FIRMAGON (Degarelix) a new-generation GnRH antagonist for advanced hormone-dependent prostate cancer. 20/04/2016 Jeffrey Hsiao 蕭哲文

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1 FIRMAGON (Degarelix) a new-generation GnRH antagonist for advanced hormone-dependent prostate cancer 20/04/2016 Jeffrey Hsiao 蕭哲文

2 Background to Androgen Deprivation Therapy (ADT) in Prostate Cancer Testosterone is essential for growth and viability of prostate tumour cells 1 ADT results in the death (apoptosis) of androgen-sensitive cells 1 Hormonal treatment of prostate cancer started in In the 1980s, luteinizing hormone-releasing hormone (LHRH) agonists were introduced 5 ADT, androgen deprivation therapy 2 1. Walsh PC. Urol Clin North Am 1975;2(1): Ockrim J, et al. Nat Clin Pract Oncol. 2006;3(10): Lepor H, et al. Rev Urol. 2012;14(1/2):1-12 doi: /riu Huggins C, et al. Arch Surg 1941; 43: Hellerstedt BA, et al. CA Cancer J Clin 2002; 52;

3 Degarelix belongs to a class of synthetic drugs: GnRH antagonists GnRH pglu His Trp Ser Tyr Gly Leu Arg Pro Gly NH 2 Leuprolide D-Leu NEt Goserelin Triptorelin D-Ser NH 2 D-Trp NH 2 GnRH agonists Buserelin D-Ser NEt Degarelix Abarelix Cetrorelix Ganirelix D-NaI D-Cpa D-PaI Aph D-Aph Lys D-Ala NH 2 D-NaI D-Cpa D-PaI N-Me Tyr D-Asn Lys D-Ala NH 2 D-NaI D-Cpa D-PaI D-Cit D-Ala NH 2 D-NaI D-CPa D-PaI D-hArg D-hArg D-Ala NH 2 GnRH antagonists GnRH, gonadotropin-releasing hormone Millar RP, et al. Endocr Rev 2004;25:235 75

4 Degarelix is a Synthetic Peptide Modelled on the Body s Own GnRH Acetate salt, amorphous, soluble in water A fully synthetic, linear decapeptide amide 7 synthetic amino acids, 5 of which are D-amino acids H 3 C O Biochemical Structure of Degarelix H O N O NH 2 NH N NH CI O NH D Ala D Phe D Ala Ser Phe D Phe O H 3 C N 6 CH 3 Leu Lys Pro D Ala NH 2 Ac Ser Leu Pro Ac-D-Nal Nal-D-Cpa Cpa-D-Pal Pal- Ser-Aph(Hor) Aph(Hor)-D-Aph(Cbm) Aph(Cbm)-Leu Leu-Lys(iPr) Lys(iPr)-Pro Pro-D-Ala Ala-NH 2 GnRH, gonadotropin-releasing hormone 4

5 Mechanism of action of GnRH agonists GnRH agonists Acute pituitary effects Surge in FSH, LH and testosterone Chronic pituitary effects LH and testosterone suppression, but microsurges on repeat injection ( acute-onchronic ) FSH suppression not maintained FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinising hormone

6 Mechanism of action of GnRH antagonists GnRH antagonists Acute pituitary effects Immediate suppression of FSH, LH and testosterone Chronic pituitary effects Prolonged suppression of FSH, LH and testosterone No microsurges FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinising hormone

7 健保資訊與適應症 藥品代碼 藥品名稱 ( 中文 ) 成分 成分含量 價格 BC 輔美康注射劑 80 毫克 Degarelix 80 MG 4,791 BC 輔美康注射劑 120 毫克 Degarelix 120 MG 4,791 健保給付規範 Degarelix( 如 Firmagon):(103/9/1) 限用於成年男性晚期荷爾蒙依賴型前列腺癌患者 適應症 成年男性晚期荷爾蒙依賴型前列腺癌 PAGE 7

8 用法用量 初始劑量 240mg, 皮下注射 2 次, 每次 120mg 第一次維持劑量應在初始 1 個月 維持劑量 ( 每月 1 次 ) 80mg, 每月 1 次 因為 degarelix 不會導致睪固酮濃度激增, 所以初始治療時不需要併用抗雄性激素藥物以抑制睪固酮激增 FIRMAGON 僅用於腹部皮下注射, 不可靜脈注射 不推薦肌肉注射, 因為無相關研究 與其他皮下注射的藥物一樣, 注射區域應該作週期性更改, 應選擇無外在壓力的區域, 不適合靠近腰帶和束帶, 也不應靠近肋骨 PAGE 8

9 FIRMAGON (Degarelix): Dosage and Administration Initiation dose: 240 mg (two 120 mg injections) Monthly maintenance dose: 80 mg (single injection) 9

10 Degarelix Forms a Gel-like Depot upon Injection After subcutaneous injection, degarelix forms a gel-like sustained-release depot when contact is made with subcutaneous tissue This sustained-release depot facilitates a steady release of the drug into the circulation and ensures that effect is maintained 10

