New Medicines Committee Briefing September 2013

Degarelix (Firmagon®)

Firmagon® is to be reviewed for use within: Primary Care 

Secondary Care 

Summary: acetate (Firmagon®) is a selective gonadotrophin releasing- (GnRH) antagonist, indicated for the treatment of adult male patients with hormone-dependent . The European Association of Urology (EAU) guidelines for recognised that degarelix may show some advantage of progression-free survival over although this is not yet proven.1 The Scottish Medicines Consortium (SMC) has accepted degarelix for use within NHS Scotland, on resubmission in 2010, taking into account the benefits of a Patient Access Scheme (PAS) that improves the cost-effectiveness of degarelix.2 The All Wales Medicines Strategy Group (AWMSG) has recommended degarelix as an option within NHS Wales for treatment of adult male patients with advanced hormone-dependant prostate cancer only in circumstances where the approved Wales PAS is utilised.3 A single technology appraisal of degarelix by NICE is in progress.4 One open-label, multi-centre, randomised, active comparator controlled, parallel-group study has shown that degarelix treatment induced suppression of and prostate-specific antigen (PSA) levels significantly faster than leuprolide treatment, and was not inferior to leuprolide at maintaining low testosterone levels for 12 months.5 Degarelix does not induce a testotesterone flare seen with GnRH agonists.

1

Formulary application:

Urology: Consultant submitting application: Mr Chris Luscombe (Urology Consultant) Clinical Director supporting application: Mr A. Golash Mr Luscombe has requested that degarelix be considered for inclusion in the North Staffordshire Joint Formulary alongside the existing LHRH agonists for the long-term treatment of patients who require a rapid reduction in testosterone levels and hence symptom relief and where patients are unsuitable for/decline orchidectomy. He also proposes the use of degarelix where patients are allergic/have contraindications to LHRH agonists and/or , although one has to bear in mind that degarelix has not been studied beyond one year and has not been tested in hepatic or renal impairment. Mr Luscombe estimates the number of patients requiring degarelix at UHNS to be 20 per year at a cost of £1155.12 per patient per year and states that the cost of degarelix can be met by reducing expenditure on anti- in combination with LHRH agonists, based on a degarelix business case submitted by its manufacturer Ferring, which shows future cost-savings.

Background:

Prostate cancer is a disease in which tumours develop in the prostate, a gland in the male reproductive system. Its cause is thought to involve both environmental and genetic factors. The incidence of prostate cancer increases with age and is higher in men of African-Caribbean family origin. In England and Wales, there were over 36,000 people newly diagnosed with prostate cancer in 2009 and over 9600 deaths from prostate cancer in 2010. Advanced prostate cancer is defined as locally advanced or metastatic disease (that is, the cancer spreads to other parts of the body). Around 55–65% of people with prostate cancer develop metastatic disease. NICE clinical guideline 58 recommends hormonal therapy for people with locally advanced prostate cancer who are receiving radical radiotherapy. Treatment with gonadotrophin-releasing hormone (GnRH) agonist therapy is recommended before and during radical radiotherapy. Hormonal therapy is additionally recommended after radical radiotherapy for those with a Gleason score of at least 8 (which indicates a poorer prognosis). NICE clinical guideline 58 on the diagnosis and treatment of prostate cancer also recommends hormonal therapy for people with prostate cancer who experience a biochemical relapse after radical treatment if they have symptomatic local disease progression, metastases or a prostate-specific antigen doubling time of less than 3 months. Standard hormonal treatments for metastatic disease are bilateral orchidectomy (surgical removal of the testes) or use of a long-acting luteinising hormone-releasing hormone (LHRH), also known as a GnRH agonist such as , leuprorelin or . During the first weeks of GnRH agonist therapy, an initial and temporary rise in serum testosterone (flare- up) due to an initial hypersecretion of luteinising hormone (LH) and follicle stimulating hormone (FSH) may cause unwanted effects. In clinical practice, the flare-up, which typically occurs within the first few days of LHRH agonist treatment and persist for about a week, is managed using an oral anti- (cyproterone, or ) which must be commenced a few days (3 to 7 days) before

2

initiation of the LHRH agonist and continued for about 3 to 4 weeks. However, other strategies for immediately ablating testosterone levels, such as bilateral orchidectomy, should be considered in patients with impending spinal cord compression. Except in this patient group, the clinical impact of the flare-up is unknown.4,2 Prostatic carcinoma is known to be androgen sensitive and responds to treatment that removes the source of androgen. In contrast to GnRH agonists, GnRH antagonists bind immediately, reversibly and competitively to GnRH receptors in the . The effect is a rapid decrease in LH and FSH, which in turn reduces the secretion of testosterone by the testes with no testosterone surge.6

