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Endocrinology of Prostate Cancer. Hormonal Pathways of the Male Endocrine System.

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Presentation on theme: "Endocrinology of Prostate Cancer. Hormonal Pathways of the Male Endocrine System."— Presentation transcript:

1 Endocrinology of Prostate Cancer

2 Hormonal Pathways of the Male Endocrine System

3 Testosterone OriginDistribution Source:Adapted from Coffey DS. In: Walsh PC, et al, eds. Campbell’s Urology. 6th ed. 1992: % from adrenals 95% from testes 2% not bound 54% bound with albumin 44% bound with sex-hormone- binding globulin

4 Circulating Androgens Daily Production Relative Potency Sources: Adapted from Partin AW, Rodriguez R. In: Walsh PC, et al, eds. Campbell’s Urology. 8th ed. 2002: ; Labrie F, et al. Cancer.1993; 71(Suppl 3): DHT(1.1%) T(20.7%) AND(5.4%) DHEA(72.7%) Ratio DHTANDDHEA T

5 Testosterone Pathway in Prostatic Cells (Free)

6 Hormonal Therapy Options

7 Hormonal Therapy Bilateral orchiectomy Bilateral orchiectomy LHRH analogs LHRH analogs Antiandrogens Antiandrogens Combined Androgen Blockade (CAB) Combined Androgen Blockade (CAB) Androgen antagonist Androgen antagonist

8 Bilateral Orchiectomy In 1941, Huggins and Hodges made original discovery of hormonal effect on prostate cancer In 1941, Huggins and Hodges made original discovery of hormonal effect on prostate cancer Same studies also showed that bilateral orchiectomy improved pain or neurological symptoms in 71% of patients with metastatic disease Same studies also showed that bilateral orchiectomy improved pain or neurological symptoms in 71% of patients with metastatic disease Advantages: Advantages: –Immediate castration without testosterone surge –Outpatient procedure, general anesthesia not required –No compliance issues Disadvantages: Disadvantages: –Irreversible Huggins C, Hodges CV. Cancer Res. 1941;1: Huggins C, et al. Arch Surgery. 1941;43:209. Schroder FH. Campbell’s Urology, 8th ed. Philadelphia, Pa. WB Saunders;2002:

9 Hormonal Therapy in Metastatic Disease HT has been most widely used in metastatic disease HT has been most widely used in metastatic disease When to initiate HT is often debated When to initiate HT is often debated MRC (UK) Study MRC (UK) Study –938 patients with locally advanced and asymptomatic, metastatic prostate cancer –Early HT (89% orchiectomy; within 6 weeks of entry) vs Deferred HT (71.5% orchiectomy) Survival, local and distant progression, major complications evaluated Survival, local and distant progression, major complications evaluated MRC Prostate Cancer Working Group Party Investigators Group Br J Urol. 1997;79:

10 MRC Trial: Results 934 evaluable patients results 934 evaluable patients results MRC Prostate Cancer Working Group Party Investigators Group Br J Urol. 1997;79: Deferred ARM (# of patients) Immediate ARM (# of patients) P values Death361328P=0.02Two-tailed Cause Specific Death P=0.001Two-tailed TUR14165 P<0.001 Two-tailed 469 in the immediate HT group and 465 in the deferred HT

11 Mechanism of Action of LHRH Analogs HYPOTHALAMUS PITUITARY PROSTATE Testosterone DHT ADRENAL CortisolTestosterone CRH ACTH LH TestosteroneAdrenalandrogens Induction/StimulationFeedback/Regulation Adapted from Foote JE, Crawford ED. Semin Urol.1988;6(4): LHRH-As LHRH TESTES

12 Time to Induction of Castration with Long-Term LHRH Analog Therapy Mean Serum Testosterone Levels Adapted from Debruyne FMJ, et al. J Urol.1988;140: Level with ZOLADEX ® (goserelin acetate implant) 3.6 mg depot Castrate level No. of patients Time (weeks) Mean serum testosterone(ng/mL)

