Introduction and Current ADT Challenges E. David Crawford, MD University of Colorado, Denver Aurora, CO

Greetings from Colorado Disclosures Consultant: MDxHealth, Myriad and Genomic Health, Speaker: Ferring, Bayer, and Myriad

Faculty Thomas E. Keane, M.D. Medical College of South Carolina Neal D. Shore, M.D. Carolina Urologic Research Center Jehonathan H. Pinthus, M.D., PhD McMaster University in Ontario Canada

Androgen Deprivation Therapy: Where we have come from 1780 John Hunter, castration 1938 Acid phosphatase 1940 Huggins, Orchiectomy and estrogen (Nobel Prize) 1965 Synthetic estrogens 1977 First generation non-steroidal anti-androgens 1989 2nd generation non-steroidal AA (bicalutamide) 1985 Schally, LHRH agonists (Nobel Prize) 2003 LHRH antagonist (abarelix) 2008 Degarelix 2009 Abiraterone 2010 Sawyer, enzalutamide

The Castration Syndrome Side Effects… Loss of libido and sexual interest, erectile dysfunction, impotence Fatigue Hot flushes Decline in intellectual capacity, emotional liability, depression Decrease in muscular strength Increase in (abdominal) fat apposition Osteoporosis Cardiovascular The Castration Syndrome

Hormone therapy side effects Conditions Side-effects Complications Bone loss Sarcopenic obesity CV events CV death Fracture (SREs) Osteoporosis

Hormone Therapy Side Effects What do the Guidelines say?

Are All Forms of ADT the Same? Objectives: Decrease testosterone level Control prostate cancer evolution Cardiovascular disease Urinary complications Musculoskeletal complications

Cardiovascular Disease

CVD is the Second Most Common Cause of Death in Men With Prostate Cancer Causes of death Prostate cancer n (%) CVD n (%) Other n (%) EORTC 308911 Immediate ADT Delayed ADT Total 94 (37) 99 (35) 193 (36) 88 (34) 97 (34) 185 (34) 75 (29) 88 (31) 163 (30) SEUG 94012 Intermittent ADT Continuous ADT 74 (44) 65 (39) 139 (41) 41 (24) 52 (31) 93 (27) 55 (32) 107 (32) 1. Studer, et al. J Clin Oncol 2006;24:1868-76 2. Calais da Silva, et al. Eur Urol 2009;55:1269–77

Oestrogen, CV Disease and Death 2,052 patients with stage I–IV prostate cancer treated using radical prostatectomy or orchiectomy with or without estrogen 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 Cause of death No oestrogen therapy (n=1,035) Received oestrogen therapy (1,017) Prostate cancer 149 (14.4%) 107 (10.5%) CV 90 (8.7%) 149 (14.7%) Pulmonary embolus 10 (1%) 11 (1.1%) Other 85 (8%) 91 (9.0%) Veterans Administration Co-operative Urological Research Group. Surg Gynecol Obstet 1967;124:1011-7

Myocardial infarction Large Observational Study Suggests Different Effects of Different Types of ADT Treatment Incident CHD Myocardial infarction Sudden cardiac death Stroke Adjusted HR (95% CI) No ADT Ref 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

GnRH Agonists: FDA Warning October 2010: US FDA asks manufacturers of GnRH 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 prostate cancer

Antagonists vs Agonists A number of phase III/IIIb trials have compared GnRH antagonists(degarelix) with a GnRH agonist Combining these data creates a comprehensive database in which to investigate CV safety outcomes What is the risk of CVD within 1 year of treatment with GnRH agonist and degarelix? Does pre-existing CVD increase the likelihood a patient will experience a CV event after initiating ADT? ADT, androgen deprivation therapy CVD, cardiovascular disease

Overall survival Very few patients died of prostate cancer over the year of the study1 Most men with prostate cancer die of other causes such as CVD2,3 Patients from CS37 were excluded (early disease and biochemical failure after primary definitive therapy) 1. Klotz L, et al. Eur Urol 2014;66:1101-8 2. Epstein MM, et al. J Natl Cancer Inst 2012;104:1335–42 3. Ketchandji M, et al. J Am Geriatr Soc 2009;57:24-30 CVD, cardiovascular disease LHRH, luteinising hormone-releasing hormone

Urinary Symptoms and Complications In PCa patients, enlargement of the prostate results in LUTS 50% of PCa patients suffer from moderate to severe symptoms1 Neoadjuvant ADT reduces tumour volume and improves LUTS1,2 IPSS is used as a tool to assess LUTS severity3 Systematic review and meta-analysis4 To assess the efficacy and tolerability of degarelix for LUTS relief, prostate volume reduction and quality of life improvement in men with prostate cancer 3 RCT with 466 patients with degarelix vs goserelin + bicalutamide IPSS, International Prostate Symptom Score LUTS, lower urinary tract symptoms PCa, prostate cancer 1. Mason M, et al. Clin Oncol 2013;25:190–6; 2. Axcona K, et al. BJU Int 2012;110:1721–8; 3. Stone NN, et al. J Urol 2010;183:634–639 4. Cui Y, et al. Urol Int 2014;93:152–9

LUTS Relief: A Meta-Analysis of Trials Comparing LHRH Antagonist with LHRH Agonists SD, standard deviation IV, inverse variance Cui Y, et al. Urol Int 2014;93:152–9

Lower Probability of Urinary Tract Events with GnRH Antagonist vs LHRH Agonists (all patients) Klotz L, et al. Eur Urol 2014 66:1101–8

Musculoskeletal events Bone is the most common site of prostate cancer metastases and is associated with significant morbidity1 Bone decay with ADT is associated with an increase in fracture risk2 When treated with ADT, over 58% of men with risk factors for skeletal complications develop at least one fracture within 12 years3 Men who sustained a fracture within 48 months experienced an almost 40% higher risk of mortality than those who did not 1. Coleman RE. Clin Cancer Res 2006;12:6243-9s 2. Cheung AS, et al. Endocr Relat Cancer 2014;21:R371–94 3. Shao YH, et al. BJU Int 2013;111:745–52

Lower Probability of Musculoskeletal Events with GnRH Antagonists vs LHRH Agonists Klotz L, et al. Eur Urol 2014 66:1101–8

Conclusion Androgen deprivation therapy is associated with many side effects including an increased risk of CV events, particularly in those with a history of CVD CVD needs to be assessed and patients may need to be referred to cardiologists Lifestyle changes: aerobic exercise programme, smoking cessation, dietary changes, moderation of alcohol consumption also decrease risk Medical interventions There is a variability of side effects related to the agents utilized-antagonists versus agonists