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Francesco Massari

Androgen suppression strategies for prostate cancer. Francesco Massari. U.O.C. di Oncologia Medica dU Azienda Ospedaliera Universitaria Integrata Università di Verona. History of hormone therapy in prostate cancer. 1941.

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Francesco Massari

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

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

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

  4. GnRH agonist

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

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

  7. Suppression of testosterone after withdrawal of treatment with agonists 3M vs. basal (BL): P=0.0034 Testosterone levels (ng/mL) BF = before therapy with LHRHa T 2.9–10.7 mg/mL 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. Steroid Antiandrogens: mechanism of action Hypotalamus • Compete with testosterone and DHT in binding to receptors in the nucleus of prostate cells by promotingapoptosis and inhibiting the growth of CaP. • Blockgonadotropinsecretion Steroid antiandrogens LHRH Pituitary gland LH Adrenal gland Testicle Adrenal Androgeng Testosterone (T) T 5--reduttasi DHT Synthesys of proteins, enzymes, etc... BLOCKADE Androgen target cell Nucleus

  11. Non-Steroid Antiandrogens: mechanism of action • Compete with testosterone and DHT in binding to receptors in the nucleus of prostate cells by promotingapoptosis and inhibiting the growth of CaP. • 2. Do notblockgonadotropinsecretion and therefore testosterone levels do notdrop, butremainnormal and mayevenslightlyincrease. Hypotalamus Antiandrogens LHRH Pituitary gland LH Adrenal gland Testicle Adrenal Androgeng Testosterone (T) T 5--reduttasi DHT Synthesys of proteins, enzymes, etc... BLOCKADE Androgen target cell Nucleus

  12. Permanent association of LHRH and antiandrogen MAB (MaximalAndrogenBlockade)

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

  14. MAB  EVIDENCES - METANALYSES • 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)

  15. MAB  METANALYSES SAMSON • 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

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

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

  18. 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) Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials PCTCG meta-analysis (n= 8275) 5-year survivalfavoured MAB (25.4% vs. 23.6%) Lancet 2000; 355: 1491-98

  19. MAB with NON-steroidal antiandrogen MAB with NON-steroidal antiandrogen Lancet 2000; 355: 1491-98

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

  21. Intermittentandrogendeprivation (IAD): Phase II studies

  22. Phase III IAD: SEUG trial • 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 Da Silva et al., EuropeanUrology 55 (2009)

  23. Phase III IAD: SEUG trial Da Silva et al., European Urology 55 (2009)

  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

  25. OverallSurvival Continous Intermittent P = 0.7

  26. Summary • Nodifference in progression-freesurvival • Nodifference in overallsurvival • Nodifference in adverseevents • 88% ofpatients off therapy on intermittent arm formorethan 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

  27. 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. 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)

  28. ADT: risk and benefits • 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 M. Hussain, J Clin Oncol 30, 2012 (suppl; abstr 4)

  29. 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]). M. Hussain, J Clin Oncol 30, 2012 (suppl; abstr 4)

  30. 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)

  31. Side-effects of hormonal therapy • 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

  32. ADT: risk and benefits • 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 Isbarn H, Eur. Urol 2008

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

  34. ADT and cardiovasculardeath Tsai, H. K. et al. J. Natl. Cancer Inst. 2007 99:1516-1524

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

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

  37. x x Degarelix: mechanism of action • 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 Princivalle M et al. J Pharmacol Exp Ther 2007; 320: 1113-1118

  38. GnRH receptors Binding of degarelix with the GnRHreceptorsisstronger and more durablethanthat of GnRHagonists

  39. Dosage of CS21 N = 610 patients (ITT) Day 0 Attack Dose Day 28-364 Maintenance Dose Degarelix 160 mg (1 x 4 ml s.c.) Degarelix 240 mg (2 x 3 ml s.c.) Degarelix 80 mg (1 x 4 ml s.c.) Leuprolide 7,5 mg (i.m.) Leuprolide 7,5 mg (i.m.)* Monthly dosing: a total for each patient were administered 12 doses. Inspections: Day 0, 1, 3, 7, 14, 28 56, +28…364 Other visits after day 3 and day 7 subsequently at 9th administration *Administration of antiandrogens at the discretion of the investigator Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

  40. 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

  41. Degarelix is not inferior in inducing suppression of testosterone <0.5 ng / ml for 1 year Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008

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

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

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

  45. Degarelix: no miniflare of testosterone * 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

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