13 Single-Therapy Androgen Suppression in Men with Advanced Prostate Cancer: A Systematic Review and Meta-Analysis 24 RCT involving 6600 patients, ( ) 24 RCT involving 6600 patients, ( ) Results Results –LHRHa are equivalent to orchiectomy (10 trials, n=1908, HR , 95% CI, ). –There was no difference in OS among the LHRH analogues Leuprolide (hazard ratio, [CI, to 5.835])Leuprolide (hazard ratio, [CI, to 5.835]) Buserelin (hazard ratio, [CI, to 2.404])Buserelin (hazard ratio, [CI, to 2.404]) Goserelin (hazard ratio, [CI, to 1.390]).Goserelin (hazard ratio, [CI, to 1.390]). –Nonsteroidal antiandrogens are associated with lower OS( 8 trials, 2717 patients, HR [CI, to 1.496]). –Treatment withdrawals are less frequent with LHRHa (0% to 4%) than with nonsteroidal antiandrogens (4% to 10%). Seidenfield et al Annals of Intern Med 2000, 132; 7:

14 Pivotal Trial Overall Survival Adapted from: Kaisary AV, et al. Br J Urol. 1991;67: Estimated Survival Probability Length of Survival (Weeks) Estimated Survival Probability Length of Survival (Weeks) Eligible “Depot Period” PatientsAll Eligible Patients ZOLADEX Bilateral Orchiectomy ZOLADEX Bilateral Orchiectomy p = 0.23p = 0.33 ® n =176 ZOLADEX ® (goserelin acetate implant) n =182 bilateral orchiectomy n = 148 ZOLADEX n = 144 bilateral orchiectomy

15 Pivotal Trial Pharmacological Adverse Events Adapted from: Kaisary AV, et al. Br J Urol. 1991;67: Percent of Event Rate 73% (37/51) 79% (34/43) 84% (43/51) 85% (41/48) 63% (96/152) 58% (94/163) 4.8% (8/168) 4% (7/173) 0.6% (1/167) 1.2% (2/173) ® ZOLADEX ® (goserelin acetate implant) Bilateral Orchiectomy

16 ARM I Goserelin 3.6 mg/ Flutamide 250 mg + RT (n = 226) RTOG Radiotherapy + Neoadjuvant/Concomitant ZOLADEX ® (goserelin acetate implant) Study Design Randomized Locally Advanced T2 – 4, N+/-, M0 (N = 471) ARM II RT Alone (n = 230) Pilepich MV, et al. Int J Radiat Oncol Biol Phys 2001; 50: Reprinted with permission. Median follow-up at 4.5 years and 6.7 years

17 RTOG Local Failure Pilepich MV, et al. Int J Radiat Oncol Biol Phys. 2001;50: Percent Years from Date of Randomization At risk RT + Hormones72/226 RT Alone98/230 Failed/Total p = 0.016

18 Locally Advanced (T1-2, N+; T3) (N=945) Randomized Radiotherapy + goserelin 3.6 mg (n=477) Radiotherapy Alone (n=468) RTOG Trial Radiotherapy + Adjuvant ZOLADEX ® (goserelin acetate implant) Radiotherapy + Adjuvant ZOLADEX ® (goserelin acetate implant) Study Design Pilepich MV et al. J Clin Oncol. 1997; 15: Lawton CA, et al. Int J Radiat Oncol Biol Phys. 2001;49: Median follow- up at 4.5 years and 5.6 years

19 RTOG Local Failure Reprinted from the International Journal of Radiation Oncology Biology and Physics, Vol. 49, CA Lawton, K Winter, K Murray, et al. Updated results of the Phase III radiation therapy for unfavorable prognosis carcinoma of the prostate, pp , with permission from Elsevier Science Percent Years from Date of Randomization ® RT + Adjuvant ZOLADEX ® 92/477 (goserelin acetate implant) RT + ZOLADEX at Relapse155/468 Failed/Total p <

20 RTOG Distant Metastases Reprinted from the International Journal of Radiation Oncology Biology and Physics, Vol. 49, CA Lawton, K Winter, K Murray, et al. Updated results of the Phase III radiation therapy for unfavorable prognosis carcinoma of the prostate, pp , with permission from Elsevier Science Percent Years from Date of Randomization ® RT + Adjuvant ZOLADEX ® 103/477 (goserelin acetate implant) RT + ZOLADEX at Relapse154/468 Failed/Total p <