11 禁忌症與注意事項 對 FIRMAGON 的活性成份或賦型劑過敏者禁用 懷孕分類等級 X 肝功能不全 : 可見輕度和短暫的 ALT 和 AST 升高, 但都不伴有膽紅素升高和臨床症狀 對於已知或懷疑肝功能不全患者, 建議在治療過程中檢測肝功能 腎功能不全 : 尚無 degarelix 應用於嚴重腎功能不全的病人的相關研究, 因此應慎用於嚴重腎功能不全患者 葡萄糖耐受性 : 在曾接受去勢手術或促性腺激素釋放激素促效劑 (GnRH agonist) 治療的男性患者中可觀察到葡萄糖耐受性減低, 可能發生糖尿病的發展或惡化, 因此糖尿病的病人在接受雄激素阻斷治療時可能需要更頻繁檢測血糖濃度 尚無相關 degarelix 對於胰島素和血糖濃度影響的研究 PAGE 11

12 常見不良反應 在 III 期臨床研究中, 使用 FIRMAGON 治療最常見的不良反應是由於睪固酮抑制導致的生理學變化, 包括潮熱和體重增加 ( 在接受治療 1 年時間內, 報告分別有 25% 和 7%), 及注射部位的副作用 注射後數小時偶爾有短暫的寒顫 發熱或類流感疾病的報導 ( 分別佔 3% 2% 和 1%) 注射部位的不良反應主要是疼痛和紅斑, 分別佔病例數的 28% 和 17% 較少出現的不良反應有腫脹 (6%) 硬結 (4%) 和結節 (3%) 這些通常發生在初始劑量治療時 而以維持劑量治療時, 這些反應的發生率為 : 每 100 次注射中, 有 3 次疼痛, 少於 1 次的紅斑 腫脹 結節和硬結 這些不良反應大多數是短暫及屬輕度至中度強度, 並且很少導致治療中斷 (<1%) PAGE 12

13 藥物交互作用 尚未進行正式藥物交互作用的相關研究 因雄性激素阻斷治療可能使心電圖 QTc interval 延長, 使用 degarelix 時如伴隨其他已知導致 QTc interval 延長或誘導 Torsades de Pointes 的藥物應謹慎評估 例如抗心律不整藥物 IA 類 ( 如 :quinidine, disopyramide) 和 III 類 ( 如 amiodarone, sotalol, dofetilide, ibutilide) 抗心律不整藥品 methadone cisapride moxifloxacin 抗精神病藥等應該小心評估 在一項 FIRMAGON 與 leuprorelin 的對照確認研究中, 進行了週期性心電圖檢查 ( 每月一次 ) 結果顯示, 兩種治療方法都使 20% 病人的 QT/QTc interval 延長 450 毫秒, 而分別有 1% 使用 FIRMAGON 的病人和 2% 使用 leuprorelin 的病人 QT/QTc interval 延長 500 毫秒 Degarelix 不是人類 CYP450 系統的受質, 並沒有證據顯示在體外會大量誘導或抑制 CYP1A2 CYP2C8 CYP2C9 CYP2C19 CYP2D6 CYP2E1 或 CYP3A4/5 的變化 因此在臨床上未必與同功酶發生與代謝相關的顯著藥物間的藥物動力學交互作用 PAGE 13

14 藥物動力學 吸收 : 前列腺癌的病人接受皮下注射濃度為 40mg/ml 的 degarelix 240mg 後, ( 血漿濃度時間 ) 曲線下面積 AUC0-28 為 635 天 *ng/ml, 最高藥物血中濃度 Cmax 為 66.0( )ng/ml, 到達最高血中濃度時間 Tmax 發生在 40(37-42) 小時 平均波谷濃度在初始劑量後大約為 ng/ml, 在維持劑量為 80mg ( 濃度 20 mg/ml) 後為 ng/ml Degarelix 以二相性形式被清除 根據群體的藥物動力學模型, 估計初始劑量的半衰期 (t1/2) 中位數大約為 43 天, 維持劑量的半衰期中位數大約為 28 天 分佈 : 在健康老年男性體內的分佈體積大約為 1 L/Kg, 血清蛋白結合率大約為 90% 代謝 :Degarelix 通過肝膽系統時經一般胜肽類降解, 主要降解為肽類殘餘物由糞便排泄 皮下注射後在血漿樣本中沒有觀察到明顯的代謝物 排泄 : 單次靜脈注射後, 在健康男性中大約 20-30% 的藥物劑量會從尿液中排泄, 顯示 70-80% 經過肝膽系統排泄 單次靜脈注射 degarelix 後 ( µg/kg), 健康年老男性的清除率為 35-50ml/h/kg PAGE 14

15 PHASE III TRIAL A multi-centre randomised trial comparing the efficacy and safety of Firmagon (degarelix) with leuprolide 7.5 mg in patients with prostate cancer requiring androgen deprivation therapy (CS21) 15

