Suffolk PCT Drug & Therapeutics Committee New Medicine Report

This drug has been reviewed because it is a product that may be prescribed in primary care.

Medicine Degarelix (Firmagon, Ferring Pharmaceuticals Ltd)

Document status Reviewed on 22nd January 2013

Date of last revision 9 January 2013 Traffic light decision Red – hospital only Prescribers rating Possibly helpful

Mechanism of action 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, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of testosterone (T) by the testes. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that removes the source of androgen. Unlike GnRH agonists, GnRH antagonists do not induce a LH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic flare after the initiation of treatment. A single dose of 240 mg degarelix, followed by a monthly maintenance dose of 80 mg, rapidly causes a decrease in the concentrations of LH, FSH and subsequently testosterone. The plasma concentration of dihydrotestosterone (DHT) decreases in a similar manner to testosterone. Degarelix is effective in achieving and maintaining testosterone suppression well below medical castration level of 0.5 ng/ml. [1, 2]

Medicine class BNF 8.3.4.2 - gonadotrophin-releasing hormone antagonists [3]

Indication Treatment of adult male patients with advanced hormone- dependent prostate cancer. [1, 2]

Dosage Starting dose: 240 mg administered as two subcutaneous injections of 120 mg each. [1, 2] Maintenance dose – monthly administration: 80 mg administered as one subcutaneous injection. The first maintenance dose should be given one month after the starting dose. [1, 2]

Treatment alternatives Bilateral subcapsular orchidectomy Gonadorelin analogues: Buserelin – subcut injection 3/day for 7 days then nasal spray 6 times/day Goserelin – monthly or 3 monthly implants Histrelin – annual implant Leuprorelin – subcut injection every 1 or 3 months Triptorelin – intramuscular injection every 1, 3 or 6 months. [3]

Place in therapy The 2012 European Association of Urology guidelines for prostate

Review prepared by Katie Smith, East Anglia Medicines Information for NHS Suffolk May be freely copied by NHS agencies Not to be used for promotional purposes

cancer state that overall, this new family of agents seems 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 GnRH antagonists is limited by a monthly formulation, compared with 3-month and 6-month depot formulations for the available GnRH analogues. Suppression of the initial flare-up with monotherapy is only clinically relevant in a few symptomatic metastatic patients. [4]

Degarelix has not been considered by NICE. The NICE clinical guidelines on prostate cancer were written in 2008 and do not include degarelix. [5]

Future alternatives None known [6]

Evidence for use The efficacy and safety of degarelix has been evaluated in an open-label, multi-centre, randomised, active comparator controlled, parallel-group study. [7]

The study investigated the efficacy and safety of two different degarelix monthly dosing regimens with a starting dose of 240 mg (40 mg/ml) followed by monthly doses subcutaneous administration of 160 mg (40 mg/ml) or 80 mg (20 mg/ml), in comparison to monthly intramuscular administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. In total 620 patients were randomised to one of the three treatment groups, of which 504 (81%) patients completed the study. In the degarelix 240/80 mg treatment group 41 (20%) patients discontinued the study, as compared to 32 (16%) patients in the leuprorelin group. Of the 620 patients treated - 31% had localised prostate cancer 29% had locally advanced prostate cancer 20% had metastatic prostate cancer 7% had an unknown metastatic status 13% had previous curative intent surgery or radiation and a rising PSA.

Baseline demographics were similar between the arms. The median age was 74 years (range 47 to 98 years).

The primary objective was to demonstrate that degarelix is effective with respect to achieving and maintaining testosterone suppression to below 0.5 ng/ml, from days 28 to 364.

In the leuprolide group, bicalutamide was allowed at the start of treatment for clinical flare protection (n=23).

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 0.5 ng/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% confidence interval (CI), Review prepared by Katie Smith, East Anglia Medicines Information for NHS Suffolk May be freely copied by NHS agencies Not to be used for promotional purposes

94.8% to 99.4%) degarelix 240 mg/80 mg; 97.2% (95% CI, 93.5% to 98.8%) 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 0.045 ng/mL (p less than 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 primary end-point in the study was testosterone suppression rates after one year of treatment with degarelix or leuprorelin. The clinical benefit for degarelix compared to leuprorelin plus anti- androgen in the initial phase of treatment has not been demonstrated.

Periodic electrocardiograms were performed during the study. Both therapies showed QT/QTc intervals exceeding 450 msec in approximately 20% of the patients. From baseline to end of study the median change for degarelix was 12.0 msec and for leuprorelin it was 16.7 msec.

Anti-degarelix antibody development has been observed in 10% of patients after treatment with degarelix for one year. There is no indication that the efficacy or safety of degarelix treatment is affected by antibody formation after one year of treatment. Efficacy and safety data in relation to antibody development beyond one year is not available.