21 RTOG Disease-Free Survival Lawton et al. Int J Radiat Oncol Biol Phys. 2001; 49: Reprinted with permission. Median follow-up of 5.6 years Percent Years from Date of Randomization RT + Adjuvant goserelin244/477 RT Alone306/468 Failed/Total p <

22 T1-4, N0, M0 (n=415) Randomized Radiotherapy + adjuvant goserelin 3.6 mg (n=207) Radiotherapy Alone (n=208) Hormonal Therapy at Progression EORTC Radiotherapy + Adjuvant ZOLADEX ® (goserelin acetate implant) vs Radiotherapy Alone vs Radiotherapy Alone Study Design EORTC = European Organization for Research and Treatment of Cancer Radiation: 50 Gy over 5 weeks + 20 Gy over 2 weeks ZOLADEX 3.6 mg sc every 4 weeks starting day 1 of radiation and continuing for 3 years Cyproterone acetate: 150 mg po qd for 1 month starting 1 week prior to ZOLADEX Bolla M, et al. NEJM. 1997; Median follow-up at 45 months and 66 months

23 EORTC Biochemical Disease Free Survival 66-Month Follow-up Bolla M, et al. Lancet. 2002;360: Combined Treatment Radiotherapy Alone Log-rank testp <.0001 Hazard ratio0.42 (95% Cl: ) Time Since Randomization (Years) ONNumber of Patients at Risk Biochemically Defined Disease-Free Survival (%)

24 EORTC Overall Survival (OS) At 66-month follow-up At 66-month follow-up –OS was 78% in the RT + ZOLADEX group and 62% for RT alone (p = ) Bolla M, et al. Lancet. 2002;360:

25 EORTC Overall Survival 66-Month Follow-up Bolla M, et al. Lancet. 2002;360: Combined Treatment Radiotherapy Alone Time Since Randomization (Years) Log-rank testp <.0001 Hazard ratio0.51 (95% Cl: ) Overall Survival (%) ONNumber of Patients at Risk

26 Antiandrogens

27 Antiandrogen Dosing Regimen Combination therapy with an LHRH-A Combination therapy with an LHRH-A –Flutamide 2 capsules (125 mg each) 3 times daily2 capsules (125 mg each) 3 times daily Half-life (T½) = 4-7 hoursHalf-life (T½) = 4-7 hours –CASODEX ® (bicalutamide) Tablets 1 tablet (50 mg) once daily1 tablet (50 mg) once daily T½ = 5.8 daysT½ = 5.8 days –Combination therapy with bilateral orchiectomy Nilutamide 2 tablets (150 mg each) once a day (300 mg) for 30 days followed by 1 tablet (150 mg each) once a day (150 mg)2 tablets (150 mg each) once a day (300 mg) for 30 days followed by 1 tablet (150 mg each) once a day (150 mg) T½ = 56 hoursT½ = 56 hours Montherapy 150mg casodex Montherapy 150mg casodex

28 Combined Androgen Blockade CAB

29 Reprinted from Urology, Vol. 50, P Schellhammer, R Sharifi, N Block, et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy in patients with advanced phase prostate cancer, pp , 1997, with permission from Elsevier Science. CASODEX ® (bicalutamide) 50 mg CAB Trial Overall Survival Proportion Surviving Day CASODEX + LHRH-A (n = 404) Flutamide + LHRH-A (n = 409) p = Median Follow-up 160 weeks

30 Overall Survival for Four CAB Groups Reprinted from Urology, Vol. 52, MF Sarosdy, PF Schellhammer, R Sharifi, et al. Comparison of goserelin and leuprolide in combined androgen blockade therapy, pp 82-88, 1998, with permission from Elsevier Science. n = 136 n = 268 n = 272 n = Proportion Surviving Time to Death (Days) leuprolide + CASODEX ® (bicalutamide) ZOLADEX ® (goserelin acetate implant) + CASODEX ZOLADEX + flutamide leuprolide + flutamide p = 0.26 p = 0.99 p = p = 0.008

