow selection elements established by Pennsylvania Health and Wellness® clinical policy for the use of Degarelix Acetate (Firmagon®). FDA Approved Indication(s) Firmagon is indicated for treatment of advanced prostate cancer. Policy/Criteria It is the policy of Pennsylvania Health and Wellness that Firmagon is medically necessary when the following criteria are met: I. Initial Approval Criteria A. Prostate Cancer (must meet all): 1. Diagnosis of prostate cancer; 2. Prescribed by or in consultation with an oncologist; 3. Request meets one of the following (a, b or c): a. Starting dose does not exceed 240 mg given as two injections of 120 mg each; b. Maintenance dose does not exceed 80 mg as a single injection per 28 days; c. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off- label use (prescriber must submit supporting evidence). Approval duration: 12 months B. Other diagnoses/indications: Refer to PA.CP.PMN.53 1. The following NCCN recommended uses for Firmagon, meeting NCCN categories 1, 2a, or 2b, are approved per the PA.CP.PMN.53: II. Continued Approval A. Prostate Cancer (must meet all): 1. Currently receiving medication via Pennsylvania Health and Wellness benefit or member has previously met approval criteria or the Continuity of Care policy (PA.LTSS.PHAR.01) applies; 2. Member is responding positively to therapy; 3. If request is for a dose increase, request meets one of the following: a.
    [Show full text]
  • Follicular and Endocrine Profiles Associated with Different Gnrh
    Reproductive BioMedicine Online (2012) 24, 153– 162 www.sciencedirect.com www.rbmonline.com ARTICLE Follicular and endocrine profiles associated with different GnRH-antagonist regimens: a randomized controlled trial Juan Antonio Garcı´a-Velasco a, Sanja Kupesic b, Antonio Pellicer c, Claire Bourgain d, Carlos Simo´n e, Milan Mrazek f, Paul Devroey g, Joan-Carles Arce h,* a IVI Foundation, Reproductive Endocrinology, Madrid, Spain; b Texas Tech University Health Sciences Center, Department of Obstetrics and Gynecology, El Paso, TX, USA; c IVI Foundation, Reproductive Endocrinology, Valencia, Spain; d UZ Brussel, Department of Pathology, Brussels, Belgium; e IVI Foundation, Research Department, Valencia, Spain; f ISCARE IVF a.s., Lighthouse, Prague, Czech Republic; g UZ Brussel, Centre for Reproductive Medicine, Brussels, Belgium; h Reproductive Health, Global Clinical and Non-Clinical R & D, Ferring Pharmaceuticals, Copenhagen, Denmark * Corresponding author. E-mail address: [email protected] (J.-C. Arce). Dr Juan Garcı´a-Velasco did his training in obstetrics and gynaecology at Madrid Autonoma University, and then his reproductive endocrinology and infertility fellowship at Yale University, USA (1997–1998). He is now Director of IVI-Madrid and Associate Professor at Rey Juan Carlos University. He has published over 100 peer- reviewed articles. He is an ad-hoc reviewer for the main journals in the field and serves on the editorial board of Reproductive BioMedicine Online. His main research interests are endometriosis, ovarian hyperstimulation syndrome, low responders and human implantation. Abstract This trial assessed the impact of early initiation of gonadotrophin-releasing hormone (GnRH) antagonist on follicular and endocrine profiles compared with the fixed GnRH-antagonist protocol.
    [Show full text]
  • 214621Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 214621Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multi-disciplinary Review and Evaluation: NDA 214, 621 Relugolix NDA/BLA Multi-disciplinary Review and Evaluation Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant, which do not necessarily reflect the positions of the FDA. Application Type NDA Application Number(s) NDA 214621 Priority or Standard Priority Submit Date(s) April 20, 2020 Received Date(s) April 20, 2020 PDUFA Goal Date December 20, 2020 Division/Office OND/CDER/OOD/DO1 Review Completion Date Established Name Relugolix (b) (4) (Proposed) Trade Name Pharmacologic Class Gonadotropin-releasing hormone (GnRH) receptor antagonist Code name TAK-385 Applicant Myovant Sciences, Inc. Formulation(s) oral tablet Dosing Regimen One time loading dose of 360 mg followed by 120 mg daily Applicant Proposed RELUGOLIX is a gonadotropin-releasing hormone Indication(s)/Population(s) (GnRH) antagonist indicated for the treatment of patients with advanced prostate cancer. Recommendation on Regular approval Regulatory Action Recommended RELUGOLIX is a gonadotropin-releasing hormone Indication(s)/Population(s) (GnRH) antagonist indicated for the treatment of (if applicable) patients with advanced prostate cancer. 1 Version date: January 2020 (ALL NDA/ BLA reviews) Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4719259 NDA/BLA Multi-disciplinary Review and Evaluation: NDA 214, 621 Relugolix Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation ..................................................
