Pr Prevention and Treatment of Osteoporosis (What more do we need - PowerPoint PPT Presentation

Pr Prevention and Treatment of Osteoporosis (What more do we need to kn know?) Fred Saad MD FRCS Professor and Chairman of Urology Director of GU Oncology Raymond Garneau Chair in Prostate Cancer University of Montreal Hospital Center

Disclosures • Received honorarium as a consultant and funding for research (institution) • Amgen • Astellas • AstraZeneca • BMS • Bayer • Janssen • Sanofi

What are we trying to prevent/treat

Why Screen and Treat?

Risk and consequences of Osteoporosis versus Peak bone mass achieved 1 Later Earlier Accelerated after Bone loss 1 Gradual menopause Hip Fractures 2 4.6% 12.1% Lifetime Risk Vertebral Fracture 21.5% 23.5% Prevalence 3 Mortality 1 year post hip 31-38% 12-28% fracture 4 1. Seeman E. J Appl Physiol . 2003;95(5):2142-2151. 2. Hopkins RB, et al. Osteoporos Int. 2012;23(3):921-7. 3. Jackson SA, et al. Osteoporos Int . 2000;11:680–687. 4. Papaioannou A, et al. Osteoporos Int. 2008;19(4):581-587.

Mortality Patients with Vertebral Compression Fracture Males Females 100 100 90 90 Control Control Survival (%) 80 Survival (%) 80 VCF VCF 70 70 60 60 5 5 0 0 40 40 30 30 20 20 10 10 0 0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Years Since VCF Diagnosis Years Since VCF Diagnosis • overall mortality twice that of the matched controls (N=97,142) Lau E et al. J Bone Joint Surg Am . 2008;90:1479.

Prevalent Vertebral Fracture at study entry Denosumab phase 3 study in nmHSPC HR: 1.57 ; P = .062 HR: 2.14 ; P = .0194 HR: 1.09 ; P = .813 Adj HR*: 1.55 ; P = .0698 Adj HR*: 2.13 ; P = .021 Adj HR*: 1.08 ; P = .837 10 Prevalent vertebral 9.2% fracture 9 No prevalent 8 7.6% vertebral fracture 7 *Adjusted for age Subjects (%) 5.8% 6 5.6% and ADT duration 5.1% 5 4.6% 4 3 2 1 0 All Patients Placebo Denosumab Subject incidence 25 53 16 23 9 30 Sample size 329 1035 174 504 155 531 Saad F, et al. ECCO/ESMO 2009

Impact of ADT

ADT is Associated with Significant Bone Loss Normal men 1 0.5% Late menopausal women 1 1.0% Early menopausal women 1 2.0% AI therapy in PMW 2 2.6% Bone marrow transplant 3 3.3% 4.6% Androgen deprivation therapy agonist 4 7.0% AI therapy plus GnRH agonist 5 7.7% Ovarian failure secondary to chemotherapy 6 0 2 4 6 8 Lumbar spine BMD loss at 1 year (%) 1. Kanis. Osteoporosis . 1997:22; 2. Eastell et al. J Bone Miner Res. 2002;17(suppl 1):S165; 3. Lee et al. J Clin Endocrinol Metab . 2002;87:329; 4. Maillefert et al. J Urol . 1999;161:1219; 5. Gnant. Breast Cancer Res Treat. 2002;76(suppl 1):S31. Abstract 12; 6. Shapiro et al. J Clin Oncol. 2001;19:3306.

ADT Leads to Increased Fracture Rates (SEER) 100 90 80 Unadjusted Fracture-free 70 Survival (%) 60 Over a 4-year period 50 19.4% fractures on ADT § 12.6% fractures not on ADT § 40 30 No ADT (n = 32,931) GnRH Agonist, 1- 4 doses (n = 3,763) GnRH Agonist, 5 - 8 doses (n = 2,171) 20 GnRH Agonist, ≥ 9 doses (n = 5,061) 10 Orchiectomy (n = 3,399) 0 1 2 3 4 5 6 7 8 9 10 Years After Prostate Cancer Diagnosis Shahinian VB, et al. N Engl J Med 2005;352:154-64.

Effect of Fracture on Survival Among Men with Prostate Cancer: From the SEER Database of Men on ADT 1.0 0.8 Survival Probability 0.6 0.4 0.2 Fracture within 48 months No fracture within 48 months 0.0 0 5 10 15 Follow-up After Cancer Diagnosis (Yrs) Shao Y-H, et al. BJU Int 2013;111:745-52.

Calculating fracture risk

Canadian Association of Radiologists and Osteoporosis Canada Risk (CAROC) Assessment tool Fragiltiy fracture of prolonged steroid use increases risk by 1 category

FRAX 10-Yr Hip Fracture Risk by Age in Men Receiving ADT for Prostate Cancer 30 25 10-Yr Hip Fracture Risk 20 15 10 5 > 3% risk 0 50 60 70 80 90 100 Age (Yrs) Saylor PJ, et al. J Urol . 2010;183:2200-2205.

