1. La terapia medica del carcinoma della prostata ed il rischio cardiovascolare Paolo Gontero Professore Associato Urologia Clinica Urologica, Università degli Studi di Torino Dir. Prof. Bruno Frea Città della Salute e della Scienza, Ospedale Molinette Torino

2. Introduction ADT pharmacotherapies: GnRH agonists and GnRH antagonists (antiandrogens) Hormonal therapies (estrogen receptor modulators, aromatase inhibitors and perhaps GnRH agonists) appear to have effect on cardiovascular system In cancer with favourable long-term survival (such as prostate) the weight of cardiovascular risk increases 2 GnRH, gonadotrophin releasing hormone LHRH, luteinising hormone releasing hormone 1. Shore ND, et al. Prostate Cancer Prostatic Dis 2013; 16: 7-15 2. Van Poppel H. Belgian J Med Oncol 2010; 4: 18–22

3. ADT (GnRH agonists) and cardiovascular risk INDIRECT MECHANISM DIRECT MECHANISM 3

4. INDIRECT MECHANISM Androgens increase and maintain muscle mass and reduce fat mass – AR present in adipose tissue – Activation of cAMP cascade could activate hormone-sensitive lipase leading to lipolysis – Androgens inhibit triglycerides uptake – Androgens mobilize lipids from the visceral fat AR on arteries have been documented (vasodilatation) ADT leads to: – Unfavorable changes in body composition (weight gain, loss of muscle mass, increased fat mass – Raising insulin levels as a consequence of increase in fat mass, ultimately leading to insulin resistance – Increase in arterial stiffness and endothelial dysfunction 4

5. Castration as a potent inducer of metabolic syndrome CondizioneHTNon HTp Sindrome metabolica55%20%0,03 Giro vita > 90 cm75%30%0,007 Glicemia a digiuno > 110 mg/dL65%30%0,006 TG ≥ 150 mg/dL55%20%0,06 HDL < 40 mg/dL35 %50%0,55 Ipertensione45%40%0,53 Braga-Basaria et al, J Clin Oncol 2006;24(24):3979-83 Metabolic changes under ADT HT= terapia ormonale

6. Incidence of metabolic sydrome and type II diabetes under ADT vs non ADT CaP vs controls Braga-Basaria et al. J Clin Oncol. 2006 24(24):3979-83. Metabolic changes under ADT Sindrome metabolica Diabete di tipo II Sindrome metabolica Diabete di tipo II

7. DIRECT MECHANISM Not clear whether cardiovascular risk is linked to loss of testosterone per se or the GnRH agonist itself GnRH binding sites found on the heart – May regulate cardiac contractility and intracellular calcium via a GnRH receptor/protein chinase A mechanism regulation calcium channels GnRH receptors on T-cells involved in atherosclerotic plaque stability 7

9. ADT and cardiovascular events: CONFLICTING CLINICAL EVIDENCES Some studies found significant association between ADT and cardiovascular events, some others have not Hypothesis: ADT potentiates preexisting cardiac risk factors, making them more evident during ADT therapy 9

10. ADT and cardiovascular events: clinical evidence in favor

11. Cause of death No oestrogen therapy (n=1,035) Received oestrogen therapy (1,017) Prostate cancer149 (14.4%)107 (10.5%) CV90 (8.7%)149 (14.7%) Pulmonary embolus10 (1%)11 (1.1%) Other85 (8%)91 (9.0%) 2,052 patients with stage I–IV prostate cancer treated using radical prostatectomy or orchidectomy with or without oestrogen – Survival significantly shorter in patients with stage I–III prostate cancer receiving oestrogens, but incidence of prostate cancer-related death reduced – Significant increase in deaths due to CV disease in patients treated with oestrogen 1967 Veterans Administration Co-operative Urological Research Group. Surg Gynecol Obstet 1967;124:1011-7 Oestrogen, CV disease and death 11

12. Androgen deprivation therapy with LHRH agonists increases risk of cardiac disease 12 73.196 patients with advanced CaP >30% treated with GnRH agonists or orchidectomy HR di 1.16 of CAD (p<0.001) HR di 1.11 of MI (p<0.03) HR di 1.16 of suddent cardiac death (p<0.004) HR di 1.44 of type II diabetes (p<0.01)

13. Increase risk of cardiovascular event associated with LHRH agonist, but not orchiectomy! 13 Keating NL, et al., JCO 2006; 24: 4448–56 Orchidectomy had higher risk of type II diabetes but NOT MI and CD