31 Overview of CAB Trials Meta-Analyses

32 *Prostate Cancer Trialists’ Collaborative Group. Lancet. 1995;346: † Crawford ED, Eisenberger MA, McLeod DG, et al. NEJM. 1989;321: Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355: PCTCG Meta-analysis Treatments Tested 27 trials involving 8275 patients 27 trials involving 8275 patients –Flutamide, 4803 –Nilutamide, 1688 –Cyproterone acetate, 1784 –88% with metastatic disease, 12% with locally –advanced disease Usual dosages: nilutamide 300 mg/daily, flutamide 750 mg/daily, cyproterone acetate 150 to 200 mg/daily Usual dosages: nilutamide 300 mg/daily, flutamide 750 mg/daily, cyproterone acetate 150 to 200 mg/daily Updated information on 13 previously analyzed trials* and 5 new trials, including SWOG-8894 (leuprolide  flutamide) † Updated information on 13 previously analyzed trials* and 5 new trials, including SWOG-8894 (leuprolide  flutamide) †

33 Meta-analyses CAB vs Castration PCTCG = Prostate Cancer Trialists’ Collaborative Group; CPA = cyproterone acetate; NSAA = nonsteroidal antiandrogen; PH = proportional hazards, LR = log hazard ratio. Due to the continual analysis of survival at different time intervals, some of the analyses above contain the same patients. 1. PCTCG. Lancet. 2000;355: ; 2. Caubet JF, et al. Urology. 1997;49:71-78; 3. Klotz LH, et al. Can J Urol. 1996;3: ; 4. Debruyne FM, et al. Eur Urol. 1996;30(suppl 2):264; 5. Bennett CL, et al. Prostate Cancer Prostate Dis. 1999;2:4-8. PCTCG 1 : overalln = 8215P > 0.1 PCTCG 1 : nilutamiden = 1751P > 0.1 PCTCG 1 : flutamiden = 4803P = 0.02 PCTCG 1 : flutamide + nilutamiden = 6354P = PCTCG 1 : CPAn = 1661P = 0.04 Caubet 2 : NSAA PCTCGn = 3732P = Caubet 2 : NSAA (PH)n = 1978P < Caubet 2 : NSAA (LR)n = 2357P < Klotz 3 : NSAAn = 3015P > Debruyne 4 : nilutamiden = 1191P > Bennett 5 : flutamiden = 1128P = 0.05 Overview of Published CAB Meta-analyses 8% to 22% lower risk of death over a given time period than castration Hazard Ratio and 95% Confidence Limits CAB BetterCAB Worse

34 Meta-Analyses 27 Randomized Trials of CAB vs AS Alone Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355: Proportion Alive (%) Time Since Randomization (Years) Androgen Suppression Only Androgen Suppression + Antiandrogen Treatment Better by 0.7% (SE 1.1) Logrank p > 0.1 Absolute Difference 1.8% (SE 1.3) 23.6% 25.4% 6.2% 5.5% 10-Year Survival >8000 Prostate Cancer Patients in 27 Trials of Antiandrogens (Nilutamide, Flutamide, or Cyproterone Acetate)

35 Meta-Analyses 20 Randomized Trials of CAB vs AS Alone Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355: Year Survival 6500 Men in 20 Trials of Nilutamide/Flutamide Proportion Alive (%) Time Since Randomization (Years) Androgen Suppression Only Androgen Suppression Antiandrogen Treatment Better by 2.9% (SE 1.3) Logrank p = % 24.7% 134

36 CAB Conclusions CAB may improve absolute 5-year survival by about 2% to 3% CAB may improve absolute 5-year survival by about 2% to 3% Choice of antiandrogen Choice of antiandrogen –Nonsteroidal antiandrogens improve outcomes while steroidal antiandrogens (CPA, not approved in the US) do not Various CAB regimens similarly well tolerated Various CAB regimens similarly well tolerated

37 Antiandrogen monotherapy

38 Efficacy and tolerability of bicalutamide in early localy advanced, non-metastatic prostate cancer.SPGC 6 Median F.U 7.1 year HR 0.47 p<0.001 progresjon %patiant Bicalutamid Placebo Iversen P et al. Efficacy and tolerability of bicalutamide in early non-metastatic prostate cancer: Latest findings from The Scandinavian Prostatic Cancer Group study no 6 (Spcg-6) of The Early Prostate Cancer Programme. Eur Urol Suppl 2006;5(2):251, Abs 914 Figur utarbeidet av AstraZeneca AS Lokalavansert

