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Home , Buserelin, Goserelin, Leuprorelin

COMMISSIONING SUPPORT (Prostap®) For the treatment of

Key issue: Can leuprorelin be considered to be cost-effective on the basis of its effect on plasma and cost? Committee opinion: The Committee agreed that the reduction in plasma testosterone produced by leuprorelin was an acceptable surrogate marker of efficacy in , given the clinical experience of this and other luteinising - releasing hormone (LHRH) analogues. Prescribing guidance: Category B (suitable for restricted prescribing under defined conditions) Leuprorelin for prostate cancer can be prescribed in primary care upon the advice of a specialist, using a shared care agreement. (A Q rating was not considered because of the use of a surrogate marker for the decision.) Commissioning guidance: • If the assumption is made that the LHRH analogues have equivalent efficacy and safety, and ignoring the differences in licensed indications, the main commissioning issue is cost, and the cheapest preparation should be used. • The comparative costs of the different LHRH analogues depend on whether the monthly or three-monthly preparation is used. • Commissioners should engage with providers to reach agreement on product use to achieve the most economic model for LHRH use across the health economy. This should take into account product price, local discounts available from manufacturers, and fees paid for administration. • The LHRH available are , , leuprorelin and ; their licensed indications for the treatment of prostate cancer differ.

Objectives month, or 11.25 mg injected subcutaneously every three months. • To appraise the clinical evidence for the efficacy and safety of leuprorelin for the treatment of For metastatic prostate cancer, deprivation (or prostate cancer withdrawal) therapy, either by orchidectomy or - • To consider the financial implications induced , has been considered to be an effective • To consider the commissioning issues treatment for over 60 years.2 Androgen deprivation therapy is also used as adjunct therapy for patients Background undergoing radiotherapy or prostatectomy for high-risk

Leuprorelin is one of the LHRH agonists, which localised or locally advanced prostate cancer. cause suppression of the secretion of testosterone. Androgen deprivation is achieved using orchidectomy, They have been used since the mid-1980s as an LHRH agonists, the anti- , alternative to orchidectomy in advanced metastatic cyproterone and , and degaralix, a prostate cancer. gonadotrophin-releasing hormone antagonist. The indications for leuprorelin for the treatment of National guidance prostate cancer are:1 • metastatic prostate cancer In April 2008, the National Institute for Clinical Excellence • locally advanced prostate cancer, as an alternative (NICE) published a Clinical Guideline on prostate cancer.2 to surgical castration NICE recommended that for metastatic prostate cancer, • as an adjuvant treatment to radiotherapy in patients bilateral orchidectomy should be offered as an alternative with high-risk localised or locally advanced prostate to continuous LHRH agonist therapy. For localised and cancer locally advanced prostate cancer, adjuvant “hormonal • as an adjuvant treatment to radical prostatectomy therapy” [type not specified] was recommended for a in patients with locally advanced prostate cancer at minimum of two years in men receiving radical high risk of disease progression radiotherapy for localised prostate cancer who have a (Leuprorelin is not licensed for neo-adjuvant Gleason score ≥ 8. Adjuvant “hormonal therapy” in treatment.) addition to radical prostatectomy was not recommended other than in a . For locally advanced prostate The recommended dose of leuprorelin is 3.75 mg cancer, neoadjuvant and concurrent LHRH agonist therapy injected subcutaneously or intramuscularly every

