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Bad to the bones: treatments for breast and prostate cancer

Richard Eastell, MD FRCP (Lond, Edin, Ireland) FRCPath FMedSci,Professor of Bone Metabolism,

University of Sheffield,Sheffield, UK

12th Annual Osteoporosis: New Insights in Research, Diagnosis, and Clinical Care23rd July 2015

E-mail r.eastell@sheffield.ac.uk

www.shef.ac.uk/aubm

Conflicts of Interest

• Research funding, consulting and honoraria from– Novartis

– Amgen

– AstraZeneca

– Pfizer

– Warner Chilcott

– Sanofi

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Bad to the bones: treatments for breast and prostate cancer: outline

• What treatments?

• How are they used?

• What is their effect on bone?– Fracture risk

– Bone mineral density

• Can the effects on bone be prevented?

• Approach to the patient

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Aromatase Inhibitors

What are they?

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Androstenedione Estrone

Testosterone Estradiol Estrogen ER-receptor mediated

effects

Aromataseinhibitors

(Anastrozole,Letrozole,Exemestane)

SERMs(Raloxifene,Tamoxifen)

Aromatase 17-HSD

DNACell

proliferation

Oestrogen Action on Breast Cancer Cells

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Premenopausalwomen

Postmenopausalwomen

Normalmen

0

40

80

120

160

200

AI

Bio

avai

lab

le E

2, p

mo

l/L

Bioavailable Oestradiol Concentrations

Khosla S, et al. J Clin. Endocrinol. Metab. 2001;86:3555-61.

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Aromatase Inhibitors

How are they used?

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Uses of Aromatase Inhibitors

• Current– Neoadjuvant therapy– Adjuvant therapy– Advanced breast cancer

• Recent– Prevention of breast cancer– Sequential therapy with tamoxifen

• Other uses– Gynaecomastia, precocious puberty, induction

of ovulation

Smith and Dowsett, New England Journal of Medicine 2003;348:2431-42

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Control (EBCTCG)

Tamoxifen (EBCTCG)

Anastrozole (ATAC)

Tamoxifen (ATAC)

Years

Estimated proportion of receptor-positivepatients withoutrecurrence (%)

100

80

00 1 2 3 4 5+

90

70

92.2% ATAC4-year recurrence-free rate:

89.6% ATAC

Comparison with Early Breast Cancer Trialists’CollaborativeGroup (EBCTCG): receptor-positive patients >50 years

84.6% EBCTCG

70.5% EBCTCG

Effect of Aromatase Inhibitors on Breast Cancer RecurrenceOxford Overview

EBCTCG. Lancet 1998; 351: 1451–1467

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-10 -5 0 5 10

Difference between anastrozole and tamoxifen AEs, %

(-5.4%)

(-1.8%)

(-3.6%)

(-8.6%)

(-1.1%)

(-1.4%)

(-0.7%)

Fractures of hip,spine, wrist

Fractures

MSK disorders

(-0.4%)

In favour of anastrozole

Hot flushes

Weight gain*

Vag. bleeding

(6.6%)

(2.1%)

(0.8%)

Endo CaICVA

VTE

DVT

Vag. discharge

In favour of tamoxifen

*Proportion with 10% gain in body weight from baseline to year 2Buzdar, et al. San Antonio Breast Cancer Symposium, 2002.

Significant Differences in Predefined Adverse Events

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Aromatase Inhibitors

What is their effect on bone?Fracture risk

Bone mineral density

Bone turnover markers

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YearsAnastrozoleTamoxifen

030923094

129232932

227242741

325532579

423932401

520702100

6845846

Number at risk

0

0.5

1

1.5

2

2.5

3

1 2 3 4 5 6

Years since randomisation

*Calculated using Kaplan-Meier estimates

An

nu

al r

ates

, %

*

Anastrozole Tamoxifen

0

ATAC 68-month analysis: Annual fracture rates over time

Buzdar A, et al. Lancet Oncol 2006 Aug;7(8):633-43.

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ATAC Trial: types of fracture1

*p<0.05; ***p<0.0001

Fractures

Hip

Spine

Wrist

Others

Total

Anastrozole

37

45

72

220

340

Tamoxifen

31

27

63

142

237

Odds ratio

1.20

1.68*

1.15

1.59***

1.49***

1ATAC Trialists Group. Lancet 2005;365:60-62.

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Bone Mineral Density (BMD) of the Spine and Total Hip by Dual Energy X-ray Absorptiometry (DXA)

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BMD % change over timeATAC, Patients with data at baseline, 1, 2 and 5 years

• Statistically significantly more BMD loss on anastrozole than tamoxifen (p<0.0001 for both lumbar spine and total hip BMD primary analysis)

Lumbar spine Total hipEstimated % change (mean and 95% CI)

Time (years) Time (years)

4

2

0

-2

-4

-6

-8

-10Baseline 1 2 5

4

2

0

-2

-4

-6

-8

-10Baseline 1 2 5

Tamoxifen

Anastrozole

Eastell R, et al. J Clin Oncol 2008; 26(7):1051-7

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0 1 2 3 4 5 6 7 Yr.

