1. Francesco Massari U.O.C. di Oncologia Medica dU Azienda Ospedaliera Universitaria Integrata Università di Verona Androgen suppression strategies for prostate cancer

2. History of hormone therapy in prostate cancer 1941 1970 Huggins has shown that surgical castration is effective in the treatment of CaP and therapy with estrogen (DES; dietilstilbestrolo) inhibits the growth of CaP Medical castration was studied Treatment with estrogen (DES) demonstrated comparable efficacy to castration in the treatment of CaP, but with important cardiovascular side effects Shally demonstrated that treatment with GnRH agonists inhibits tumor growth of CaP 1977 1982 Andrew Schally Nobel 1977 Charles Huggins Nobel 1966 1985-9 Today, GnRH agonists are still the predominant form of androgen deprivation therapy (ADT) Leuprorelin and goserelin, GnRH agonists, are introduced as a treatment of CaP

3. HORMONE THERAPY ORCHIECTOMY ESTROGEN THERAPY AGONIST GnRH ANTIANDROGEN GnRH ANTAGONIST

4. GnRH agonist

5. Brawer MK, Rev Urol, 2001 GnRH Agonist: biphasic mechanism of action ↑LH, ↑FSH, ↑T ↓LH, ↓T, ↑FSH Step 1 Step 2

6. GnRH agonist vs orchidectomy Patients prefer injections to surgery Testosterone suppression is reversible 22% (n=32) 78% (n=115) 0 20 40 60 80 100 GoserelinOrchidectomy Patients’ preference Cassileth BR, et al. Qual Life Res 1992; 1: 323–330 Kaku H, et al. The Prostate 2006; 66: 439–444 GnRH agonist efficacy is similar to orchidectomy

7. Suppression of testosterone after withdrawal of treatment with agonists Testosterone levels (ng/mL) BF = before therapy with LHRHa T 2.9–10.7 mg/mL 3M vs. basal (BL): P=0.0034 Kaku H, et al. The Prostate 2006; 66: 439–444

8. ANTIANDROGENS

9. ANTIANDROGENS CLASSIFICATION Antiandrogens are classified on the basis of their chemical structure, in: - Steroid Antiandrogens (acetate ciproterone) - Non steroid Antiandrogens (Bicalutamide, Flutamide, Nilutamide)

10. Hypotalamus Pituitary gland Testicle Adrenal gland T Androgen target cell DHT Nucleus 5-  -reduttasi Synthesys of proteins, enzymes, etc... Testosterone (T) LH LHRH Adrenal Androgeng Steroid Antiandrogens: mechanism of action Steroid antiandrogens BLOCKADE 1.Compete with testosterone and DHT in binding to receptors in the nucleus of prostate cells by promoting apoptosis and inhibiting the growth of CaP. 2.Block gonadotropin secretion

11. Androgen target cell Hypotalamus Pituitary gland Testicle Adrenal gland T DHT Nucleus 5-  -reduttasi Synthesys of proteins, enzymes, etc... Testosterone (T) LH LHRH BLOCKADE Adrenal Androgeng Antiandrogens 1.Compete with testosterone and DHT in binding to receptors in the nucleus of prostate cells by promoting apoptosis and inhibiting the growth of CaP. 2.Do not block gonadotropin secretion and therefore testosterone levels do not drop, but remain normal and may even slightly increase. Non-Steroid Antiandrogens: mechanism of action

12. Permanent association of LHRH and antiandrogen MAB (Maximal Androgen Blockade)

13. New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen. Clin Invest Med. 1982;5(4):267-75. F. Labrie, maximal (complete) androgen blockade

14. Schmitt B. et al., Maximal androgen blockade for advanced prostate cancer (Cochrane database – 2009) Samson D. et al., Systematic review and metanalysis of monotherapy compared with combined androgen blockade for patients with advanced prostatic cancer (Cancer – 2002) MAB  EVIDENCES - METANALYSES

15. 21 trials comparing survival (n= 6871 patients) 2 years survival (20 trials)  NO SIGNIFICANT IMPROVEMENT 2 years survival (10 trials)  MODEST SIGNIFICANT DIFFERENCE IN FAVOR OF MAB MAB  METANALYSES SAMSON

16. MAB produces a modest overall and cancer-specific survival at five years but is associated with increased adverse events and reduced quality of life MAB  METANALYSES SCHMITT 2009

17. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials Prostate Cancer Trialists’ Collaborative Group Lancet 2000; 355: 1491-98 36 studies 31 studies 27 studies relevant eligible for analysis Evaluable (8275 patients)

18. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials With NON-STEROIDAL antiandrogens, there was a significant 8% reduction in the risk of death (p= 0.005) With STEROIDAL antiandrogens there was a significant 13% increase in the risk of death (p= 0.04) PCTCG meta-analysis (n= 8275) 5-year survival favoured MAB (25.4% vs. 23.6%) Lancet 2000; 355: 1491-98

19. MAB with NON-steroidal antiandrogen

20. Use intermittent administration of LHRH agonists IAD (Intermittent Androgene Deprivation)

21. Intermittent androgen deprivation (IAD): Phase II studies StudyYearNCyclesOff (month) Akakura19937LHRH42 -11 Goldemberg199547CAB210 Higano199622CAB36 Tuun199620CAB29 Oliver199720CAB29 – 42 Theyer199723CAB17 Horwich199816LHRH28 Bruchowsky1998110CAB19 Crook19994CAB58.8 Strum200019CAB315.5 Grossfeld200127CAB59 De La Taille200374CAB1 - 810

22. 626 randomised for continuous vs intermittent  50% patients off therapy for > 52 weeks  20% patients off therapy for > 36 weeks No difference in overall survival Intermittent ADT was associated with fewer side effects and better sexual activity Phase III IAD: SEUG trial Da Silva et al., European Urology 55 (2009)

23. Phase III IAD: SEUG trial

24. In conclusion, IAD is at present widely offered to patients with prostate cancer in various clinical settings, and its status should no longer be regarded as investigational

27. Intermittent P = 0.7 Continous Overall Survival

28. No difference in progression-free survival No difference in overall survival No difference in adverse events 88% of patients off therapy on intermittent arm for more than 50% of time There are now 4 RCT’s with a total of >1000 patients randomized that support non-inferiority of intermittent ADT for PFS and overall survival Summary

32. Maha Hussain, Catherine M. Tangen, Celestia S. Higano, E. David Crawford, Glenn Liu, George Wilding, Stephen Prescott, Atif Akdas, Eric Jay Small, Nancy Ann Dawson, Bryan J Donnelly, Peter Venner, Ulka N. Vaishampayan, Paul F. Schellhammer, David I. Quinn, Derek Raghavan, Nicholas J. Vogelzang, Ian Murchie Thompson J Clin Oncol 30, 2012 (suppl; abstr 4) Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial.

33. The trial accrued 3,040 patients with newly diagnosed hormone-sensitive metastatic prostate cancer between 1995 and 2008. Noninferiority Design  The trial was designed to assess whether overall survival (OS) with IAD was noninferior to CAD The design of the trial specified that survival with IAD would be noninferior to CAD if the 95% confidence interval for the hazard ratio (HR; IAD versus CAD) excluded 1.2 ADT: risk and benefits M. Hussain, J Clin Oncol 30, 2012 (suppl; abstr 4)

34. Overall Survival The mean OS was 5.8 years for patients receiving CAD and 5.1 for patients receiving IAD, representing a 9% increase in relative risk of death for IAD (HR 1.09, 95% CI [0.95 - 1.24]).

35. Because the upper limit of the CI did not exclude 1.2, the noninferiority criterion was not met. M. Hussain, J Clin Oncol 30, 2012 (suppl; abstr 4)

36. Loss of libido and sexual interest, erectile dysfunction, impotence Fatigue Hot flushes Decline in intellectual capacity, depression Decrease in muscular strenght Increase in (abdominal) fat apposition Decline in physical activity and general vitality Osteoporosis Cardiovascular diseases Side-effects of hormonal therapy

37. ADT is associated with an increased risk of multiple side effects (may reduce QoL and/or OS) Osteoporosis, obesity, sarcopenia, lipid alterations, insuline resistence, increased risk of diabetes and cardiovascular morbidity Lifestyle interventions, especially in setting with the highest risk-benefit ratio,to alleviate comorbidites ADT: risk and benefits Isbarn H, Eur. Urol 2008

38. ADT and cardiovascular events D'Amico, A. V. et al. J Clin Oncol; 25:2420-2425 2007

39. ADT and cardiovascular death Tsai, H. K. et al. J. Natl. Cancer Inst. 2007 99:1516-1524

40. GnRH Antagonist: a new pharmacological class for the treatment of advanced prostate cancer hormone- sensitive

41. ↓LH, ↓FSH, ↓T GnRH Antagonist : mechanism of action GnRH receptor blockade Brawer MK, Rev Urol, 2001

42. Mechanism of GnRH receptor blocking direct Immediate Action with rapid suppression of testosterone No initial stimulation of pituitary GnRH receptor and therefore no initial transient increase in testosterone Degarelix: mechanism of action Degarelix Princivalle M et al. J Pharmacol Exp Ther 2007; 320: 1113-1118