39 Overall survival– locally advanced PC SPCG-6 HR=0.65 (0.50, 0.85) p=0.001 Bicalutamid events = 105 (41.2%) placebo events = 131 (52.4%) Placebo Bicalutamid Time to death (year) Overall survival Median F. U: 7.1 year Iversen P et al. Efficacy and tolerability of bicalutamide in early non-metastatic prostate cancer: Latest findings from The Scandinavian Prostatic Cancer Group study no 6 (Spcg-6) of The Early Prostate Cancer Programme. Eur Urol Suppl 2006;5(2):251, Abs 914 Figur utarbeidet av AstraZeneca AS

40 Early versus Late ADT 4 trials (n=2,167) 4 trials (n=2,167) –All trials were conducted prior to use of PSA testing & were heterogenous –All studies found PFS was consistently better in the early intervention group at all time points. Wilt T, et al Cochrane Reviews 2001, Issue 4. Overall Survival (%) 1 yr2 yr5 yr10 yr Early ADT Deferred ADT OR % CI: 0.90 to % CI: 0.89 to % CI: 0.95 to % CI: 1.04 to 2.16

41 Timing of ADT Conclusions Early ADT offers a statistically significant benefit in PFS & OS Early ADT offers a statistically significant benefit in PFS & OS Early ADT reduces disease progression and complications due to progression. Early ADT reduces disease progression and complications due to progression. There was no statistically significant difference in prostate cancer specific survival There was no statistically significant difference in prostate cancer specific survival Early ADT leads to higher costs Early ADT leads to higher costs Treatment is most cost effective when started after the onset of symptoms Treatment is most cost effective when started after the onset of symptoms Complications due to disease progression are more frequent in the deferred treatment group. Complications due to disease progression are more frequent in the deferred treatment group. Adverse events due to treatment are more frequent in the early treatment group. Adverse events due to treatment are more frequent in the early treatment group.

42 Is intermittent ADT better than continuous ADT? Rationale Rationale –Prolonged ADT may cause androgen independence –Side effects are lesser with intermittent ADT No prospective randomized trials No prospective randomized trials No guidelines for starting & stopping therapy No guidelines for starting & stopping therapy No data available on testosterone levels, QOL, BMD & sexual function No data available on testosterone levels, QOL, BMD & sexual function Two phase III studies are underway Two phase III studies are underway

43 Hormonal changes associated with aging correlate with bone loss Hormonal changes associated with aging correlate with bone loss –Lower testosterone levels –Leads to less aromatization (conversion) of testosterone to estradiol –Estradiol protects / strengthens bone Therefore lower levels = less protection Therefore lower levels = less protection E2E2 Osteoporosis Risk Factors for men

44 Hormonal Therapy BMD loss with hormonal therapy BMD loss with hormonal therapy –Decrease T by >95% –Decrease E 2 by >80% –With orchiectomy the BMD loss is 2.4% at 1 year and 10% at 2 years –With GnRH Agonist, the BMD loss is 3.4% at 1 year and 6.5% at 2 years 1 yr2 yr Orchiectomy2.4%10% GnRH Agonist3.4%6.5%

45 Hormonal Therapy This decrease in BMD is associated with an increase in fractures This decrease in BMD is associated with an increase in fractures Men without prostate cancer over the age of 65 who are not on hormonal therapy have a fracture rate of 0.5% per year Men without prostate cancer over the age of 65 who are not on hormonal therapy have a fracture rate of 0.5% per year With hormone therapy there was a 5% incidence of osteoporotic fractures seen in a median of 22 months With hormone therapy there was a 5% incidence of osteoporotic fractures seen in a median of 22 months In one series, within 7 years 28% of prostate cancer patients treated with orchiectomy had a fracture vs. 1% of patients who did not undergo orchiectomy In one series, within 7 years 28% of prostate cancer patients treated with orchiectomy had a fracture vs. 1% of patients who did not undergo orchiectomy