43210-1-2-3-4-5-6-7-8

x

x

% changeIn BMD from baseline

Anastrazole (ATAC)

Tamoxifen (ATAC) Tamoxifen (IES)

Exemestane (IES)

x x

x

x xLetrozole (MA-17)

Placebo (MA-17)

x

ATAC IES MA-17

x

Immediate Switch Extended

Influence of Different AromataseInhibitor Strategies on BMD

Coleman R, et al. Lancet Oncology 2007

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Effect of Aromatase Inhibitors on Bone

• Increase fracture risk by up to 60%

• Accelerate bone loss to a rate of 1 to 2% per year– Effect is similar, year on year

• Increase bone turnover by 10 to 40%– Similar effect with all aromatase inhibitors

• When they are stopped– Fracture risk decreases

– BMD increases

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Aromatase Inhibitors

Can the effects on bone be prevented?

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Risedronate Prevents AI-induced Bone Loss: the SABRE Study

Van Poznak C…Eastell R. J Clin Oncol. 2010 Feb 20;28(6):967-75

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Risedronate Prevents AI-induced Bone Loss: the SABRE Study

Van Poznak C…Eastell R. J Clin Oncol. 2010 Feb 20;28(6):967-75

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IBIS-II bone study designSestak I…Eastell R. Lancet Oncol. 2014 Dec;15(13):1460-8

N=1410

Stratum III‐4.0≤T‐score≤ ‐2.5All on risedronate

N=149

Stratum II‐2.5<T‐score<‐1.0

N=500

Stratum IT‐score≥ ‐1.0No treatment

N=761

AN=378

PN=383

A/RN=73

P/RN=76

P/PN=124

P/RN=116

A/PN=123

A/RN=137

FUP

DXA

X X X X X X

X X X X X

B 6M 12M 24M 36M 60M 84M

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IBIS-II bone study 3-year resultsSestak I…Eastell R. Lancet Oncol. 2014 Dec;15(13):1460-8

Risedronate

Placebo

‐5‐4

‐3‐2

‐10

12

34

B 12M 36M

Mean % BMD change (%)

‐2.6%

1.1%

P<0.0001

Osteopenic women (stratum II) all on anastrozole: Risedronate vs. Placebo

01

23

45

B 12M 36M

Mean % BMD change (%)

1.2%

3.9%

P=0.006

Anastrozole

Placebo

Osteoporotic women (stratum III) all on risedronate: Anastrozole vs. Placebo

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Aromatase Inhibitors

Approach to the patient

www.shef.ac.uk/aubm

Aromatase Inhibitor Treatment AlgorithmUK National Osteoporosis Society

Reid DM…Eastell R…Cancer Treat Rev. 2008;34 Suppl 1:S3-18.

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Anti-Androgen Therapy for Prostate Cancer

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Anti-Androgen Therapy for Prostate Cancer

• Given to 50% of men with prostate cancer– Used for 2-3 years

– Usually GnRH agonists or orchidectomy

– Adverse events• Fatigue

• Hot flashes

• Loss of libido

• Sarcopenia

• Bone loss

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www.shef.ac.uk/aubmShahinian VB et al. N Engl J Med 2005;352:154-164.

Unadjusted Fracture-free Survival among Patients with Prostate Cancer, According to Androgen-Deprivation Therapy

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Anti-androgen therapy causes bone loss

Bone loss notprevented withCalcium and Vitamin D

Alibahi SM, et al. Osteoporos Int. 2013 Oct;24(10):2571-9

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Zoledronic Acid (4 mg every 6 months) Prevents Bone Loss from ADT

Kachnic LA, et al. Prostate Cancer Prostatic Dis. 2013 Dec;16(4):382-6

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Smith MR et al. N Engl J Med 2009361:745-755

Denosumab (60 mg every 6 months) Prevents Bone Loss from ADT

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Endocrine Society Guidelines for Male Osteoporosis

• We recommend pharmacological treatment for osteoporosis for men with prostate cancer receiving ADT who have a high risk of fracture– Hip or spine fracture

– BMD T-score < -2.5

– BMD T-score < -1, FRAX 10-year hip fracture risk >3%

Watts NB…Eastell R…J Clin Endocrinol Metab. 2012 Jun;97(6):1802-22

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Summary

Aromatase inhibitors

• Adjuvant therapy of breast cancer

• Increase risk of fracture

• Accelerated bone loss

• Prevention of bone loss– Bisphosphonates

– Denosumab

• Guidelines available

Anti-androgen therapy

• Adjuvant therapy of prostate cancer

• Increase risk of fracture

• Accelerated bone loss

• Prevention of bone loss– Bisphosphonates

– Denosumab

• Guidelines available