16 Dosing Schedule: CS21 Patients N = 610 (ITT) Day 0 Starter dose Degarelix 240 mg (2 x 3 ml s.c.) Leuprolide 7.5 mg (i.m.) Day Maintenance dose Degarelix 160 mg (1 x 4 ml s.c.) (n = 202) Degarelix 80 mg (1 x 4 ml s.c.) (n = 207) Leuprolide 7.5 mg (i.m.)* (n = 201) Dosing Monthly; in total, 13 doses are given to each patient i.m., intra-muscular; ITT, intent to treat; s.c., subcutaneous *Antiandrogen was allowed at the discretion of the investigator Klotz L, et al. BJU Int. 2008;102(11):

17 CS21- Study Endpoints Primary endpoint Probability of testosterone 0.5 ng/ml at all monthly measurements from day 28 to day 364 Secondary endpoints Proportion of patients with testosterone surge Proportion of patients with testosterone 0.5 ng/ml at day 3 (testosterone microsurges) Percentage change in PSA from baseline to day 28 and time to PSA failure Frequency and severity of adverse events PSA, prostate-specific antigen Klotz L, et al. BJU Int. 2008;102(11):

18 Patient Demographics and Disease Characteristics Baseline Characteristics Degarelix mg Degarelix mg* Leuprolide 7.5 mg Number of patients (ITT) Age, years Median testosterone, ng/ml Median PSA, ng/ml Localised PCa stage, % Locally advanced Metastatic Gleason score, % ITT, intent to treat; PCa, prostate cancer; PSA, prostate-specific antigen * 240/80 mg is the approved and marketed dose regimen Klotz L, et al. BJU Int. 2008;102(11):

19 Degarelix is Non-inferior to Leuprolide in Suppressing Testosterone to <0.5 ng/ml for 1 Year Probability of testosterone 0.5 ng/ml from day Success criterion Degarelix mg (n = 202) Degarelix mg * (n = 207) Leuprolide 7.5 mg (n = 201) Patients with treatment response Response rate FDA: CI 90% 98.3% ( %) 97.2% ( %) 96.4% ( %) Difference to leuprolide EMEA: CI -10% points 1.9 % (-1.8 to 5.7%) 0.9% (-3.2 to 5.0%) * 240/80 mg is the approved and marketed dose regimen Klotz L, et al. BJU Int. 2008;102(11): ; 2. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008.

20 Degarelix Rapid Testosterone Reduction, No Risk of Clinical Flare Median percentage change in testosterone (%) * P < Degarelix 240/80 mg* (n = 207) Leuprolide 7.5 mg (n = 201) Time (days) Klotz L, et al. BJU Int. 2008;102(11): * 240/80 mg is the approved and marketed dose regimen 20

21 Degarelix Very Low Testosterone Levels Maintained Over 1 Year 9 Median testosterone (ng/ml) ± interquartile range Time (days) Degarelix 240/80 mg* (n = 207) Leuprolide 7.5 mg (n = 201) Castration level * 240/80 mg is the approved and marketed dose regimen Klotz L, et al. BJU Int. 2008;102(11):

22 Degarelix - No Testosterone Microsurges Testosterone microsurges* Change: Day 3 and 7 after 9th injection Degarelix mg** (n = 207) Leuprolide 7.5 mg (n = 201) >0.25 ng/ml 0 8 (4%)* 22 * Increase in testosterone >0.25 ng/ml at any two measurements 3 and 7 days post-dose Klotz L, et al. BJU Int. 2008;102(11): ** 240/80 mg is the approved and marketed dose regimen

23 Degarelix Significantly Faster Reduction in PSA Change in PSA From Baseline in all Patients 20 Change from baseline, % Treatment Degarelix 240/80 mg** (n = 207) Leuprolide 7.5 mg (n = 201) * * Time (days) * The differences in the PSA reduction from baseline between degarelix and leuprolide patients at days 14 and 28 were statistically significant (P < 0.001); 11% of leuprolide patients received bicalutamide as flare protection Klotz L, et al. BJU Int. 2008;102(11): ** 240/80 mg is the approved and marketed dose regimen 23

24 Degarelix Faster PSA Suppression; Sustained Over 1 Year Median PSA (ng/ml) Time (days) Degarelix 240/80 mg* (n = 207) Leuprolide 7.5 mg (n = 201) * 240/80 mg is the approved and marketed dose regimen Klotz L, et al. BJU Int. 2008;102(11):

25 Higher Probability of PSA PFS with Degarelix in Patients with Baseline Metastatic Disease Probability (%) P = Time (days) Number at risk Degarelix 240/80 mg* Leuprolide 7.5 mg PSA, prostate-specific antigen; PSA PFS, PSA progression-free survival * 240/80 mg is the approved and marketed dose regimen Tombal B, et al. Eur Urol. 2010;57(5):