    [Show full text]
  • LHRH Analogues and Degarelix for Treatment of Prostate Cancer – Sorted by Drug
    LHRH analogues and degarelix for treatment of prostate cancer – sorted by drug Drug Degarelix Goserelin Leuprorelin Triptorelin Drug & Dose Degarelix Goserelin Goserelin Leuprorelin Leuprorelin Leuprorelin Leuprorelin Triptorelin Triptorelin Triptorelin Triptorelin 80mg 3.6mg 10.8mg 3.75mg 3.75mg 11.25mg 22.5mg 3mg 3.75mg 11.25mg 22.5mg Administration Monthly 28 days 12 weekly Monthly Monthly 3 monthly 3 monthly 28 days 4 weekly 3 monthly 6 monthly interval Brand Name Firmagon Zoladex Zoladex Lutrate Prostap SR Prostap 3 Lutrate 3 Decapeptyl Gonapeptyl Decapeptyl Decapeptyl LA Depot DCS DCS month SR Depot SR SR 3.75mg Depot Form Powder with Implant in Implant in Powder for Powder plus Powder plus Powder for Powder for Powder for Powder for Powder for a prefilled prefilled prefilled suspension solvent in solvent in suspension suspension suspension suspension suspension syringe syringe syringe with diluent prefilled prefilled with diluent with diluent with vehicle with diluent with diluent containing in syringe syringe syringe syringe (in ampoule) filled (in ampoule) (in solvent. syringe ampoule) Administration Monthly 28 days 12 weekly Monthly Monthly 3 monthly 3 monthly 28 days 4 weekly 3 monthly 6 monthly interval Needle safety No Yes Yes Yes Yes Yes No No No No No device Needle size 25 gauge 16 gauge 14 gauge 20 gauge 23 gauge 23 gauge 20 gauge 20 gauge 21 gauge 20 gauge 20 gauge Injection route Deep S/C S/C S/C I/M S/C or I/M S/C I/M I/M S/C or I/M I/M I/M Injection site Abdomen Anterior Anterior Upper outer Arm, thigh Arm, thigh Upper outer Buttock SC (e.g.
    [Show full text]
  • Firmagon®) SMC No
    degarelix 120mg and 80mg powder and solvent for solution for injection (Firmagon®) SMC No. (560/09) Ferring Pharmaceuticals Ltd 17 December 2010 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE: following a resubmission degarelix (Firmagon®) is accepted for use within NHS Scotland. Indication under review: degarelix is a gonadotropin-releasing hormone (GnRH) antagonist indicated for the treatment of adult male patients with advanced hormone-dependent prostate cancer. In one study that included patients with all stages of prostate cancer, degarelix was shown to be non-inferior to a luteinising hormone releasing hormone (LHRH) agonist in suppressing testosterone levels over a one year treatment period without an initial testosterone flare. This SMC advice takes account of the benefits of a patient access scheme (PAS) that improves the cost-effectiveness of degarelix. This SMC advice is contingent upon the continuing availability of the patient access scheme in NHS Scotland. Overleaf is the detailed advice on this product. Chairman, Scottish Medicines Consortium Published 17 January, 2011 1 Indication Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist indicated for the treatment of adult male patients with advanced hormone-dependent prostate cancer. Dosing Information Starting dose: 240mg (administered as two 120mg/3mL subcutaneous injections). Maintenance dose: 80mg/4mL administered as one subcutaneous injection every month. Product availability date 5 May 2009 Summary of evidence on comparative efficacy Degarelix is a novel testosterone ablating therapy that acts as an antagonist at the gonadatropin releasing hormone (GnRH) receptor.