Current formulary status:

The North Staffordshire Joint Formulary currently lists the following agents: 8.3 SEX AND HORMONE ANTAGONISTS IN MALIGNANT DISEASE 

8.3.4.2 analogues and gonadotrophin-releasing hormone antagonists Gonadorelin analogues Goserelin 2  MTRAC Leuprorelin 2  MTRAC Anti-androgens Bicalutamide 2  MTRAC 2  MTRAC Flutamide 2 Abiraterone Restriction: In line with NICE Guidance only NICE TA259

Therapeutic class and mode of action:6,7

Degarelix acetate is indicated for treatment of adult male patients with advanced hormone-dependent prostate cancer

Licensed indication:6

Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins, LH and FSH, and thereby reducing the secretion of testosterone by the testes. 3

Dosage and administration:6

Starting dose Maintenance dose – monthly administration

240 mg administered as two 80 mg administered as one subcutaneous , given one subcutaneous injections of 120 mg each month after the starting dose

Presentation:6

Powder and solvent for solution for injection (powder for injection and solvent). Each vial contains 80 mg degarelix (as acetate). After reconstitution, each ml of solution contains 20 mg of degarelix.

Guidance:

Nice Guidance published No

A NICE Technology appraisal of degarelix is in development.4

SMC recommended use within NHS Scotland:2 Yes

The SMC, following a resubmission, assessed the evidence for degarelix in December 2010 and accepted it for use within NHS Scotland. The evidence was based on a study that included patients with all stages of prostate cancer, where degarelix was shown to be non-inferior to the LHRH agonist, leuprorelin, in suppressing testosterone levels over a one year treatment period without an initial testosterone flare. SMC noted that the cost utility model supporting degarelix was based upon a secondary endpoint data of PSA recurrence derived from a one year study and interim results from an extension phase extended over 20 years. In this model, the increased drug cost of degarelix was offset by reduced costs of more expensive therapy incurred upon disease progression. However, goserelin was the comparator used in the model, whilst leuprorelin was the comparator used in the trial. SMC clinical experts also advised that degarelix may have a particular role in the treatment of patients at high risk of spinal cord compression. The SMC advice takes account of the benefits of the PAS that improves the cost-effectiveness of degarelix. The SMC advice is contingent upon the continuing availability of the PAS in NHS Scotland, the details of which were not revealed by the SMC.

4

All Wales Medicines Strategy Group (AWMSG)3 Yes

In November 2012, AWMSG, after resubmission, accepted degarelix as an option for use within NHS Wales for the treatment of adult male patients with advanced hormone-dependent prostate cancer, but only in circumstances where the approved Wales PAS is utilised. AWMSG noted that the non-inferiority of degarelix to leuprorelin and goserelin was demonstrated in terms of the surrogate primary endpoints of testosterone suppression and reduction in total prostate volume. AWMSG states that it is still unclear whether degarelix offers any clinical benefit over a LHRH agonist in terms of avoidance of testosterone flare, provided an anti-androgen is given concomitantly, as is standard practice in wales. AWMSG referred to EAU guidelines which recommend that where a depot LHRH agonist is used, anti-androgen treatment should be should be initiated concurrently. However, during study CS21, anti-androgen treatment, bicalutamide, was administered to only 11% of patients receiving leuprorelin, who experienced a lower incidence of testosterone surge during the first 2 weeks of treatment when compared to patients receiving leuprorelin alone. PSA reduction was also more rapid in patients on leuprorelin plus bicalutamide than in those receiving leuprorelin alone. AWMSG pointed out that leuprorelin 7.5mg dose administered during study CS21/CS21A is currently unlicensed in the UK. They noted that the clinical studies enrolled patients with prostate cancer, including localised and non-classifiable disease but marketing authorisation was subsequently granted for use in patients with advanced prostate cancer alone, which encompassed only 50% of the pivotal study population. AWMSG also highlighted that degarelix is administered monthly and requires reconstitution prior to whereas some of the LHRH agonist comparators are available in formulations that can be administered less frequently (every 3 to 6 months) and do not require reconstitution eg. goserelin and do not require reconstitution but leuprorelin, triptorelin and degarelix do.

