Bad to the bones: treatments for breast and prostate cancer

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1 12 th Annual Osteoporosis: New Insights in Research, Diagnosis, and Clinical Care 23 rd July 2015 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 Conflicts of Interest Research funding, consulting and honoraria from Novartis Amgen AstraZeneca Pfizer Warner Chilcott Sanofi 1

2 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 Aromatase Inhibitors What are they? 2

3 Oestrogen Action on Breast Cancer Cells Androstenedione Estrone Aromatase Testosterone Estradiol Estrogen ERreceptor mediated effects Aromatase inhibitors (Anastrozole, Letrozole, Exemestane) 17 -HSD SERMs (Raloxifene, Tamoxifen) DNA Cell proliferation Bioavailable Oestradiol Concentrations 200 Bioavailable E2, pmol/l Premenopausal women Postmenopausal women Normal men AI Khosla S, et al. J Clin. Endocrinol. Metab. 2001;86:

4 Aromatase Inhibitors How are they used? 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:

5 Effect of Aromatase Inhibitors on Breast Cancer Recurrence Oxford Overview Control (EBCTCG) Tamoxifen (EBCTCG) Anastrozole (ATAC) Tamoxifen (ATAC) Estimated proportion of receptor-positive patients without recurrence (%) year recurrence-free rate: 92.2% ATAC 89.6% ATAC 84.6% EBCTCG % EBCTCG 0 Years Comparison with Early Breast Cancer Trialists Collaborative EBCTCG. Lancet 1998; 351: Group (EBCTCG): receptor-positive patients >50 years Significant Differences in Predefined Adverse Events In favour of anastrozole In favour of tamoxifen Hot flushes Weight gain* Vag. bleeding Vag. discharge (-8.6%) Endo Ca ICVA VTE DVT (-5.4%) (-3.6%) (-1.8%) (-0.4%) (-1.1%) (-1.4%) (-0.7%) (2.1%) (0.8%) (6.6%) MSK disorders Fractures Fractures of hip, spine, wrist Difference between anastrozole and tamoxifen AEs, % *Proportion with 10% gain in body weight from baseline to year 2 Buzdar, et al. San Antonio Breast Cancer Symposium,

6 Aromatase Inhibitors What is their effect on bone? Fracture risk Bone mineral density Bone turnover markers Annual rates, %* Number at risk Years 0 Anastrozole 3092 Tamoxifen 3094 ATAC 68-month analysis: Annual fracture rates over time Anastrozole Tamoxifen Years since randomisation *Calculated using Kaplan-Meier estimates Buzdar A, et al. Lancet Oncol 2006 Aug;7(8):

$ATAC Trial: types of fracture 1 Fractures Anastrozole Tamoxifen Odds ratio Hip 37$ 49*** 1 ATAC Trialists Group. Lancet 2005;365:60-62. *p<0.05; ***p<0.

7 ATAC Trial: types of fracture 1 Fractures Anastrozole Tamoxifen Odds ratio Hip Spine * Wrist Others *** Total *** 1 ATAC Trialists Group. Lancet 2005;365: *p<0.05; ***p< Bone Mineral Density (BMD) of the Spine and Total Hip by Dual Energy X-ray Absorptiometry (DXA) 7

8 BMD % change over time ATAC, Patients with data at baseline, 1, 2 and 5 years Anastrozole Tamoxifen Estimated 4 Lumbar spine % change 2 (mean and 0 95% CI) Baseline Time (years) Total hip Baseline Time (years) Statistically significantly more BMD loss on anastrozole than tamoxifen (p< for both lumbar spine and total hip BMD primary analysis) Eastell R, et al. J Clin Oncol 2008; 26(7): % change In BMD from baseline Anastrazole (ATAC) Tamoxifen (ATAC) Influence of Different Aromatase Inhibitor Strategies on BMD Immediate Switch Extended x x ATAC IES MA Yr. Exemestane (IES) x x Placebo (MA-17) Tamoxifen (IES) x xletrozole (MA-17) x x Coleman R, et al. Lancet Oncology

9 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 Aromatase Inhibitors Can the effects on bone be prevented? 9

10 Risedronate Prevents AI-induced Bone Loss: the SABRE Study Van Poznak C Eastell R. J Clin Oncol Feb 20;28(6): Risedronate Prevents AI-induced Bone Loss: the SABRE Study Van Poznak C Eastell R. J Clin Oncol Feb 20;28(6):

IBIS-II bone study design Sestak I Eastell R. Lancet Oncol. 2014 Dec;15(13):1460-8 N=1410 Stratum I T score 1.0 No treatment N=761 Stratum II 2.5<T score< 1.0 N=500 Stratum III 4.0 T score 2.

11 IBIS-II bone study design Sestak I Eastell R. Lancet Oncol Dec;15(13): N=1410 Stratum I T score 1.0 No treatment N=761 Stratum II 2.5<T score< 1.0 N=500 Stratum III 4.0 T score 2.5 All on risedronate N=149 A N=378 P N=383 A/R N=73 P/R N=76 P/P N=124 P/R N=116 A/P N=123 A/R N=137 B 6M 12M 24M 36M 60M 84M FUP DXA X X X X X X X X X X X IBIS-II bone study 3-year results Sestak I Eastell R. Lancet Oncol Dec;15(13): Mean % BMD change (%) Osteopenic women (stratum II) all on anastrozole: Risedronate vs. Placebo Risedronate Placebo B 12M 36M 1.1% P< % Osteoporotic women (stratum III) all on risedronate: Anastrozole vs. Placebo Mean % BMD change (%) Anastrozole Placebo P=0.006 B 12M 36M 3.9% 1.2% 11

12 Aromatase Inhibitors Approach to the patient Aromatase Inhibitor Treatment Algorithm UK National Osteoporosis Society Reid DM Eastell R Cancer Treat Rev. 2008;34 Suppl 1:S

13 Anti-Androgen Therapy for Prostate Cancer 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 13

14 Unadjusted Fracture-free Survival among Patients with Prostate Cancer, According to Androgen-Deprivation Therapy Shahinian VB et al. N Engl J Med 2005;352: Anti-androgen therapy causes bone loss Bone loss not prevented with Calcium and Vitamin D Alibahi SM, et al. Osteoporos Int Oct;24(10):

15 Zoledronic Acid (4 mg every 6 months) Prevents Bone Loss from ADT Kachnic LA, et al. Prostate Cancer Prostatic Dis Dec;16(4):382-6 Denosumab (60 mg every 6 months) Prevents Bone Loss from ADT Smith MR et al. N Engl J Med :

16 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 Jun;97(6): 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 16

Integrated care: guidance on fracture prevention in cancer-associated bone disease; treatment options

$Integrated care: guidance on fracture prevention in cancer-associated bone disease; treatment options$ Paris, November 1st 2016 Integrated care: guidance on fracture prevention in cancer-associated bone disease; treatment options René Rizzoli MD International Osteoporosis Foundation and Division of Bone