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

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

3. 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

4. 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

5. 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

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

7. Hormone Therapy Side Effects
What do the Guidelines say?

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

9. Cardiovascular Disease

10. 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
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: Calais da Silva, et al. Eur Urol 2009;55:1269–77

11. 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

12. 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

13. 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

14. 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

15. 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: 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

16. 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– Cui Y, et al. Urol Int 2014;93:152–9

17. 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

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

19. 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

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

21. 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