European Association of Urology (EAU) 2012:1 Yes

The EAU current guidelines on prostate cancer commented that that the clinical advantage of suppression of the initial testosterone flare up is only clinically relevant in a minority of metastatic patients, namely in impending spinal cord compression, increased bone pain, acute bladder outlet obstruction, obstructive renal failure and fatal cardiovascular events due to hypercoagulation status. Overall, the LHRH antagonist agents seem appealing, but their advantages over LHRH agonists are far from proven. Further trials are needed to confirm the preliminary observed increased efficacy compared to leuprorelin. The use of degarelix is limited by a monthly formulation, compared with 3-month depot formulations for the available LHRH analogues

5

Efficacy:

CS21 Study:5 Klotz et al evaluated the efficacy and safety of 2 doses of degarelix in comparison to leuprorelin in 52-week, open-label, multi-centre, non-inferiority, randomised, active comparator controlled, parallel-group, phase III study. 620 patients were randomised to three treatment arms in a 1:1:1 ratio consisting of degarelix at 2 dosing regimens (Starting dose of 240 mg followed by either a monthly subcutaneous administration of 160 mg or 80 mg) versus a monthly intramuscular administration of 7.5 mg leuprorelin. In the leuprolide treatment arm, bicalutamide was allowed at the start of treatment for only 23 patients for clinical flare protection. The subjects were of a median age of 74 years (range 47 to 98 years), with median testosterone 3.93 ng/ml and median PSA level of 19.0 ng/ml. 31% of the participants had localised prostate cancer, 29% had locally advanced prostate cancer and 20% had metastatic prostate cancer. 7% had an unknown metastatic status. 13% had previous curative intent surgery or radiation and a rising PSA. The primary objective of the study was to demonstrate that degarelix is effective with respect to achieving and maintaining medical with testosterone suppression to 0.5 ng/ml or less, from days 28 to 364. Secondary endpoints included percentage change in PSA from baseline to 14-28 days, the proportion of patients with testosterone surge during the first 2 weeks of treatment and frequency and severity of adverse events. 504 (81%) patients completed the study. In the degarelix 240/80 mg treatment group, 41 (20%) patients discontinued the study compared to 32 (16%) patients in the leuprorelin group. On day 3, 95.5% and 96.1% of patients in the degarelix 240/160 mg and 240/80 mg groups, respectively, had achieved testosterone levels of 0.5 ng/mL or less. In the leuprolide treated patients, median testosterone levels rose by 65% from baseline by day 3 and median testosterone levels were greater than 0.5ng/mL until day 28. Medical castration rates from day 28 to day 364 (the primary endpoint) were: degarelix 240 mg/160 mg: 98.3% (95% CI, 94.8% - 99.4%); degarelix 240 mg/80 mg: 97.2% (95% CI, 93.5% to 98.8%) and leuprolide 7.5 mg group: 96.4% (95% CI, 92.5% to 98.2%). PSA levels (secondary endpoint) decreased in 14 days (65%, 64%,18%) and 28 days (83%, 85%, 68%) in the degarelix 240/160 mg, degarelix, 240/80 mg and leuprolide groups, respectively. Testosterone levels in the leuprolide treated patients increased by 0.045ng/mL (p <0.001); while no testosterone increase was detected in patients treated with degarelix. None of the degarelix-treated patients experienced a testosterone surge (defined as testosterone exceeding baseline by ≥15% within the first 2 weeks); there was an average decrease of 94% in testosterone at day 3. Most of the leuprorelin- treated patients experienced testosterone surge; there was an average increase of 65% in testosterone at day 3. This difference was statistically significant (p<0.001). The study concluded that degarelix treatment induced suppression of testosterone and PSA levels significantly faster than leuprorelin treatment, and was not inferior to leuprorelin at maintaining low testosterone levels for 12 months. The overall incidence of adverse events (AEs) during study CS21 was comparable between the degarelix (80 mg maintenance dose regimen) and leuprorelin groups (163/207 [79%] versus 156/201 [78%] respectively), 6