NNT 125 to achieve testosterone <0.5ng/ml from days 28 to 364 with degarelix 240/80 instead of leuprorelin. [7]

Cautions / side effects Cautions [info from the SPCS, Long-term androgen deprivation therapy may prolong the QT ref 1, 2] interval. Degarelix has not been studied in patients with a history of a corrected QT interval over 450 msec, in patients with a history of or risk factors for torsades de pointes and in patients receiving concomitant medicinal products that might prolong the QT interval. Therefore in such patients, the benefit/risk ratio of degarelix must be thoroughly appraised.

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.

Degarelix has not been studied in patients with severe renal impairment and caution is therefore warranted. Review prepared by Katie Smith, East Anglia Medicines Information for NHS Suffolk May be freely copied by NHS agencies Not to be used for promotional purposes

Cautions / side effects Degarelix has not been studied in patients with a history of severe cont. [info from the untreated asthma, anaphylactic reactions or severe urticaria or SPCS, ref 1, 2] angioedema.

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.

Drug interactions No formal drug-drug interaction studies have been performed. Since androgen deprivation treatment may prolong the QTc interval, the concomitant use of degarelix with medicinal products known to prolong the QTc interval or medicinal products able to 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, moxifloxacine, antipsychotics, etc. should be carefully evaluated.

Ability to drive No studies on the effects of degarelix on the ability to drive and use machines have been performed. However, fatigue and dizziness are common adverse reactions that might influence the ability to drive and use machines.

Adverse 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 discontinuations (<1%).

Changes in laboratory values seen during one year of treatment in the phase III study were in the same range for degarelix and leuprorelin. Markedly abnormal (>3xULN) liver transaminase values (ALT, AST and GGT) were seen in 2-6% of patients with normal values prior to treatment, following treatment with both

Review prepared by Katie Smith, East Anglia Medicines Information for NHS Suffolk May be freely copied by NHS agencies Not to be used for promotional purposes

medicinal products. Marked decrease in haematological values, hematocrit (≤0.37) and hemoglobin (≤115 g/l) were seen in 40% and 13-15%, respectively, of patients with normal values prior to treatment, following treatment with both medicinal products. It is unknown to what extent this decrease in haematological values was caused by the underlying prostate cancer and to what extent it was a consequence of androgen deprivation therapy. Markedly abnormal values of potassium (≥5.8 mmol/l), creatinine (≥177 μmol/l) and BUN (≥10.7 mmol/l) in patients with normal values prior to treatment, were seen in 6%, 2% and 15% of degarelix treated patients and 3%, 2% and 14% of leuprorelin treated patients, respectively.

NNH 2.88 for injection site reaction with degarelix 240/80 instead of leuprorelin [7] Cost within PbR tariff? Yes Cost (prices from BNF £1812 for 1 years treatment 64) Comparative annual Bilateral subcapsular orchidectomy: £?? costs of other medicines (prices Buserelin: £918 from BNF 64) Goserelin: £761 - £1175 Histrelin: £990 Leuprorelin: £903 Triptorelin: £828 - £1062

Potential number of In the UK, the incidence of prostate cancer is 97 per 100,000 patients & usage in people. [8] Suffolk PCT Therefore in NHS Suffolk (~population 600,000) there may be up to 582 men with prostate cancer of which a small proportion will have advanced hormone-dependent prostate cancer.

A paper presented at the Anglia Cancer Network meeting has suggested that there will be 20 patients eligible for degarelix across the network (Norfolk, Suffolk, Cambridgeshire and North Bedfordshire, population 2.7 million). The patients would be those who present with advanced disease with a high tumour burden (e.g. new spinal cord compression) and there is a significant advantage in implementing rapid onset androgen deprivation. The Anglia Cancer Network have not yet made a decision about degarelix and the paper was deferred to the next meeting in 2013.

Points for One open-label, multi-centre, randomised, active comparator consideration controlled, parallel-group study has shown that degarelix treatment induced suppression of testosterone 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. In contrast to GnRH agonists, GnRH antagonists bind immediately and competitively to GnRH receptors in the pituitary gland. The effect is a rapid decrease in LH, FSH and testosterone levels without any flare. This seemingly more desirable mechanism of action has made GnRH antagonists very attractive, but their advantages over GnRH agonists are far from proven. Degarelix may be especially useful when a rapid reduction in the testosterone levels is of critical importance. The advantage of degarelix compared to a GnRH agonist plus routine short-term anti-androgen therapy for testosterone flare in the majority of patients is unclear. Review prepared by Katie Smith, East Anglia Medicines Information for NHS Suffolk May be freely copied by NHS agencies Not to be used for promotional purposes

Further trials are needed to confirm the preliminary observed increased efficacy compared to leuprorelin. Suppression of the initial flare-up with monotherapy is only clinically relevant in a few symptomatic metastatic patients (for example, in patients with impending spinal cord compression).

Is the drug on the West Suffolk Hospital - WSH or IHT Ipswich Hospital - No formularies? Decisions from other Cambridgeshire JPG – not assessed bodies Norfolk TAG – not assessed

SMC - The Scottish Medicines Consortium (SMC) assessed the evidence for degarelix in December 2010 and accepted it for use within NHS Scotland. [9] The report of the assessment states that 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. In their assessment the SMC advised that the increased drug and administration costs associated with degarelix were offset largely due to the difference in PSA failure rate resulting in patients in the goserelin arm progressing to the more expensive subsequent treatments earlier. The results of a higher risk subgroup analysis also showed degarelix to be the dominant treatment with cost savings of £3,204 and a QALY gain of 0.49. 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 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.