14. Majority of events occur within first year of therapy 14 Keating NL, et al., JCO 2006; 24: 4448–56

15. Large observational study suggests different effects of different types of ADT Observational study of 37,443 men with prostate cancer 39% received some form of ADT during follow-up, primarily LHRH agonists (37.5%)  Few were treated with orchiectomy (0.8%) or oral antiandrogen monotherapy (3.3%) at any time or CAB (4.9%) for >6 weeks at the start of LHRH agonist therapy Treatment Incident CHD Myocardial infarction Sudden cardiac death Stroke Adjusted HR (95% CI) Adjusted HR (95% CI) Adjusted HR (95% CI) Adjusted HR (95% CI) No ADTRef LHRH agonist 1.19* (1.10–1.28) 1.28* (1.08–1.52) 1.35* (1.18–1.54) 1.21* (1.05–1.40) Orchiectomy 1.40* (1.04–1.87) 2.11* (1.27–3.50) 1.29 (0.76–2.18) 1.49 (0.92–2.43) CAB 1.27* (1.05–1.53) 1.03 (0.62–1.71) 1.22 (0.85–1.73) 0.93 (0.61–1.42) Antiandrogen 1.10 (0.80–1.53) 1.05 (0.47–2.35) 1.06 (0.57–1.99) 0.86 (0.43–1.73) ADT, androgen deprivation therapy CAB, combined androgen blockade CHD, coronary heart disease; ref, reference Keating, et al. J Natl Can Inst 2010;102:39–46 *p<0.05 15

16. ADT and cardiovascular events: clinical evidence against

17. EORTC 22961; Bolla et al - Prospective randomised - Radioterapy + 6 months ADT vs 3 years ADT in patients with locally advanced CaP (n=970) Deaths: 132 in short term group 98 in long term group No significant difference in fatal CV events at 5 y f.u. (4.0% vs 3.0%) Patients treated with ADT for 6 months had a lower survival than patients treated with 3 years ADT Bolla M, de Reijke TM, Van Tienhoven G, et al. EORTC Radiation Oncology Group and Genito-Urinary Tract Cancer Group. Duration of androgen suppression in the treatment of prostate cancer. NEJM. 2009; 360: 2516-2527.

18. ADT and cardiovascular risk Summary  Proven impact on standard CV risk factor  Proven impact on CV events  Disputable effect of CV death Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology Levine et al. Circulation 2010; 121;833-40

19. LHRH agonists: FDA warning October 2010: US FDA asks manufacturers of LHRH agonists to add extra safety information to drug labels – Increased risk of diabetes and certain CV diseases (heart attack, sudden cardiac death, stroke) in men with PCa 19 US FDA, United States Food and Drug Administration

20. 20 234.198 patients with non-metastatic CaP Contemporary (between 1995-2009) 140.474 after excluding previous CV disease 29.984 on ADT and 29.984 ADT-naive after propensity score matching Events: CAD, AMI and SCD

21. 21 PROTECTIVE EFFECT OF ORCHIDECTOMY: -GnRH agonists direct control on cardiac contractility -GnRH receptors trigger atherosclerotic plaque rupture mediated by T-cells

22. GnRH antagonist (degarelix) treatment: Analysis of CV events 22 Smith et al J Urol 186:1835-1842, 2011 QUESTION: Do GnRH antagonists carry the same risk of CV disease as LHRH agonists?

23. Pooled patient population 23 12-month phase III trials 3-month phase IIIB trials CS28 Degarelix 240/80 mg; n=27 Goserelin 3.6 mg; n=13 CS30 Degarelix 240/80 mg; n=181 Goserelin 3.6 mg; n=64 CS35 Degarelix 240/480 mg; n=565 Goserelin 3.6/10.8 mg; n=283 CS21 Degarelix 240/80 mg; n=207 Degarelix 240/160 mg; n=202 Leuprolide 3.6 mg; n=201 CS37 Degarelix 240/80 mg; n=175* Degarelix 240/80 mg; n=50 Leuprolide 3.6 mg; n=178 CS31 Degarelix 240/80 mg; n=83 Goserelin 3.6 mg; n=98 *Patients received 7 months of treatment

24. Pooled patient population The pooled database comprised 2328 patients 1686 patients received 12 months and 642 patients 3-7 months of treatment 1491patients received degarelix and 837 patients an LHRH agonist Of the 2328 patients, 707 had pre-existing CVD Data classified according to the MedDRA system 24 MedDRA, medical dictionary for regulatory activities

25. Selected baseline demographics relating to CV risk 25 Variable Degarelix n=1491 LHRH agonist n=837 Age (yrs) 71.771.6 Body mass index BMI >30, n (%) 27.2 334 (22) 27.5 200 (24) History of cardiovascular disease, n (%) 463 (31)244 (29) Smoking, n (%) 724 (49) 437 (52) Alcohol, n (%) 839 (56)452 (54) Elevated blood pressure, n (%) 493 (33)276 (33) Cholesterol >6.2 mmol/L, n (%) 191 (13)83 (10) Statin medication, n (%) 388 (26)224 (27) Diabetes, n (%) 238 (16)139 (17) Albertsen P, et al., Eur Urol 2014

26. Results: Overall incidence of CV events A serious CV event was an event considered life-threatening or that required hospitalization 26 Degarelix, n (%) n=1491 LHRH agonist, n (%) n=837 Any CV event 40 (2.7)37 (4.4) Serious CV event 25 (1.7)24 (2.9) Albertsen P, et al., Eur Urol 2014