October 2010 Page 1 of 2 was recommended for three to six months in men Commissioning issues receiving radical radiotherapy. When considering cost effectiveness and which product to Appraisal of clinical evidence for efficacy and use, patient frequency of GP surgery attendance, the safety of leuprorelin frequency of drug administration and associated monitoring, and any GP practice fees for administration of Advanced metastatic prostate cancer the injections need to be taken into account. Fees for drug There is evidence that goserelin therapy produces a administration may vary since goserelin is an implant and reduction in serum testosterone equivalent to leuprorelin is a liquid . bilateral orchidectomy.3,4 Leuprorelin has not been compared with orchidectomy, but similar reductions References in testosterone (to near castration levels in over 90% 1. Leuprorelin ( Prostap 3 11.25mg and of patients) have been reported in uncontrolled Prostap SR). Takeda UK Ltd. 2010. trials5-7 and four trials comparing its effect with that of http://emc.medicines.org.uk/emc 8 9,10 11 2. National Institute for Health and Clinical Excellence. Clinical goserelin, triptorelin, diethylstilboestrol and Guideline 58. Prostate cancer. NICE. 2008. 12 . www.nice.org.uk/nicemedia/pdf/CG58EvidenceReview.pdf 3. Kaisary AV et al. Comparison of LHRH analogue (Zoladex) with Patient-oriented outcomes were used in the orchiectomy in patients with metastatic prostatic carcinoma. Br J comparison with diethylstilboestrol, an open-label Urol 1991;67:502-508 randomised trial that involved 186 patients with 4. Soloway MS et al. Zoladex versus orchiectomy in treatment of 11 advanced prostate cancer: a randomized trial. Urology metastatic prostate cancer. Serum testosterone 1991;37:46-51. concentrations (the main outcome measure) were 5. Perez-Marreno R et al. A six-month, open-label study assessing similarly suppressed in both groups, measured for a new formulation of leuprolide 7.5 mg for suppression of up to 48 weeks. Clinical response to treatment testosterone in patients with prostate cancer. Clin Ther 2002;24:1902-1914. (based on a set of criteria) were also similar 6. Sharifi R, Browneller R. Serum testosterone suppression and between the groups. Survival rates were not potential for agonistic stimulation during chronic treatment with different between the groups at one year (87% for monthly and 3-month depot formulations of leuprolide acetate for leuprorelin and 78% for diethylstilboestrol). advanced prostate cancer. J Urol 2002;168:1001-1004. 7. Jocham D. Leuprorelin three-month depot in the treatment of Localised and locally advanced prostate cancer advanced and metastatic prostate cancer: long-term follow-up No relevant studies were identified using leuprorelin results. Urol Int 1998;60 Suppl 2:18-24. 8. Fujii Y et al. Equivalent and sufficient effects of leuprolide acetate as an alternative to surgical castration in locally and goserelin acetate to suppress serum testosterone levels in advanced prostate cancer, or as patients with prostate cancer. BJU Int 2008;101:1096-1100. with either radiotherapy or prostatectomy. 9. Heyns CF et al. Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer. BJU Int Adverse effects 2003;92:226-231. 10. Kuhn JM et al. A randomised comparison of the clinical and In clinical trials, reported adverse events with hormonal effects of two GnRH agonists in patients with prostate included hot flushes, . Eur Urol 1997;32:397-403. tenderness, decreased , asthenia, dyspnoea 11. The Leuprolide Study Group. Leuprolide versus for metastatic prostate cancer. N Engl J Med 1984;311:1281- on exertion, and diarrhoea. Several 1286. retrospective studies of androgen deprivation 12. Klotz L et al. The efficacy and safety of degarelix: a 12-month, therapy (including LHRH agonists, anti-androgens comparative, randomized, open-label, parallel-group phase III and orchidectomy, or not specified) have reported a study in patients with prostate cancer. BJU Int 2008;102:1531- 1538. higher risk of cardiovascular disease or myocardial 13,14 15,16 17 13. D'Amico AV et al. Influence of androgen suppression therapy for infarction, fractures and diabetes. prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol 2007;25:2420-2425. Financial issues 14. Tsai HK et al. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst Costs at current prices from MIMS and the Drug 2007;99:1516-1524. Tariff for a year’s treatment: 15. Smith MR et al. Risk of clinical fractures after - leuprorelin (Prostap) 3.75 mg monthly £903 releasing hormone agonist therapy for prostate cancer. J Urol leuprorelin (Prostap) 11.25 mg three-monthly £903 2006;175:136-139. goserelin (generic Novgos) 3.6 mg monthly £808 16. Abrahamsen B et al. Fracture risk in Danish men with prostate goserelin (Zoladex) 3.6 mg every 28 days £847 cancer: a nationwide register study. BJU Int 2007;100:749-754. 17. Derweesh IH et al. Risk of new-onset diabetes mellitus and goserelin (Zoladex) 10.8 mg every 12 weeks £1,021 worsening glycaemic variables for established diabetes in men triptorelin 11.25 mg three-monthly £828 undergoing androgen-deprivation therapy for prostate cancer. triptorelin 3 mg every 28 days £899 BJU Int 2007;100:1060-1065.

Launch date: 1990 Manufacturer: Takeda PL 16189/0008, 0009 WARNING: This sheet should be read in conjunction with the Summary of Product Characteristics This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. MTRAC can be contacted at the Dept. of Medicines Management, School of Pharmacy, Keele University, Keele, Staffs ST5 5BG Tel: 01782 584131 Fax: 01782 713586 Email: [email protected] Web: www.mtrac.co.uk Date: October 2010 ©Midlands Therapeutics Review & Advisory Committee SS02/10