as was the incidence of serious AEs (21 [10%] versus 28 [14%]). Discontinuations due to AEs occurred in 15 (7%) degarelix-treated patients and 12 (6%) in the leuprorelin group. A total of five and nine deaths occurred in the degarelix and leuprorelin treatment groups respectively, none of which were considered related to treatment. Degarelix treatment was associated with higher incidences of injection site reaction (40% versus <1% in the leuprorelin group, p < 0.001). When treatment-related injection site reactions were excluded, the incidence of remaining AEs were comparable. CS21A extension study:8 Patients who completed study CS21 were eligible to enter this extension study conducted by Crawford et al, and either continued on the same monthly degarelix maintenance dose (80 mg monthly dose: n = 125; 160 mg monthly dose n = 126), or, if they had received leuprorelin, were re-randomised to receive a degarelix dose of 160 mg (n = 66) or 80 mg (n = 69). All patients were later switched to receive 80 mg following marketing authorisation. Although the study primary endpoints were safety analyses, efficacy data were collected as secondary endpoints. Kaplan-Meier estimates of the probabilities of the testosterone response rate (levels ≤ 0.5ng/ml) over five years were 82.0% and 84.1% for the degarelix 80 mg and leuprorelin/degarelix 80 mg groups, respectively. Comparison of degarelix with goserelin:9 Axcrona et al conducted a 12-week, randomised, parallel-arm, active-controlled, multicentre, open-label, phase III trial on 182 prostate cancer patients who received degarelix (starting dose 240 mg followed by monthly maintenance dose of 80 mg) or goserelin (3.6 mg implants inserted monthly with 50 mg bicalutamide daily for initial 28 days of treatment). The primary efficacy endpoint was mean percentage change in total prostate volume; this was similar between the treatment groups (−37.2% in the degarelix group versus −39.0% in goserelin-treated patients) and met the predefined non-inferiority criterion. This was supported by secondary endpoints including decreased International Prostate Symptom Score and testosterone suppression; PSA level decreases from baseline were also similar between the two arms. Both treatments were safe and well-tolerated.

Safety:

Contraindications: Hypersensitivity to the active substance, and/or to the excipients mannitol (E421) (contained in the powder) and water for injection (solvent). Caution: The data available on efficacy and safety experience with degarelix is limited to a one year treatment. Renal impairment: Degarelix has not been studied in patients with severe renal impairment and caution is therefore warranted. Hepatic Impairment: Patients with known or suspected hepatic disorder have not been included in long- term clinical trials with degarelix. Mild, transient increases in ALT and AST have been seen, these were not accompanied by a rise in bilirubin or clinical symptoms. Monitoring of liver function in patients with known or suspected hepatic disorder is advised during treatment. Cardiovascular disease: Long-term androgen deprivation therapy may prolong the QT interval. Degarelix has not been studied in patients with a history of a corrected QT interval over 450 msec, in patients with a 7

history of or risk factors for torsades de pointes and in patients receiving concomitant medicinal products that might prolong the QT interval or induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, cisapride, moxifloxacin, antipsychotics, etc.. Therefore in such patients, the benefit/risk ratio of degarelix must be thoroughly appraised. Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist. It can be anticipated that long periods of testosterone suppression in men will have effects on bone density. Bone density has not been measured during treatment with degarelix. A reduction in glucose tolerance has been observed in men who have had orchiectomy or who have been treated with a GnRH agonist. Development or aggravation of diabetes may occur; therefore diabetic patients may require more frequent monitoring of blood glucose when receiving androgen deprivation therapy. The effect of degarelix on insulin and glucose levels has not been studied. Undesirable effects: The most commonly observed adverse reactions during degarelix therapy in the phase III study were due to the expected physiological effects of testosterone suppression, including hot flushes and weight increase (reported in 25% and 7%, respectively, of patients receiving treatment for one year), or injection site adverse events. Transient chills, fever or influenza like illness were reported to occur hours after dosing (in 3%, 2% and 1% of patients, respectively). The injection site adverse events reported were mainly pain and erythema, reported in 28% and 17% of patients, respectively, less frequently reported were swelling (6%), induration (4%) and nodule (3%). These events occurred primarily with the starting dose whereas during maintenance therapy with the 80 mg dose, the incidence of these events per 100 injections was: 3 for pain and <1 for erythema, swelling, nodule and induration. The reported events were mostly transient, of mild to moderate intensity and led to very few For a comprehensive list of adverse effects, refer to the Summary of Product Characteristics (SPC).

Drug Interactions:6,7 No formal drug-drug interaction studies have been performed.