26 Incidence and Probability of PSA Progression or Death Degarelix mg* (n = 207) Leuprolide 7.5 mg (n = 201) Incidence of PSA progression, n (%) 16 (7.7) 26 (12.9) Probability of PSA progression a, % (95% CI) 8.9 ( ) 14.1 ( ) Incidence of death, n (%) 5 (2.0) 9 (4.0) Probability of death a, % (95% CI) 2.6 ( ) 4.9 ( ) a Probability of experiencing PSA progression or death by day 364 (estimated using Kaplan-Meier method) Patients receiving degarelix had a statistically lower risk of PSA progression or death compared with leuprolide (P = 0.05, log rank) CI, confidence interval; PSA, prostate-specific antigen * 240/80 mg is the approved and marketed dose regimen Tombal B, et al. Eur Urol. 2010;57(5):

27 Higher Probability of PSA PFS with Degarelix in Patients with Baseline PSA >20 ng/ml Probability (%) P = Number at risk Time (days) Degarelix 240/80 mg* Leuprolide 7.5 mg PSA, prostate-specific antigen; PSA PFS, PSA progression-free survival * 240/80 mg is the approved and marketed dose regimen Tombal B, et al. Eur Urol. 2010;57(5):

28 PSA progression by Baseline Disease Stage and PSA Levels Patients with PSA progression (%) Patients with PSA progression (%) Prostate cancer stage PSA (ng/ml) PSA progression occurred more frequently in both treatment groups in patients with higher baseline PSA and in patients with more advanced disease In patients with baseline PSA >20 ng/ml, risk of PSA progression was significantly lower with degarelix (P = 0.04) PSA, prostate-specific antigen Tombal B, et al. Eur Urol. 2010;57(5):

29 Faster and More Profound S-ALP Control With Degarelix in Metastatic Disease Absolute change in S-ALP normalized to baseline, IU/L Disease stage at baseline Localized Locally advanced Metastatic Treatment Degarelix 240/80 mg (n = 207) Leuprolide 7.5 mg (n = 201) Degarelix 240/80 mg (n = 207) Leuprolide 7.5 mg (n = 201) Degarelix 240/80 mg (n = 207) Leuprolide 7.5 mg (n = 201) Number of patients (metastatic disease) Time, days Degarelix Leuprolide Degarelix has a faster and more profound effect on the suppression of S-ALP levels in the subgroup of patients with metastatic disease (day 364; 96 vs. 179 IU/L; P = 0.014) S-ALP, serum alkaline phosphatase Data are means ± standard error; P = for overall S-ALP suppression vs. leuprolide Schröder F, et al. BJU Int. Jul 2010;106(2):

30 CS21 (Phase III) Efficacy Conclusions Firmagon (degarelix) achieves immediate testosterone reduction and maintains the hormone at low and constant concentrations 1 No need for flare protection with Firmagon (degarelix); a simplified treatment approach 1 Firmagon (degarelix) causes a rapid and sustained PSA suppression, indicating a beneficial tumour response in patients with prostate cancer 1 Patients receiving degarelix had a statistically lower risk of PSA progression or death compared with leuprolide 2 Patients with metastatic disease or elevated PSA levels ( 50 ng/ml) at baseline had greater reductions in S-ALP levels with Firmagon (degarelix) than with leuprolide 3 Firmagon (degarelix) achieves a rapid and sustained decrease in FSH level 1 FSH, follicle-stimulating hormone; PSA, prostate-specific antigen; S-ALP, serum alkaline phosphatase 1. Klotz L, et al. BJU Int. 2008;102(11): Tombal B, et al. Eur Urol. 2010;57(5): Schröder F, et al. BJU Int. Jul 2010;106(2):

31 CS21 Adverse Events AE (%) Degarelix mg (n = 202) Degarelix mg # (n = 207) Degarelix pooled (n = 409) Leuprolide 7.5 mg (n = 201) Any AE Injection site AEs <1*** Hot flush Weight increased Back pain Arthralgia * Hypertension Fatigue Urinary tract infection ** Nausea Constipation Hypercholesterolaemia Chills ** *P < 0.05, **P < 0.01, and ***P < vs. degarelix pooled # 240/80 mg is the approved and marketed dose regimen Klotz L, et al. BJU Int. 2008;102(11):

32 Injection Site Reactions Predominantly with Starter Dose Degarelix mg Degarelix mg* Total number of doses Number of doses associated with ISR % Total number of doses Number of doses associated with ISR % Starter dose Maintenance dose(s) ISR, injection site reaction * 240/80 mg is the approved and marketed dose regimen Klotz L, et al. BJU Int. 2008;102(11):

33 CS21 (Phase III) Safety Conclusions Incidence of adverse events similar with Firmagon (degarelix) and leuprolide 1 The most frequent events tended to be related to androgen suppression i.e. hot flushes, weight increase, and the majority were of mild or moderate intensity Degarelix had a higher incidence of injection site reactions and chills but a lower incidence of sideeffects like urinary tract infection and musculoskeletal events (arthralgia) Most injection site reactions with degarelix occurred with first dose No serious adverse events considered related to degarelix Majority of the injection site reactions were managed with analgesics (53.2 %), typically paracetamol (23.4%) and NSAIDs (19.4%, mostly ibuprofen) 2 NSAIDS, non-steroidal anti-inflammatory drugs Klotz L, et al. BJU Int. 2008;102(11): Ferring Internal Data: Injection site reactions document (for internal use) 2013.