43. Binding of degarelix with the GnRH receptors is stronger and more durable than that of GnRH agonists GnRH receptors

44. Dosage of CS21 Degarelix 240 mg (2 x 3 ml s.c.) Day 0 Attack Dose Day 28-364 Maintenance Dose Leuprolide 7,5 mg (i.m.) Degarelix 160 mg (1 x 4 ml s.c.) Degarelix 80 mg (1 x 4 ml s.c.) Leuprolide 7,5 mg (i.m.)* Monthly dosing: a total for each patient were administered 12 doses. Inspections: Day 0, 1, 3, 7, 14, 2856, +28…364 Other visits after day 3 and day 7 subsequently at 9 th administration * Administration of antiandrogens at the discretion of the investigator N = 610 patients (ITT) Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

45. CS21: End-points Primary End-point: Probability of testosterone ≤ 0.5 ng / ml at all monthly measurements from day 28 to day 364 Secondary end-points: Percentage of patients with initial transient increase in testosterone Percentage of patients with testosterone ≤ 0.5 ng/ml on day 3 (miniflare) Percentage change in PSA from baseline at day 28 and time to PSA failure Frequency and severity of adverse events Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

46. Degarelix is not inferior in inducing suppression of testosterone <0.5 ng / ml for 1 year Success criteria Degarelix 240  160 mg Degarelix 240  80 mg Leuprolide 7,5 mg Responders to therapy 199202194 % response FDA: IC ≥90% 98,3 % (94,8-99,4 %) 97,2 % (93,5-98,8 %) 96,4 % (92,5-98,2 %) Difference compared to leuprolide EMEA: IC ≥-10 percentage points 1,9 % (da –1,8% a 5,7%) 0,9 % (da –3,2% a 5,0%) Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

47. Degarelix: immediate reduction of testosterone levels Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

48. Degarelix: faster suppression of testosterone Patients (%) with testosterone levels ≤ 0.5 ng/ml during the first month of treatment *p <0,001 (vs leuprolide) Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

49. Degarelix: maintaining low levels of testosterone for 1 year Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

50. Degarelix: no miniflare of testosterone Miniflare of testosterone* Variazione: days 3 e 7 after 9 th administration Degarelix 240  160 mg Degarelix 240  80 mg Leuprolide 7,5 mg >0,25 ng/ml008 (5%)* * Increased testosterone> 0.25 ng / ml detected in any two measurements at 3 and 7 days after drug administration Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

51. Degarelix: faster reduction of PSA *p <0,001 vs leuprolide; 11% of patients in the leuprolide group receiving bicalutamide as anti-flare therapy Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

52. Degarelix: faster suppression of PSA; maintaining value for one year Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

53. PSA failure during first year of therapy PSA failure* Degarelix 240  160 mg Degarelix 240  80 mg Leuprolide 7,5 mg N. Patients with PSA failure 26/ 20216/ 20726/ 201 Probability of PSA failure 14,2% (9,9-20,2%) 8,8% (5,5-14,0%) 14,1% (9,8-20,1%) *Two consecutive increases >50% (≥5,0 ng/ml) Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

54. Progression free survival (time to PSA failure/death – all patients) Leuprolide 7,5 mg Degarelix 240/80 mg 100 95 90 85 80 Probability (%) Time (days) 0285684112140168196224252280308336364 Degarelix 80 mg vs leuprolide HR= 0,664; IC 95% 0,385, 1,146; p = 0,0495 (log-rank) Tombal M et al, poster EAU 2009

55. CS21: adverse events Degarelix 240  160 mg Degarelix 240  80 mg Degarelix both doses Leuprolide 7,5 mg Adverse events83%79%81%78% Injection site reaction44%35%40%<1%*** Flushing26% 21% Increase weight11%9%10%12% Lumbar pain6% 8% Artrhalgia3%5%4%9%* Hypertension7%6% 4% Affaticamento6%3%5%6% Urinary tract infection1%5%3%9%** Nausea5%4%5%4% Constipation3%3%5%4%5% Hypercolesterolemia6%6%3%5%2% Chills3%5%4%0%** *p <0,05, **p <0,01 e ***p <0,001 vs degarelix a both doses Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

56. GnRH agonists are used successfully as androgen deprivation therapy, but have some limits:  Initial transient increase in testosterone with consequent delay of castration  Exacerbation of clinical symptoms (flare-up)  Miniflare e breakthrough  Adverse events CONCLUSIONS

57. GnRH Antagonist have a mechanism for blocking direct receptor:  Immediate reduction in PSA and testosterone  Low levels of PSA and testosterone, maintained over time No need of anti-flare therapy CONCLUSIONS