46 Overall Conclusions Numerous options available for treatment of prostate cancer at different stages of disease Numerous options available for treatment of prostate cancer at different stages of disease No consensus on therapy of curative intent No consensus on therapy of curative intent Treatment options should be discussed with patients Treatment options should be discussed with patients Risk and benefits of treatment need to be carefully considered Risk and benefits of treatment need to be carefully considered Hormonal therapy for locally advanced and metastatic prostate cancer is effective but not curative Hormonal therapy for locally advanced and metastatic prostate cancer is effective but not curative Further clinical studies in localized, locally advanced and metastatic prostate cancer need to be considered Further clinical studies in localized, locally advanced and metastatic prostate cancer need to be considered

47 CASTRATED RESISTANCE PC. CRPC

48 Hormone refractory prostate carcinoma Definition: Disease progression despite castrate serum levels of testosterone Definition: Disease progression despite castrate serum levels of testosterone Progression’ is defined by: Progression’ is defined by: –Increase in size of measurable lesions –Appearance of new measurable lesions – Increase in PSA >50% on at least 2 consecutive measurements –Increase in pain associated with new bony lesions Duration of response Duration of response –Limited or no metastases-5 years –Metastatic disease-2 years Median survival approximately 1 year Median survival approximately 1 year

49 CRPC :Progresjon av PSA, Symptomer

50 Harris W P et al. (2009) Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion Nat Clin Pract Urol doi: /ncpuro1296 Androgen deprivation therapy (ADT) Androgen action

51 Mechanisms of castration resistance in prostate cancer Harris W P et al. (2009) Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion Nat Clin Pract Urol doi: /ncpuro1296

52 Treatment of CRCP Casteration? Testestron? <20 ng 1-Total androgen blokade(TAB) -LHRH +Antiandrogen response ca.25% i ca 6-8 man -LHRH +Antiandrogen response ca.25% i ca 6-8 man 2- Withdrawal. 3-Antiandrogen "switching (bicalutamide  flutamide ) Biochemist response up to 40% ca 6 man 4-Stroid (Prednisolon) 5-Østrogen (Response rate ca 86%) cardivasculare side effect 6-Ketoconazole (hemmer steroid synthesis) % response 7-Abiratern

53 Definition of Castrate Testosterone: A Treatment Decision Algorithm from NCCN 2003 Guidelines Hormone ablation (advanced PCa) Orchiectomy LHRH agonist Testosterone < 20 ng/dL > 20 ng/dL Consider orchiectomy If patient refuses orchiectomy, add antiandrogen or change LHRH dose or product Continue LHRH therapy NCCN, National Comprehensive Cancer Network; PCa, prostate cancer. Adapted from Oefelein MG et al. J Urol. 2000;164: NCCN 2008 Guidelines for patients changed the testosterone trigger from 20 ng/dL to 50 ng/dL due to lack of level 1 evidence

54 Ketoconazole (KC) Ketoconazole (KC) is an antifungal drug that is a nonspecific inhibitor of P450 enzymes Ketoconazole (KC) is an antifungal drug that is a nonspecific inhibitor of P450 enzymes Inhibition of (CYP17), which is a key enzyme that mediates androgen synthesis. KC in combination with hydrocortisone (HC) has been widely used to treat patients with CRPC as a secondary hormonal agent in patients whose disease is progressing following ADT and AAWD. Inhibition of (CYP17), which is a key enzyme that mediates androgen synthesis. KC in combination with hydrocortisone (HC) has been widely used to treat patients with CRPC as a secondary hormonal agent in patients whose disease is progressing following ADT and AAWD. KC is associated with significant toxicities without a definitive demonstration of improvement in overall survival. (e.g., fatigue, nausea, liver enzyme elevations and neurotoxicity) KC is associated with significant toxicities without a definitive demonstration of improvement in overall survival. (e.g., fatigue, nausea, liver enzyme elevations and neurotoxicity)