Cost analysis:

Dr Luscombe estimated that 20 patients will be treated per year and for the long term. The estimated total expenditure during the first year for I patient will therefore be £211.34 + (£129.37 x 11 months) = £1,634.41 For 20 patients per year = £1,634.41 x 20 = £32,688.20

8

Cost of relevant comparators:

UHNS cost per Primary Care cost per Drug Dose Regimen10 pack (inc. VAT) pack* (exc. VAT)

Degarelix injection 240mg starting dose (given as 2 separate £211.34 £260.00 2x120mg subcutaneous injections of 120mg) ,

followed by 80mg monthly as maintenance 240mg starting dose (given as 2 separate Degarelix injection subcutaneous injections of 120mg) , 80mg £106.80 £129.37 followed by 80mg monthly as maintenance Goserelin One subcutaneous injection every 28 days £78 £65.00 3.6 mg injection Goserelin One subcutaneous injection every 12 £282 £235.00 weeks 10.8mg injection Leuprorelin One subcutaneous/ £60 £75.24 3.75mg injection every month Leuprorelin One subcutaneous injection every 3 £180 £225.72 11.25mg injection months Cyproterone 200 to 300mg daily in divided doses £33.84 / £55.33 / acetate 100mg 84-tab pack 84-tab pack tablet * C&D Aug 2013 and online Drug Tariff

Estimated cost during the first year of treatment where initial dose is administered at UHNS and subsequent doses in primary care: Drug Cost Degarelix £1634.41 Goserelin 3.6mg + 4 weeks of cyproterone 300mg £1435.47 Goserelin 10.8mg + 4 weeks of cyproterone 300mg £1186.83 Leuprorelin 3.75mg + 4 weeks of cyproterone 300mg £1530.11 Leuprorelin 11.25mg + 4 weeks of cyproterone 300mg £1056.99

9

Expenditure of GnRH analogues + antiandrogens across the Health Economy from June 2012 – May 2013

Product UHNS CCG STOKE CCG NORTH STAFF CCG Degarelix injection £422.69 £0 £0 Goserelin (Zoladex®) £11,700 £7,377.63 £6,717.15 3.6 mg injection Goserelin (Zoladex® LA) £14,664.88 £348,417.85 £319,145.06 10.8mg injection Leuprorelin (Prostap® SR £120.00 £7,430.78 £6,177.49 DCS) 3.75mg injection Leuprorelin (Prostap® 3 £13,028.25 £27,280.34 £46,850.87 DCS) 11.25mg injection Cyproterone acetate £10,088.52 £2,964.56 £9,626.41 100mg tablet

References:

1 Heidenreich A et al. Guidelines on Prostate Cancer. European Association of Urology 2012 2 Scottish Medicines Consortium. Degarelix 120mg and 80mg powder and solvent for solution for injection (Firmagon®) SMC No.560/09. December 2010. Accessed via: http://www.scottishmedicines.org.uk 3 All Wales Medicines Strategy Group. Final Appraisal Recommendation. Degarelix (Firmagon®) for the treatment of advanced hormone-dependent prostate cancer. Advice No: 4112 – November 2012. Accessed via: http://www.wales.nhs.uk 4 National Institute for Health and Clinical Excellence (NICE). Draft scope for the proposed appraisal of degarelix for the treatment of advanced hormone-dependent prostate cancer. Accessed via: http://guidance.nice.org.uk/TA/WaveR/163/DraftScope. 5 Klotz L, Boccon-Gibod L, Shore ND, et al: The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int 2008; 102(11):1531-1538. 6 Summary of Product Characteristics. Firmagon 120mg Injection. Ferring Pharmaceutical Ltd. Last updated 06/03/13.accessed via: http://www.medicines.org.uk 7 Summary of Product Characteristics. Firmagon 80mg Injection. Ferring Pharmaceutical Ltd. Last updated 06/03/13. Accessed via: http://www.medicines.org.uk 8 Crawford ED, Tombal B, Miller K et al. A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of -releasing hormone agonist and antagonist effect on prostate cancer. J Urol 2011; 186 (3): 889-97. 9 Axcrona K, Aaltomaa S, da Silva CM et al. Androgen deprivation therapy for volume reduction, other urinary tract symptom relief and quality of life improvement in patients with prostate cancer: degarelix vs goserelin plus bicalutamide. BJU Int. 2012 Dec;110(11):1721-8. 10 British National Formulary (BNF) 65 March 2013. Accessed via: http://www.bnf.org

Produced by Susheela Sumelingam Rotational Specialist Pharmacist University Hospital of North Staffordshire Telephone: 01782 674542 e-mail: [email protected] Produced for use within the NHS. Not to be reproduced for commercial purposes.

10