General Guidelines: BMD for who? Papaioannou A, et al. .CMAJ 2010 http://www.cmaj.ca/cgi/doi/10.1503/cmaj.100771

General Guidelines: Who to treat? Papaioannou A, et al. .CMAJ 2010 http://www.cmaj.ca/cgi/doi/10.1503/cmaj.100771

Treatment options Everyone knows HOW The problem is DECIDING to screen and treat

Are patients getting enough calcium?

Exercise: Yes but how? osteoporosis.ca/health-care-professionals/clinical-practice-guidelines/exercise-recommendations/

Exercise http://www.osteoporosis.ca/osteoporosis-and-you/too-fit-to-fracture/

Bone health agents Basically they all work

Pamidronate IV q 3months (n=47) 2 P≤ 0.005 for each comparison 1 BMD Percent Change 0 -1 No pamidronate Pamidronate -2 -3 -4 Final 12-month data -5 Lumbar Total Spine Hip Smith MR et al. N Eng J Med. 2001;345:948.

Zoledronic Acid IV q 3 months (n=106) 8 P <0.001 for each comparison 6 BMD Percent Change 4 Placebo 2 Zoledronic acid 0 -2 Final 12-month data -4 Lumbar Total spine hip Smith MR et al. J Urol. 2003;169:2008.

Zoledronic Acid IV q 12 Months (n=40) 6 P <0.005 for each comparison 4 BMD Percent Change 2 Placebo 0 Zoledronic acid -2 -4 Final 12-month data -6 Lumbar Total spine hip Michaelson MD et al. J Clin Oncol. 2006;25:1038.

Alendronate PO weekly (n=112) 5 P <0.04 for each comparison 4 except P =0.08 for total hip on placebo BMD Percent Change 3 2 Placebo 1 Alendronate 0 -1 -2 Final 12-month data -3 Lumbar Total spine hip Greenspan SL et al. Ann Intern Med. 2007;146:416.

Denosumab 60mg q 6 months (n=1468) Lumbar Spine Total Hip Placebo (n = 734) Placebo (n = 734) 10 10 Denosumab 60 mg sc Denosumab 60 mg sc every 6 mos (n = 734) every 6 mos (n = 734) 8 8 * Percentage Change in Percentage Change in BMD from Baseline BMD from Baseline * 6 6 * 4 4 * * Difference at 24 mos, * * * 6.7 percentage points 2 2 * * * Difference at 24 mos * 0 0 4.8 percentage points – 2 – 2 – 4 – 4 – 6 – 6 0 1 3 6 12 24 36 0 1 3 6 12 24 36 Study Month Study Month p < 0.001 at all measured sites Smith MR, et al. N Engl J Med 2009;361:745-55. *Prolia

Denosumab 60 q 6 months New Vertebral Fractures at 3 years Placebo (n = 673) Denosumab 60 mg sc 8 every 6 mos (n = 679) RR 0.15 RR 0.31 RR 0.38 p = 0.004 p = 0.004 p = 0.006 acture (%) 6 al Frac 3.9 4 3.3 New Vertebral 1.9 1.5 2 Ne 1.0 0.3 13 13 n n = 2 22 22 7 26 26 10 10 0 12 24 36 Mo Months Smith MR, et al. N Engl J Med 2009;361:745-55.

Basic Principles • BMD : for patients on long term ADT • Vitamin D : 800-2000 IU/1day • Calcium : Diet +/- supplements for > 1200/day • Exercise : Important but will it get done? • Smoking : STOP • Alcohol : limit < 2 drinks/day • Medication if high risk: Bisphosphonates or Denosumab

Fractures and Impact of bone protective agents in recent studies What can we learn?

ERA 223 (NCT02043678) Primary endpoint Abiraterone acetate 1000 mg qd and • SSE-FS prednisone/prednisolone 5 mg bid (AAP) Study population + Radium-223 Secondary endpoints Target Accrual 55 kBq/kg IV every 4 weeks for 6 cycles • Patients with bone- • OS N=800 predominant mCRPC (≥2 • rPFS • Time to chemotherapy bone metastases) Stratification factors 1:1 • Time to opiate use for cancer • Asymptomatic or mildly • Geographical region Randomisation, pain symptomatic • Use of bone health agents* • Safety Double blind • ECOG PS of 0 or 1 • Total ALP level at baseline (ALP <90 vs. ≥90 U/L) • No prior chemotherapy for Exploratory endpoints CRPC or AR antagonists • PSA response Abiraterone acetate 1000 mg qd and • No known brain or visceral • Time to PSA progression prednisone/prednisolone 5 mg bid (AAP) metastases • ALP response + Matching placebo • Time to ALP progression • HRQoL Accrual dates 3/2014 – 8/2016 389 events were required to detect a 39% increase in SSE-FS using a test with a 2- Bone health agents (denosumab or bisphosphonates) only permitted in patients receiving them at baseline; sided alpha of 0.05, 90% power and 1:1 Initiation during study was prohibited to prevent confounding effects. randomisation ALP, alkaline phosphatase; CRPC, castration-resistant prostate cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; HRQoL, health-related quality of life; IV, intravenous; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PSA, prostate-specific antigen; rPFS, radiological progression-free survival; SSE-FS, symptomatic skeletal event-free survival. Smith M et al. Presented at European Society for Medical Oncology; Munich, Germany; October 19–23, 2018.