55 Abiraterone Acetate: A Promising Drug for the Treatment of Castration-resistant Prostate Cancer Neeraj Agarwal; Thomas E Hutson; Nicholas J Vogelzang; Guru Sonpavde Authors and Disclosures Posted: 06/18/2010; Future Oncology. 2010;6(5): © 2010 Future Medicine Ltd. An orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosysnthesis, CYP17, and blocks the synthesis of androgens in the testes, adrenal glands and prostate without causing adrenal insufficiency. An orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosysnthesis, CYP17, and blocks the synthesis of androgens in the testes, adrenal glands and prostate without causing adrenal insufficiency. Randomised phase III trial. Randomised phase III trial. OS OS Abiraterone + prednisone: 14.8 monthsAbiraterone + prednisone: 14.8 months Placebo + prednisone: 10.8 monthsPlacebo + prednisone: 10.8 months The PSA response The PSA response –Abiraterone + prednisone: 38.0% –Placebo + prednisone: 10.1% Adverse Adverse –Adverse events with abiraterone treatment were obviously higher than for placebo, but in general it appeared well tolerated and an important common side effect was fluid retention (30.5% of patients, with 2.4% of them being severe ie grade 3/4 in severity)

56

57 Firmagon® - A novel GnRH receptor blocker for hormonal treatment of prostate cancer Gero Kramer Clinic for Urology Medical University of Vienna

58 GnRH agonists: disadvantages Testosterone surge delay in castration 1 flare symptoms 2 Testosterone surge delay in castration 1 flare symptoms 2 Testosterone microsurges Testosterone microsurges Testosterone breakthroughs Testosterone breakthroughs Testosterone control not comparable with orchiectomy Testosterone control not comparable with orchiectomy 1 Thompson IM. Rev Urol 2001; 3 (Suppl 3): S10-S14; 2 Heidenreich A et al. EAU Guidelines on prostate cancer 2007

59 Objectives for Firmagon development To mimic the effects of surgical castration No testosterone surge Fast and sustained suppression of testosterone and PSA Similar or better safety profile compared with GnRH agonists

60 x x Firmagon a GnRH blocker Direct mode of action Immediate onset with fast testosterone and PSA suppression Immediate onset with fast testosterone and PSA suppression No testosterone surge No testosterone surge Princivalle M, J Pharmacol Exp Ther 2007; 320: Firmagon

61 Molecule A fully synthetic, linear decapeptide amide A fully synthetic, linear decapeptide amide A natural gelling depot A natural gelling depot Requires no additional constituents Requires no additional constituents Low histamine release Low histamine release White, 1st European Multidisciplinary Meeting on Urological Cancers, Barcelona, Spain, 2007.

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

63 Dosing schedule CS21 Dosing monthly with a total of 12 days N=610 patients (ITT) Firmagon 240 mg (2x3 mL s.c) Day 0 Starter dose Day Maintenance dose Leuprolide 7.5 mg (i.m.) Firmagon 160 mg (1x4 mL s.c) Firmagon 80 mg (1x4 mL s.c) Leuprolide 7.5 mg (i.m.)* *Anti-androgen was allowed Klotz L et al. BJU Int 2008;102:1531-8

64 CS21- study endpoints Primary endpoint: Probability of testosterone ≤0.5 ng/mL at all monthly measurements Secondary endpoints included: Patients with testosterone surge and microsurges Change in PSA from baseline to day 28 and time to PSA failure Safety

65 Klotz L et al. BJU Int 2008;102: Number of pats. Age (median), yrs. Testosterone (ng/ml) PSA (ng/ml) Firmagon 240  (3-5.3) 20 (9-46) Leuprolide 7.5mg (2.9-5) 17 (8-56) Demographics and disease characteristics

66 Leuprolide 7.5 mg Firmagon 240  80 mg PCA stage 31%33% Localized 26%31% Loc. Advanced 23%18% Metastatic Gleason Score 44%43% ≤ 6 26%27% %30% 7 19%18% Unclassified Klotz L et al. BJU Int 2008;102:1531-8

67 Firmagon is noninferior to leuprolide in suppressing testosterone to <0.5 ng/mL for 1 year Probability of testosterone ≤0.5 ng/mL from day Difference to leuprolide Response rate Patients with treatment response 0.9 % (-3.2 to 5.0 %) 96.4 %97.2 % Leuprolide 7.5 mg Firmagon 240  80 mg Klotz L et al. BJU Int 2008;102:1531-8

68 -100 Median percentage change in Testosterone (%) Degarelix 240/160mg Degarelix 240/80mg Leuprolide 7.5mg days Firmagon – immediate testosterone reduction, no risk of clinical flare *P<0.001 Firmagon (both doses) versus leuprolide Klotz L et al. BJU Int 2008;102: T ng/ml T-6,3ng/ml