27. Risk of CV event or death (all patients) 27 Albertsen P, et al., Eur Urol 2014

28. Risk of CV event or death in men with no baseline CVD 28 Albertsen P, et al., Eur Urol 2014

29. Risk of CV event or death in men with baseline CVD 29 Albertsen P, et al., Eur Urol 2014

30. Risk of a serious CV event or death in men with baseline CVD 30 Tombal B, et al. EAU 2013; Poster 677

31. Pooled analysis: summary When treated with degarelix compared with a LHRH agonist, patients with pre-existing CVD: – Had significantly fewer CV events during the first year of treatment – Had a relative risk reduction of 56% (absolute risk reduction 8.2) – Number needed to treat = 12 What kind of mechanism can explain this? CVD, cardiovascular disease Albertsen, et al. Eur Urol 2014:65;565-73 31

32. Potential mechanisms for differences in CV risk with different forms of ADT Differences in CV risk could be due to differences in the effect of different ADTs on: 1.Metabolic changes 2.GnRH receptor activation 3.FSH receptor activation 32

33. Lipid core Fibrous cap Lumen Fibrous cap Lipid core Vulnerable plaque Plaque instability is at the heart of cardiovascular disease Stable plaque Libby. Circulation. 1995;91:2844-50 ThickCapThin Rich in SMC and matrixCompositionRich in inflammatory cells: proteolytic activity PoorLipidRich Less inflammatoryInflammatory stateMore inflammatory 33

34. T lymphocytes are key drivers of collagen metabolism in atherosclerotic plaques T Ly Disruption of the fibrotic cap Increased risk of thrombo-embolic complications and cardiovascular disease Plaque instability Libby. Lipid Res 2009;50:S352-S357 34

35. T cells express GnRH receptors: agonists and antagonists have different effects T cells GnRH-R GnRH or LHRH agonist Increased proliferation and activity Fibrotic cap disruption and plaque instability T cells GnRH-R GnRH antagonist Increased proliferation and activity Maintain plaque stability Chen, et al. J Clin Endocrinol Metab 1999;84:743-50 Tanriverdi, et al. Clin Exp Immunol 2005;142:103-10 Grasso, et al. Life Sci 1998;62:2005-14; Jacobson, et al. Endocrinol 1994;134:2516-23 IFN, interferon 35

36. Preclinical study of differences between leuprolide, degarelix and orchiectomy FSH and LH levels were significantly lower with degarelix than leuprolide – FSH may have a role in adipogenesis Weight gain and fat mass were significantly greater with leuprolide than controls Significantly lower triglyceride levels and better glucose tolerance were observed with degarelix Atherosclerotic plaque surface area smaller with degarelix than with leuprolide or orchiectomy Pinthus, Klotz, et al. 2014 Hamilton, et al. EAU 2014 (Poster 308 ) a p<0.05 vs control; b p<0.05 vs orchiectomy; c p<0.05 vs leuprolide 12 10 8 6 4 2 0 Total plaque area (% of total) Necrotic plaque area (% of total) 2 1 0 ControlOrchiectomyLeuprolideDegarelix a a bc a a 36

37. ADT: mechanism of action in relation to CV risk LHRH agonist GnRH antagonist X X X FSH, follicle-stimulating hormone LH, luteinising hormone Inhibition of GnRH receptors Stimulation of GnRH receptors Potential for LHRH agonists to have a plaque destabilising effect due to T cell stimulation Prolonged suppression of FSH, LH and testosterone FSH suppression not maintained long term Increased potential for metabolic syndrome and atherogenesis with LHRH agonist therapy DegarelixLHRH agonists Rapid suppression of FSH, LH and testosterone Initial surge in FSH, LH and testosterone No microsurges Microsurges on repeat injection Unlikely that testosterone suppression can explain differences in risk 37

38. Management of patients under ADT Potential risk on cardiovascular events must be weighted with benefits of ADT Identify and warn men with CV comorbidity and significant CV risk factors Screen for pre-existing risk factors of CV toxicity prior to initiation of ADT 38 Levine GN, Cyrculation 2010

39. How to manage patients needing ADT Prior to initiation of ADT: – Abdominal perimeter, blood pressure – Fasting glucose, LDL, HDL, colesterol, triglicerides, PCR Repeat tests every 3 months for the first year Encourage healthy lifestyle – Low-fat diet, exercise, smoking cessation… – Treat diabetes, hyperlipidemia, hypertension 39 Levine GN, Cyrculation 2010

41. Conclusions ADT is likely to increase the risk of CV events Patients with preexisting CV risk factors are more exposed Since CV events occurs as early as 3 months, it is important to carry initial evaluation of cardio-metabolic and glycemic profile within 3-6 months after initiation of ADT, above all in patients with preexisting CV risk factors 41 Conteduca V, Critical Rev Oncol Hematol 2013