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). Two authors ▪ Quality of evidence for all assessed outcomes visit the journal online independently screened identified articles, extracted was rated low according to GRADE. Available evi- (http://dx.doi.org/10.1136/ data, evaluated risk of bias and rated quality of dence is hampered by risk of bias, selective http://bmjopen.bmj.com/ bmjopen-2015-008217). evidence according to GRADE. reporting and limited follow-up. ▪ Received 10 May 2015 Results: 13 studies (10 RCTs, 3 non-RCTs) were The question that was addressed by this system- Revised 12 September 2015 included. No study reported cancer-specific survival atic review was in some points different from the Accepted 9 October 2015 or clinical progression. There were no differences in available evidence. There is currently insufficient overall mortality (RR 1.35, 95% CI 0.63 to 2.93), evidence to make firm conclusive statements on treatment failure (RR 0.91, 95% CI 0.70 to 1.17) or the efficacy of GnRH antagonist compared to prostate-specific antigen progression (RR 0.83, 95% standard androgen suppression therapy for CI 0.64 to 1.06). While there was no difference in advanced prostate cancer and there is a need for quality of life related to urinary symptoms, improved further high quality research on GnRH antago- on October 1, 2021 by guest. Protected copyright. quality of life regarding prostate symptoms, measured nists with long-term follow-up. with the International Prostate Symptom Score (IPSS), with the use of GnRH antagonists compared with the use of standard androgen suppression There is need for further high-quality research on therapy (mean score difference −0.40, 95% CI −0.94 GnRH antagonists with long-term follow-up. to 0.14, and −1.84, 95% CI −3.00 to −0.69, Trial registration number: CRD42012002751. respectively) was found. Quality of evidence for all assessed outcomes was rated low according to GRADE. The risk for injection-site events was increased, but cardiovascular events may occur less INTRODUCTION often by using GnRH antagonist. Available evidence is For numbered affiliations see hampered by risk of bias, selective reporting and Gonadotropin-releasing hormone (GnRH) end of article. limited follow-up. antagonists, such as abarelix or degarelix, are Conclusions: There is currently insufficient evidence new agents for androgen suppression therapy Correspondence to to make firm conclusive statements on the efficacy of in advanced prostate cancer. They act by Dr Frank Kunath; frank. GnRH antagonist compared to standard androgen competitively binding to receptors in the [email protected] suppression therapy for advanced prostate cancer. pituitary gland, leading to reduced amounts Kunath F, et al. BMJ Open 2015;5:e008217. doi:10.1136/bmjopen-2015-008217 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2015-008217 on 13 November 2015. Downloaded from of luteinising hormone and follicle-stimulating advanced (T3-4, N0, M0), local to regionally advanced hormone. GnRH antagonists are, thereby, able to (T1-4, N1, M0), disseminated disease (T1-4, N0-1, M1) decrease the level of testosterone immediately to castra- or PSA relapse after local therapy. – tion levels without flare.1 3 Testosterone is important for Included studies had to compare GnRH antagonists the growth of prostate cells and its suppression slows (abarelix or degarelix) with standard androgen suppres- down the disease progression and leads to a decrease in sion. The standard androgen suppression therapy prostate-specific antigen (PSA). included monotherapy with surgical or medical castra- Data from published randomised controlled trials tion, antiandrogen monotherapy or maximal androgen support the use of degarelix as an alternative to standard blockade (combination of either surgical or medical cas- androgen suppression therapies.45Abarelix appears to tration with antiandrogens). be equally effective.26Androgen suppression therapy Our prospectively defined primary outcomes were with degarelix may also be more cost-effective in patients overall survival and adverse events. We defined cancer- – with locally advanced prostate cancer7 9 and may specific survival, clinical or PSA progression, treatment increase PSA progression-free and overall survival.510 failure and quality of life as secondary outcomes. No Additionally, degarelix might also have beneficial effects study was excluded solely because the outcome of inter- on lower urinary tract symptoms.11 Furthermore, GnRH est was not reported. antagonists might provide an alternative to castration in Unit of analysis was the study rather than publications, symptomatic patients with advanced prostate cancer and we named the studies according to their study iden- because there is no risk for testosterone flare associated tification numbers assigned by the sponsors. We used with GnRH agonists that might aggravate clinical symp- the sponsors identification numbers for differentiation toms.12 Despite these positive findings, the current because several authors were involved in more than one European guideline indicate that there is no definitive study, publications were identified reporting information evidence that GnRH antagonists have advantages over on several studies (pooled analyses of individual patient GnRH agonists.13 data of five randomised controlled trials: CS21, CS28, An analysis of pooled individual patient data of five CS30, CS31, CS35), and as there were several publica- randomised clinical trials found clinical benefits with tions available for some studies (eg, different follow-up degarelix compared with GnRH agonists.10 However, no time or reporting different outcomes). systematic review based on a comprehensive literature We searched the Cochrane Library (CENTRAL, Issue search using predefined methodology have yet evaluated 3, 2015), MEDLINE (via Ovid; 1946 to March 2015), the efficacy and tolerability of GnRH antagonists in com- Web of Science (Thomson Reuters Web of Knowledge; parison with standard androgen suppression therapy for 1970 to March 2015), and EMBASE (via DIMDI; 1947 to advanced prostate cancer. Therefore, the objectives of March 2015) databases. For details on the search strat- this systematic review are to determine the efficacy and egy, see table 1. safety of GnRH antagonists compared with standard Additionally, we searched three trial registries: Current http://bmjopen.bmj.com/ androgen suppression therapy for advanced prostate Controlled Trials (ISRCTN; http://www.controlled-trials. cancer treatment. com/; last search in March 2015), ClinicalTrials.gov (http://www.clinicaltrials.gov/; last search in March 2015), and the WHO International Clinical Trials METHODS Registry Platform Search Portal (WHO ICTRP Search For details on our predefined methodology and Portal; http://www.who.int/ictrp/en/; last search in outcomes see the prospective registry entry in the March 2015). We used the following keywords for this ‘International Prospective Register of Systematic search: ‘abarelix’, ‘degarelix’, ‘plenaxis’, ‘firmagon’. on October 1, 2021 by guest. Protected copyright. Reviews’ (http://www.crd.york.ac.uk/PROSPERO;CRD We also searched the electronically available abstract 42012002751). books from three major conferences: American Society We included studies that compared GnRH antagonists of Clinical Oncology (ASCO; jco.ascopubs.org; 2004 to (abarelix and degarelix) with standard androgen sup- March 2015), European Association of Urology (EAU; pression therapy in patients with advanced prostate http://www.uroweb.org; 2004 to March 2015), and cancer. Included studies had to be randomised con- American Urological Association (AUA; http://www. trolled trials (that were used for efficacy