    [Show full text]
  • Gonadotropin-Releasing Hormone Antagonists Versus Standard Androgen Suppression Therapy for Advanced Prostate Cancer a Systematic Review with Meta-Analysis
    Open Access Research BMJ Open: first published as 10.1136/bmjopen-2015-008217 on 13 November 2015. Downloaded from Gonadotropin-releasing hormone antagonists versus standard androgen suppression therapy for advanced prostate cancer A systematic review with meta-analysis Frank Kunath,1,2 Hendrik Borgmann,2,3 Anette Blümle,4 Bastian Keck,1 Bernd Wullich,1,2 Christine Schmucker,4 Danijel Sikic,1 Catharina Roelle,1 Stefanie Schmidt,2 Amr Wahba,5 Joerg J Meerpohl4 To cite: Kunath F, ABSTRACT et al Strengths and limitations of this study Borgmann H, Blümle A, . Objectives: To evaluate efficacy and safety of Gonadotropin-releasing gonadotropin-releasing hormone (GnRH) antagonists ▪ hormone antagonists versus We searched CENTRAL, MEDLINE, Web of compared to standard androgen suppression therapy standard androgen Science, EMBASE, trial registries and conference suppression therapy for for advanced prostate cancer. books. Two authors independently screened advanced prostate cancer A Setting: The international review team included identified articles, extracted data, evaluated risk systematic review with meta- methodologists of the German Cochrane Centre and of bias and rated quality of evidence according analysis. BMJ Open 2015;5: clinical experts. to GRADE. e008217. doi:10.1136/ Participants: We searched CENTRAL, MEDLINE, Web ▪ There were no statistically significant differences bmjopen-2015-008217 of Science, EMBASE, trial registries and conference in overall mortality, treatment failure, or prostate- books for randomised controlled trials (RCT) for specific antigen progression and no study ▸ Prepublication history for effectiveness data analysis, and randomised or non- reported cancer-specific survival or clinical this paper is available online. randomised controlled studies (non-RCT) for safety progression. To view these files please data analysis (March 2015).
    [Show full text]
  • Elagolix for Treating Endometriosis
    Elagolix for Treating Endometriosis Evidence Report June 15, 2018 Prepared for ©Institute for Clinical and Economic Review, 2018 ICER Staff/Consultants University of Colorado Skaggs School of Pharmacy Modeling Group* Steven J. Atlas, MD, MPH R. Brett McQueen, PhD Director, Primary Care Research and Quality Assistant Professor Improvement Network Department of Clinical Pharmacy Massachusetts General Hospital Center for Pharmaceutical Outcomes Research Geri Cramer, BSN, MBA Jonathan D. Campbell, PhD Research Lead, Evidence Synthesis Associate Professor Institute for Clinical and Economic Review Department of Clinical Pharmacy Center for Pharmaceutical Outcomes Research Patricia G. Synnott, MALD, MS Senior Research Lead, Evidence Synthesis Melanie D. Whittington, PhD Institute for Clinical and Economic Review Research Instructor Department of Clinical Pharmacy Varun Kumar, MBBS, MPH, MSc Health Economist Samuel McGuffin Institute for Clinical and Economic Review Professional Research Assistant Department of Clinical Pharmacy Celia Segel, MPP Program Manager Institute for Clinical and Economic Review Daniel A. Ollendorf, PhD Chief Scientific Officer *The role of the University of Colorado Skaggs Institute for Clinical and Economic Review School of Pharmacy Modeling Group is limited to the development of the cost-effectiveness Steven D. Pearson, MD, MSc model, and the resulting ICER reports do not President necessarily represent the views of CU. Institute for Clinical and Economic Review DATE OF PUBLICATION: June 15, 2018 Steven Atlas served as the lead author for the report. Geri Cramer and Patricia Synnott led the systematic review and authorship of the comparative clinical effectiveness section. Varun Kumar was responsible for oversight of the cost-effectiveness analyses and developed the budget impact model.