34 Overall Conclusions Firmagon (degarelix) has a direct mechanism of action which provides o Rapid and profound PSA and testosterone reductions 1,2 o Low PSA and testosterone levels, maintained over time o Better PSA PFS in patients with baseline PSA >20 ng/ml 3 o Specific reduction of both LH and FSH levels 1,2 No need for antiandrogen flare protection with Firmagon (degarelix), providing a simple treatment Degarelix provides faster and more profound control of S-ALP levels compared to leuprolide over time 4 Lower probability of experiencing a urinary tract AE 5 AA, antiandrogen; AE, adverse event; FSH, follice-stimulating hormone; LH, luteinizing hormone; PSA, prostate-specific antigen PSA PFS, PSA progression-free survival; S-ALP, serum alkaline phosphatase Van poppel H, et al. Int J Urol. 2012;19(7): Drudge-Coates L. Int J Urol. Nursing. 2009;3: Tombal B, et al. Eur Urol. 2010;57(5): Schröder F, et al. BJU Int. Jul 2010;106(2): Klotz L, et al. BJU Int. 2008;102(11):

35 Faster and more sustained FSH control with degarelix vs leuprolide CS21: degarelix or leuprolide CS21A: All degarelix FSH stimulates PCa cell growth in hormone-refractory cell lines 3 In man, FSH levels are higher in those with more advanced disease 4 Data are median (quartiles) 1. Klotz et al. BJU Int 2008;102:1531-8; 2. Crawford et al. J Urol 2011; 186:889 97; 3. Ben-Josef et al. J Urol 1999;161:970 6; 4. Heracek et al. Neuro Endocrinol Lett 2007;28:

36 PSA PFS significantly improved after crossover from leuprolide to degarelix (all patients) CS21: degarelix or leuprolide CS21A: all patients received degarelix* *Month 13 to 60 Extension study. Crossover at 12 months was pre-planned and not due to failure of leuprolide treatment. PFS, progression-free survival; PSA, prostate-specific antigen Crawford ED, et al. Urology 2014;83:

37 PSA PFS significantly improved after crossover from leuprolide to degarelix (all patients) CS21: degarelix or leuprolide CS21A: all patients received degarelix* Significant hazard rate change following crossover (p=0.002) *Month 13 to 60 Extension study. Crossover at 12 months was pre-planned and not due to failure of leuprolide treatment. PFS, progression-free survival; PSA, prostate-specific antigen Crawford ED, et al. Urology 2014;83:

38 Data from randomized phase III/IIIb trials of degarelix vs GnRH agonists were pooled Study CS21 Pivotal phase III, monthly dose CS35 3-month depot formulation CS28 LUTS relief CS30 Neoadjuvant to radical RT CS31 TPV reduction CS37 a Intermittent dosing Duration (months) Comparator Publication 12 Leuprolide Klotz et al. BJU Int Goserelin Shore et al. SUO Goserelin b Anderson et al. Urol Int Goserelin b Mason et al. Clin Oncol Goserelin b Axcona et al. BJU Int Leuprolide Trial completed Q Efficacy data was collected from the degarelix clinical trials database Safety data was patient reported and categorised by MedDRA criteria GnRH, gonadotropin-releasing hormone; LUTS, lower urinary tract symptoms; RT, radiotherapy; TPV, total prostate volume 38

39 Pooled analysis: Background Key differences between degarelix and LHRH agonists have been reported from a phase III randomized trial 1 Pooled data from multiple trials allows robust analysis of outcomes from a large patient population Individual patient data were pooled from 6 prospective phase III or IIIb trials comparing degarelix with an LHRH agonist. Patients received 1 year or 3 months of degarelix or LHRH agonist treatment. The initial degarelix dose was 240mg in all trials. Maintenance doses were 80mg except in CS21, which compared maintenance doses of 80mg and 160mg, and CS35, which used a maintenance regimen of 480mg every 3 months. LHRH, luteinising hormone-releasing hormone 1 Klotz et al. BJU Int 2008;102:

40 Pooled analysis: Improved PSA PFS with degarelix vs GnRH agonists HR=0.71 (95% CI ) p=0.017 Number at risk GnRH, gonadotropin-releasing hormone; LHRH, luteinising hormone-releasing hormone; PFS, progressionfree survival; PSA, prostate-specific antigen Klotz L, et al. Eur Urol 2014;66:

41 Pooled analysis: Improved overall survival with degarelix vs LHRH agonists (1 st year) HR=0.47 (95% CI ) p=0.023 Number at risk Data in the graph is risk of death from any cause Very few patients died of prostate cancer over the year of the study Most men with prostate cancer die of other causes such as CVD CVD, cardiovascular disease; LHRH, luteinising hormone-releasing hormone Klotz L, et al. Eur Urol 2014;66:

42 Pooled analysis: Treatment emergent adverse events (>5% in either group) Event, n (%) Degarelix n=1266 GnRH agonist n=659 Any adverse event 942 (74) 445 (68) Hot flush 386 (30)* 171 (26) Injection-site reactions Pain Erythema Swelling Nodule 380 (30)* 257 (20)* 76 (6)* 73 (6)* 6 (<1) 0 (0) 0 (0) 0 (0) Fatigue 59 (5) 35 (5) Arthralgia 45 (4) 41 (6) Back pain 50 (4) 41 (6)* Urinary tract infection 43 (3) 37 (6)* *p<0.05 GnRH, gonadotropin-releasing hormone Klotz L, et al. Eur Urol 2014;66:

43 Pooled analysis: Lower probability of musculoskeletal events with degarelix vs GnRH agonists p=0.007 (log-rank) Number at risk GnRH, gonadotropin-releasing hormone; LHRH, luteinising hormone-releasing hormone Klotz L, et al. Eur Urol 2014;66:

44 Pooled analysis: Lower probability of joint-related signs and symptoms with degarelix vs GnRH agonists HR=0.64 (95% CI ) p=0.041 Number at risk Adapted from original reference GnRH, gonadotropin-releasing hormone; LHRH, luteinising hormone-releasing hormone Klotz L, et al. Eur Urol 2014;66:

45 Degarelix and high risk patients 45

46 Baseline PSA >20 ng/ml: Longer time to PSA failure with degarelix vs leuprolide Probability of freedom from PSA failure Patients with more advanced disease are likely to have faster progression differences between treatments may therefore be easier to detect p= (log-rank) PSA, prostate-specific antigen Tombal B et al. Eur Urol 2010;57:

47 Baseline PSA >20ng/mL: Reduced risk of PSA progression with degarelix 40 Degarelix 240/80 mg Leuprolide 7.5 mg PSA progression (%) >20 50 >50 (n=215) (n=90) (n=103) PSA level at baseline (ng/ml) The risk of PSA progression after 1 year was significantly lower in patients with baseline PSA >20 ng/ml treated with degarelix (p= 0.04) vs leuprolide PSA, prostate-specific antigen Tombal B et al. Eur Urol 2010;57:

48 Baseline PSA 20 ng/ml: Longer time to PSA failure or death with degarelix vs leuprolide 7 months longer time to PSA failure/death vs leuprolide TTP 25% was significantly greater for degarelix 240/80 mg vs leuprolide in analyses using degarelix data beyond 1 year: 514 vs 303 days (P=0.01) The magnified area of the graph shows the time for 25% of patients with baseline PSA 20 ng/ml to experience PSA failure or death. KM, Kaplan Meier; PSA, prostate-specific antigen; TTP 25%, time to progression in 25% of patients Boccon-Gibod L et al. Therap Adv Urol 2011;3:

49 PSA PFS significantly improved after crossover from leuprolide to degarelix (baseline PSA 20 ng/ml) CS21: degarelix or leuprolide CS21A: all patients received degarelix* *Month 13 to 60 Extension study. Crossover at 12 months was pre-planned and not due to failure of leuprolide treatment. PFS, progression-free survival; PSA, prostate-specific antigen Crawford ED, et al. Urology 2014;83:

50 PSA PFS significantly improved after crossover from leuprolide to degarelix (baseline PSA 20 ng/ml) CS21: degarelix or leuprolide CS21A: all patients received degarelix* Significant hazard rate change following crossover (p=0.019) *Month 13 to 60 Extension study. Crossover at 12 months was pre-planned and not due to failure of leuprolide treatment. PFS, progression-free survival; PSA, prostate-specific antigen Crawford ED, et al. Urology 2014;83:

51 Lower probability of a urinary tract event in men with baseline PSA >20 ng/ml Degarelix GnRH agonist HR=0.44 (95% CI ) p< Degarelix GnRH agonist Number at risk GnRH, gonadotropin-releasing hormone; PSA, prostate-specific antigen Data on file 51

52 Pooled analysis: Lower probability of musculoskeletal events with degarelix vs GnRH agonists p=0.007 (log-rank) Number at risk GnRH, gonadotropin-releasing hormone; LHRH, luteinising hormone-releasing hormone Klotz L, et al. Eur Urol 2014;66:

53 Improved control of S-ALP in metastatic patients with degarelix vs LHRH agonists p=0.038 p=0.037 Data are mean ± 95% CI Elevated S-ALP levels have been associated with progression of skeletal metastases and reduced survival times LHRH, luteinising hormone-releasing hormone; S-ALP, serum alkaline phosphatase Miller K et al. EAU Congress 2013, Klotz L, et al. Eur Urol 2014;66:

54 Patients with cardiovascular disease 54

55 Pooled data from randomized phase III/IIIb trials of degarelix vs GnRH agonists Study CS21 Pivotal phase III, monthly dose CS35 3-month depot formulation CS37 Intermittent dosing CS28 LUTS relief CS30 Neoadjuvant to radical RT CS31 TPV reduction Duration (months) Comparator Publication 12 Leuprolide Klotz et al. BJU Int Goserelin Shore et al. SIU 2012 *All patients on goserelin also received antiandrogen flare protection 7-12 Leuprolide Crawford et al. SUO Goserelin* Anderson et al. Urol Int Goserelin* Mason et al. Clin Oncol Goserelin* Axcrona et al. BJU Int 2012 Efficacy data was collected from the degarelix clinical trials database Safety data was patient reported and categorised by MedDRA criteria GnRH, gonadotropin-releasing hormone; LUTS, lower urinary tract symptoms; RT, radiotherapy; TPV, total prostate volume 55

56 Pooled analysis: Lower incidence of CV events (all patients) Degarelix, n (%) n=1491 GnRH agonist, n (%) n=837 Any CV event 42 (2.8) 37 (4.4) Death 20 (1.3) 22 (2.6) Degarelix GnRH agonist HR=0.60 (95% CI ) p=0.008 CV, cardiovascular; CVD, cardiovascular disease Albertsen PC, et al. Eur Urol 2014;65:

57 Pooled analysis: Lower incidence of CV events (baseline CV disease) Degarelix, n (%) n=463 GnRH agonist, n (%) n=245 Any CV event 21 (4.5) 23 (9.4) Death 9 (1.9) 13 (5.3) Degarelix GnRH agonist HR=0.44 (95% CI ) p=0.002 CV, cardiovascular; CVD, cardiovascular disease Albertsen PC, et al. Eur Urol 2014;65:

58 Pooled analysis: A different impact on CVD morbidity with degarelix vs agonists Risk reduction of CV events or death after the first year of treatment in men with pre-existing CVD (n=708) 56% relative risk reduction The absolute risk reduction after the first year was 8.2%, which yielded a number needed to treat to avoid 1 CV event or death of 12 (HR: 0.44; 95% CI, ; p=0.002) Adapted from original reference Several study limitations confine findings to hypothesis generating: the nature of a post hoc analysis, the studies were open-label and CV events may have been underreported, CV events were reported as adverse events and were not independent study endpoints, and finally, reported CV events were not systematically validated. Cardiac events were defined as: arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease. CV, cardiovascular; CVD, cardiovascular disease Albertsen PC, et al. Eur Urol 2014;65:

59 ADT and possible pathogenesis of CV risk Indirect mechanisms Androgen (testosterone) deficiency causing increased weight and metabolic complications may destabilize/ accelerate the atherosclerotic process, or exacerbate preexisting cardiac risk factors Primarily depression of LH by LHRH agonists vs LH and FSH supression by GnRH antagonists. FSH receptors play a role in endothelial cell function, lipid metabolism, and fat accumulation Direct mechanisms Role of potentially functional GnRH receptors on lymphocytes and cardiomyocytes/secondary messengers (protein kinase A) and CV events? CV, cardiovascular; FSH, follicle stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinising hormone; LHRH, luteinising hormone-releasing hormone 59

60 Plaque instability is at the heart of cardiovascular disease Stable plaque Vulnerable plaque Fibrous cap Lumen Lipid core T cell Macrophage Lumen Fibrous cap Lipid core Thick Cap Thin Rich in SMC and matrix Composition Rich in inflammatory cells: proteolytic activity Poor Lipid Rich Inflammatory Inflammatory state Highly inflammatory SMC, smooth muscle cells Libby P J. Lipid Res. 2009;50:S

61 Further FSH suppression after crossover from leuprolide to degarelix CS21: degarelix or leuprolide CS21A: all degarelix FSH, follicle stimulating hormone Crawford ED et al. J Urol 2011;186:

62 FSH and adipogenesis Stimulation of FSH receptors possibly alters endothelial cell function, lipid metabolism and fat accumulation Pre-clinical studies have shown: Mice treated with degarelix have lower FSH levels than those treated with LHRH agonist or orchiectomy Degarelix-treated mice gain less weight and visceral fat than mice treated with LHRH agonists FSH, follicle stimulating hormone; LHRH, luteinising hormone-releasing hormone Hopmans SN, et al. Urol Oncol 2014;32:

63 FSH and total and necrotic plaques Total plaque area (% of total) Pre-clinical mouse model with four treatment arms: no treatment, orchiectomy, leuprolide, degarelix a a Control Orchiectomy Leuprolide Degarelix Significantly less plaque area changes were observed with degarelix Aortic atherosclerotic plaque area in mice receiving different modes of ADT at 4 months calculated as percentage of plaque and necrotic plaque area of aortic tissue. a p<0.05 vs control; b p<0.05 vs orchiectomy; c p<0.05 vs leuprolide a a bc Necrotic plaque area (% of total) ADT, androgen deprivation therapy; FSH, follicle-stimulating hormone Hopmans SN, et al. Urol Oncol 2014;32:

64 FSH and plaques Aortic atherosclerotic plaque area in mice receiving different modes of ADT at 4 months calculated as percentage of plaque and necrotic plaque area of aortic tissue. This animal data is not directly applicable to humans. ADT, androgen deprivation therapy; FSH, follicle-stimulating hormone Hopmans SN, et al. Urol Oncol 2014;32:

65 A role for the GnRH receptor: Agonists and antagonists act differently on T lymphocytes LHRH agonist GnRH antagonist GnRH-R GnRH-R T-cells T-cells Increased interleukin-2γ receptor expression Increased proliferation Complete blockade of receptors with no signal transduction Fibrotic cap disruption and plaque instability Inhibition of stimulated responses GnRH, gonadotropin-releasing hormone; LHRH, luteinising hormone-releasing hormone Chen HF, et al. J Clin Endocrinol Metab 1999;84:743-50; Tanriverdi F, et al. Clin Exp Immunol 2005;142:103-10; Grasso G, et al. Life Sci 1998;62: ; Jacobson JD, et al. Endocrinol 1994;134:

66 Neo-adjuvant therapy and LUTS 66

67 Degarelix studies vs. LHRH agonists - Prostate size and symptom control Study Comparator Patient population Duration Primary endpoint CS28 1 Goserelin + bicalutamide PCa all stages (80% T3/4) PSA >10 ng/ml, IPSS 12 N=40 12 weeks IPSS CS30 2 (Neoadjuvant) Goserelin + bicalutamide Intermediate- to high-risk PCa (T2b/c 4/N0/M0 or Gleason 7 or PSA 10 ng/ml) TPV >30cm 3 N= weeks TPV CS31 3 Goserelin + bicalutamide PCa all stages PSA >2 ng/ml, TPV >30 ml N= weeks TPV IPSS, International Prostate Symptom Score; PCa, prostate cancer; PSA, prostate-specific antigen; TPV, total prostate volume 1. Anderson et al. Urol Int 2013;90:321-8; 2. Mason M, et al. Clin Oncol 2013;25:190-6; 3. Axcrona K, et al. BJU Int 2012;110:

68 Non-inferior reduction in TPV after 3m with degarelix vs goserelin + bicalutamide before RT % change in total prostate volume (SEM) Degarelix (n=176) Goserelin + bicalutamide (n=62) Full analysis set Rapid reduction in testosterone and PSA levels consistent with goserelin plus bicalutamide in patients eligible for ADT neoadjuvant to radiotherapy ADT, androgen deprivation therapy; PSA, prostate-specific antigen; RT, radiotherapy; SEM, standard error of the mean; TPV, total prostate volume Mason M, et al. Clin Oncol 2013;25:

69 Testosterone and PSA reduction similar Median (± interquartile range) PSA, prostate-specific antigen Mason M, et al. Clin Oncol 2013;25:

70 CS30: Significant reduction in IPSS with degarelix After 12 weeks: ± 0.42 with degarelix vs ± 0.65 with goserelin plus bicalutamide Adjusted (for baseline IPSS) difference: (-2.81, ); p=0.044 IPSS reduction before RT is important as RT can cause LUTS IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms; RT, radiotherapy Mason M, et al. Clin Oncol 2013;25:

71 Pooled analysis: Significant reduction in IPSS (all patients) Adjusted mean treatment difference was (p=0.03) IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms Mason M, et al. LUTS 2015: DOI: /luts

72 Pooled analysis: Significant IPSS reduction based on LUTS data ( 13 points) Adjusted mean treatment difference was (p<0.01) in the group of patients with moderate to severe LUTS IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms Mason M, et al. LUTS 2015: DOI: /luts

73 Pooled analysis: Total Prostate Volume based on LUTS data (all patients) Median percentage decrease was 37.0% for degarelix and 38.4% for goserelin IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms; TPV, total prostate volume Mason M, et al. EAU congress

74 Pooled analysis: Significantly lower probability of urinary tract events with degarelix vs GnRH agonists Overall: p=0.001 Number at risk (all patients) GnRH, gonadotropin-releasing hormone; LHRH, luteinising hormone-releasing hormone Klotz L, et al. Eur Urol 2014;66:

75 Summary Degarelix achieves immediate and sustained low testosterone levels and fast PSA reduction compared to leuprolide PSA PFS and overall survival is improved with degarelix compared to GnRH agonists at 1 year A pooled analysis showed an absolute risk reduction of 8.2% on cardiovascular event/death after the first year with degarelix compared to GnRH agonists in men with pre-existing CV disease A pooled analysis showed a significant decrease in IPSS with degarelix compared to GnRH agonist within the first 3 months. This was even more pronounced in patients with a baseline IPSS score 13 Degarelix is suitable for intermittent treatment CV, cardiovascular; GnRH, gonadotropin-releasing hormone; IAD, intermittent androgen deprivation; IPSS, International Prostate Symptom Score; PFS, progression-free survival; PSA, prostate-specific antigen 75

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