69 Firmagon – very low testosterone levels maintained over 1 year Median (± quartile) testosterone level over time Castration level 0 Median Testosterone (ng/ml) Degarelix 240/160mg Degarelix 240/80mg Leuprolide 7.5mg days Klotz L et al. BJU Int 2008;102: Med T – ng/ml vs 0.078

70 Firmagon - no testosterone microsurges 8 pts (4%)** 0> 0.25 ng/mL* Leuprolide 7.5 mg Firmagon 240  80 mg *Change: Day 3 and day 7 after 9th injection ** 4 pts with testosterone breakthrough (>0.5 ng/ml) Klotz L et al. BJU Int 2008;102:1531-8

71 Median percentage change in PSA (%) Firmagon – significantly faster reduction in PSA *P<0.001 versus leuprolide (Wilcoxon pairwise comparisons); 11% of leuprolide patients received bicalutamide as flare protection days Degarelix 240/160mg Degarelix 240/80mg Leuprolide 7.5mg Klotz L et al. BJU Int 2008;102: % - 18% -85% -68%

72 Two consecutive increases of more than 50% (at least >5.0 ng/mL) Firmagon 240/80 mg Leuprolide 7.5 mg No. of failures16 / / 201 Probability of PSA failure 8.9% ( %) 14.1% ( %) PSA failures Klotz L et al. BJU Int 2008;102:1531-8

73 Number at risk Firmagon Leuprolide Leuprolide 7.5 mg Firmagon 240/80 mg Probability (%) Time (days) PSA progression-free survival (time to PSA failure/death: ITT population) ITT, intent-to-treat; HR, hazard ratio HR=0.664; P= (log-rank test) Tombal B et al. EAU 2009; poster #38

74 CS21 adverse events *p<0.05, **p<0.01, and ***p<0.001 versus Firmagon pooled <1%***35%Injection site AEs 9%*5%Arthralgia Leuprolide 7.5 mg Firmagon 240  80 mg Chills Urinary tract infection Any AE 0%**5% 9%**5% 78%79%

75 Injection site reactions – predominantly with starter dose Klotz et al 2008 n% Firmagon 240  80 mg N % Maintenance dose(s) 32%Starter dose Any injection site reaction(s)

76 Musculoskeletal events FirmagonLeuprolide 7.5 mg Patients with localised disease Musculoskeletal and connective tissue disorders 20 (16%)16 (25%) Patients with locally advanced disease Musculoskeletal and connective tissue disorders 13 (10%)10 (19%) Back pain6 (5%)4 (8%) Arthralgia2 (2%) 7 (13%) Iversen P et al. CURy 2009; poster #618148

77 Patients with metastatic disease Musculoskeletal and connective tissue disorders 16 (21%)17 (36%) Back pain4 (5%) 6 (13%) Arthralgia4 (5%) 6 (13%) Pain in extremity1 (1%)4 (9%) Musculoskeletal events FirmagonLeuprolide 7.5 mg Iversen P et al. CURy 2009; poster #618148

78 FIRMAGON efficacy Fast testosterone suppression without a surge or micro-surges Fast testosterone suppression without a surge or micro-surges Fast and sustained PSA suppression Fast and sustained PSA suppression No need for flare protection No need for flare protection Lower risk of PSA failure Lower risk of PSA failure

79 FIRMAGON conclusions Incidence of adverse events similar with leuprolide Incidence of adverse events similar with leuprolide Related to androgen suppression Related to androgen suppression Higher incidence of injection site reactions and chills Higher incidence of injection site reactions and chills Lower incidence of urinary tract infections and musculoskeletal events Lower incidence of urinary tract infections and musculoskeletal events No immediate-onset systemic allergic reactions No immediate-onset systemic allergic reactions

80 Neoadjuvant + adjuvant Intermittent Options for short term treatment for Firmagon® Phase III studies ongoing

81 QUESTIONS Is firmagon the best castration therapy ? Is firmagon the best castration therapy ? What is the absolute minimal level of testosterone to effectively prevent prostate cancer growth (20 ng/ml) ? What is the absolute minimal level of testosterone to effectively prevent prostate cancer growth (20 ng/ml) ?


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