    [Show full text]
  • Scottish Medicines Consortium
    Scottish Medicines Consortium degarelix 120mg, 80mg powder and solvent for solution for injection (Firmagon ) No. (560/09) Ferring Pharmaceuticals Limited 10 July 2009 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE: following a full submission degarelix (Firmagon ) is not recommended for use within NHS Scotland for the treatment of adult male patients with advanced hormone-dependent prostate cancer. In one study that included patients with all stages of prostate cancer, degarelix was shown to be non-inferior to a luteinising hormone releasing hormone (LHRH) agonist in suppressing testosterone levels over a one year treatment period without an initial testosterone flare. However the benefit relative to current Scottish practice involving use of an LHRH agonist plus a short course of anti-androgen therapy to prevent flare is unclear. The manufacturer did not present a sufficiently robust economic analysis to gain acceptance by SMC. Overleaf is the detailed advice on this product. Chairman, Scottish Medicines Consortium Published 10 August 2009 1 Indication Degarelix is a gonadotropin releasing hormone (GnRH) antagonist indicated for the treatment of adult male patients with advanced hormone-dependent prostate cancer. Dosing information Starting dose: 240mg (administered as two 120mg/3mL subcutaneous injections) Maintenance dose: 80mg/4mL administered as one subcutaneous injection every month Product availability date 01 May 2009 Summary of evidence on comparative efficacy Degarelix is a novel testosterone ablating therapy that acts as an antagonist at the gonadatropin releasing hormone (GnRH) receptor.
    [Show full text]
  • Firmagon, INN-Degarelix
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT FIRMAGON 80 mg powder and solvent for solution for injection FIRMAGON 120 mg powder and solvent for solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION FIRMAGON 80 mg powder and solvent for solution for injection Each vial contains 80 mg degarelix (as acetate). After reconstitution, each ml of solution contains 20 mg of degarelix. FIRMAGON 120 mg powder and solvent for solution for injection Each vial contains 120 mg degarelix (as acetate). After reconstitution, each ml of solution contains 40 mg of degarelix. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection Powder: white to off-white powder. Solvent: clear, colourless solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications FIRMAGON is a gonadotrophin releasing hormone (GnRH) antagonist indicated for treatment of adult male patients with advanced hormone-dependent prostate cancer. 4.2 Posology and method of administration Posology Starting dose Maintenance dose – monthly administration 240 mg administered as two consecutive 80 mg administered as one subcutaneous subcutaneous injections of 120 mg each injection The first maintenance dose should be given one month after the starting dose. The therapeutic effect of degarelix should be monitored by clinical parameters and prostate specific antigen (PSA) serum levels. Clinical studies have shown that testosterone (T) suppression occurs immediately after administration of the starting dose with 96% of the patients having serum testosterone levels corresponding to medical castration (T≤0.5 ng/ml) after three days and 100% after one month.
    [Show full text]
  • Degarelix DTC Summary
    LTHT Drug and Therapeutics Committee Summary Degarelix For symptomatic, advanced metastatic high PSA prostate cancer patients at risk of impending spinal cord compression or urinary obstruction Supported for use in a specific group of patients NHS Leeds Traffic Light Classification: RED Application summary - March 2012 • Degarelix injection is a gonadotropin-releasing hormone (GnRH) antagonist. It induces a rapid and sustainable decrease in both testosterone and prostate specific antigen (PSA) levels without an initial testosterone surge after administration. • Licensed for the treatment of adult male patients with advanced hormone dependant prostate cancer. At LTH it will be used in those adult patients who have symptomatic, advanced metastatic, high PSA prostate cancer who are at risk of impending spinal cord compression or urinary obstruction (this is a licensed use). • Patients will only receive degarelix as an inpatient. It is estimated patients will receive no more than 1-3 doses before being converted to a suitable alternative, leuprorelin/goserelin. • The pivotal trial is a phase III open label study in 610 men with histologically confirmed prostate cancer. This compared two different doses of degarelix with leuprorelin. Clinical flare protection with bicalutamide was given to patients in the leuprorelin group at the discretion of the investigator. In addition, the non-inferiority of degarelix versus leuprorelin acetate in achieving and maintaining castrate levels of testosterone was demonstrated. • The EMA acknowledges that the major clinical added value of degarelix was the avoidance of the testosterone flare seen with LHRH agonists (in other words, no requirement for concomitant anti-androgen therapy), and they note that degarelix is thus especially useful when a rapid reduction in the testosterone levels is of critical importance.
    [Show full text]