AWMSG – In December 2009 the All Wales Medicines Strategy Group (AWMSG) recommended that degarelix is not recommended for use within NHS Wales for the treatment of advanced hormone-dependent prostate cancer as the case for the cost effectiveness of has not been proven. [10]

Decision review date Jan 2015

References 1. Summary of Product Characteristics. Firmagon 120mg Injection. Ferring Pharmaceutical Ltd. Last updated 21/03/12. 2. Summary of Product Characteristics. Firmagon 80mg Injection. Ferring Pharmaceutical Ltd. Last updated 26/03/12 3. Martin J, editor. British National Formulary No 63. London: British Medical Association and The Royal Pharmaceutical Society of Great Britain; March 2012 4. Heidenreich A et al. Guidelines on Prostate Cancer. European Association of Urology 2012. http://www.uroweb.org/gls/pdf/08%20Prostate%20Cancer_LR%20March%2013th%202012.p df 5. NICE Clinical Guideline 58. Prostate cancer: diagnosis and treatment. February 2008 6. UK Medicines Information. Prescribing Outlook, New Medicines. Sept 2011 7. 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. 8. UK Medicines Information. Prescribing Outlook, New Medicines. Sept 2011 Review prepared by Katie Smith, East Anglia Medicines Information for NHS Suffolk May be freely copied by NHS agencies Not to be used for promotional purposes

9. Scottish Medicines Consortium. Degarelix 120mg and 80mg powder and solvent for solution for injection (Firmagon®) SMC No. (560/09). December 2010. http://www.scottishmedicines.org.uk/files/advice/degarelix_Firmagon_RESUBMISSION_FINA L_DECEMBER_2010.doc_for_website.pdf 10. All Wales Medicines Strategy Group. Final Appraisal Report. Degarelix (Firmagon®) for the treatment of advanced hormone-dependent prostate cancer. Advice No: 2109 – December 2009. http://www.wales.nhs.uk/sites3/Documents/371/degarelix_Firmagon_%20FAR.pdf

Review prepared by Katie Smith, East Anglia Medicines Information for NHS Suffolk May be freely copied by NHS agencies Not to be used for promotional purposes

Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications

For many years scientists have recognised two types of research: Primary: original studies, based on observation or experimentation on subjects. Secondary: reviews of published research, drawing together the findings of two or more primary studies.

In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this-

Rank: Methodology Description

1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality. Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re-analysing the original data, also sometimes called: pooling, quantitative synthesis. Both are sometimes called "overviews."

Randomised controlled trials Individuals are randomly allocated to a control group and a group who receive a specific 2 (finer distinctions may be drawn within this intervention. Otherwise the two groups are identical for any significant variables. They are followed group based on statistical parameters like the up for specific end points. confidence intervals)

3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes.

4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to look for differences between the two groups.

5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time

6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series

7 Expert opinion A consensus of experience from the good and the great.

8 Anecdotal Something a bloke told you after a meeting or in the bar.

Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008

To Decide if a Medication Is To Be Used In Suffolk

Criterion to be measured Poor -5 4 Medium-3 2 Tends to good- 1 Quality of evidence in the papers reviewed Cross Case Cohort RCTs Systematic sectional controlled studies reviews and surveys or studies meta- analyses lower Magnitude of effect inferred from trials reviewed Low Medium High Are trial end-points surrogate markers or clinical outcomes? Surrogate markers Clinical usefulness of trial end-points Medium Known Side Effect Profile High Medium Low Known Interactions High Medium 2 Low Concern re Possible Side Effects Not Yet Uncovered High Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium Good NNT High Medium Low Comparison Of Effectiveness With Other Medicines In Use For The Poor Medium Good Same Condition Severity of Condition to be Treated Trivial Medium Severe Novel drug or member of existing class Novel drug Uptake (estimated proportion of people with this condition likely to be Very low – about 6 in Suffolk prescribed the medication under consideration – maximum and minimum uptake) Is the drug to be used in Suffolk? Yes

Prescriber’s Rating Definitions Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are “me-too” products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire)

Review prepared by Katie Smith, East Anglia Medicines Information for NHS Suffolk May be freely copied by NHS agencies Not to be used for promotional purposes

Criterion Red Amber Green Blue Skills of the Experience Of The Condition Specific Specific Specific General prescriber Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General

Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy

References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14:172-174 1 Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2

Traffic light: Red – hospital only

QIPP rating – This treatment is only likely to be of benefit to a very small group of patients who present with advanced disease with a high tumour burden (e.g new spinal cord compression) and there is a significant advantage in implementing rapid onset androgen deprivation. If these select criteria are adhered to there will not be any significant financial impact.

Review prepared by Katie Smith, East Anglia Medicines Information for NHS Suffolk May be freely copied by NHS agencies Not to be used for promotional purposes