E. David Crawford, MD University of Colorado, Denver - PowerPoint Presentation

Slide1

E. David Crawford, MD

University of Colorado, DenverAurora, CO

Introduction and Current ADT ChallengesSlide2

Greetings from Colorado

Disclosures Consultant: MDxHealth, Myriad and Genomic Health,

Speaker: Ferring, Bayer, and Myriad Slide3

Faculty

Thomas E. Keane, M.D. Medical College of South CarolinaNeal D. Shore, M.D. Carolina Urologic Research CenterJehonathan H. Pinthus, M.D., PhD McMasterUniversity in Ontario Canada Slide4

Androgen Deprivation Therapy: Where we have come from

1780 John Hunter, castration1938 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 Degarelix2009 Abiraterone2010 Sawyer, enzalutamide Slide5

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 SyndromeSlide6

Hormone therapy side effects

Conditions

O

steoporosis

CV events

Side-effects

CV death

F

racture (SREs)

Complications

Bone loss

Sarcopenic obesitySlide7

Hormone Therapy Side Effects

What do the Guidelines say?Slide8

Are All Forms of ADT the Same?

Objectives:Decrease testosterone levelControl prostate cancer evolutionCardiovascular diseaseUrinary complications

Musculoskeletal complicationsSlide9

Cardiovascular DiseaseSlide10

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 30891

1

Immediate ADT

Delayed ADT

Total

94 (37)

99 (35)

193 (36)

88 (34)

97 (34)

185 (34)

75 (29)

88 (31)

163 (30)

SEUG 9401

2

Intermittent ADT

Continuous ADT

Total

74 (44)

65 (39)

139 (41)

41 (24)

52 (31)

93 (27)

55 (32)

52 (31)

107 (32)

1.

Studer,

et al. J Clin Oncol

2006;24:1868-76

2

. Calais da

Silva,

et al. Eur Urol

2009;55:1269–77Slide11

Oestrogen, CV Disease and Death

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%)

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

Veterans

Administration Co-operative

Urological Research

Group. Surg Gynecol Obstet

1967;124:1011-7Slide12

Large Observational Study Suggests Different Effects

of Different Types of ADT

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 ADT

Ref

Ref

Ref

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)

Keating,

et al

. J Natl Can Inst 2010;102:39–46

ADT, androgen deprivation

therapy

CAB

, combined androgen

blockade

CHD, coronary heart disease;

ref

, referenceSlide13

GnRH Agonists: FDA Warning

October 2010: US FDA asks manufacturers of GnRH agonists to add extra safety information to drug labelsIncreased risk of diabetes and certain CV diseases (heart attack, sudden cardiac death, stroke) in men with prostate cancerSlide14

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 Slide15

Overall survival

Very few patients died of prostate cancer over the year of the

study

1

Most men with prostate cancer die of other causes such as CVD

2,3

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

LH

RH, luteinising hormone-releasing hormoneSlide16

Urinary Symptoms and Complications

In PCa patients, enlargement of the prostate results in LUTS

50% of

PCa

patients suffer from moderate to severe symptoms

1

Neoadjuvant ADT reduces tumour volume and improves LUTS

1,2

IPSS is used as a tool to assess LUTS severity

3

Systematic review and meta-analysis4To assess the efficacy and tolerability of degarelix for LUTS relief, prostate volume reduction and quality of life improvement in men with prostate cancer3 RCT with 466 patients with degarelix vs goserelin + bicalutamide

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

IPSS

, International Prostate Symptom

Score

LUTS, lower urinary tract symptoms

PCa

, prostate cancerSlide17

LUTS Relief: A Meta-A

nalysis of Trials Comparing LHRH Antagonist with LHRH Agonists

Cui

Y, et al. Urol

Int 2014;93:152–9

SD, standard deviation

IV, inverse varianceSlide18

Lower Probability of Urinary Tract Events with

GnRH Antagonist vs LHRH Agonists (all patients)

Klotz L, et al. Eur Urol 2014 66:1101–8Slide19

Musculoskeletal events

Bone is the most common site of prostate cancer metastases and is associated with significant morbidity1Bone decay with ADT is associated with an increase in fracture risk2When treated with ADT, over 58% of men with risk factors for skeletal complications develop at least one fracture within 12

years

3

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;111:745–52Slide20

Lower Probability of Musculoskeletal Events with

GnRH Antagonists vs LHRH Agonists

Klotz L, et al. Eur Urol 2014 66:1101–8Slide21

Conclusion

Androgen deprivation therapy is associated with many side effects including an increased risk of CV events, particularly in those with a history of CVDCVD needs to be assessed and patients may need to be referred to cardiologistsLifestyle changes: aerobic exercise programme, smoking cessation, dietary changes, moderation of alcohol consumption also decrease riskMedical interventions

There is a variability of side effects related to the agents utilized-antagonists versus agonists