Osteoporosis management in cancer patients

Osteoporosis management in cancer patients Belgian Menopause Society - Osteoporosis - Brussels, Oct 2017 Prof. JJ Body CHU Brugmann Univ. Libre de Bruxelles Brussels

Bone loss associated with hormone ablation therapy is both rapid and clinically significant BMD loss at 1 year (%) CMCE/XGE/0036c/12(2) January 2015 10 Naturally occurring bone loss CTIBL 8 7.4 7.7 6 4.6 4 2 0.5 1.0 2.0 2.6 0 1. Higano CS. Nat Clin Pract Urol 2008;5:24 34; 2. Eastell R, et al. J Bone Miner Res 2006;21:1215 23; 3. Maillefert JF, et al. J Urol 1999;161:1219 22; 4. Gnant M, et al. Lancet Oncol 2008;9:840 9; 5. Shapiro CL, et al. J Clin Oncol 2001;19:3306 11. ADT, androgen deprivation therapy; AI, aromatase inhibitor.

BREAST CANCER Fracture risk and aromatase inhibitors

Percent change Percent change HRpQCT 0 Total volumetric BMD Cortical volumetric BMD Trabecular volum. BMD -2-4 -6 0 1 2 0 Number assessed 1 2 0 1 2 Placebo 162 107 162 107 162 107 Exemestane 164 109 164 109 164 103 DXA 0 Lumbar spine areal BMD Total hip areal BMD Femoral neck areal BMD -2-4 Placebo Exemestane -6 0 1 2 0 1 2 0 1 2 Number assessed Years from baseline Years from baseline Years from baseline Placebo 165 108 164 107 164 107 Exemestane 165 111 164 111 164 111

Percent change Percent change HRpQCT 0 Total volumetric BMD Cortical volumetric BMD Trabecular volum. BMD -2-4 -6 0 1 2 0 Number assessed 1 2 0 1 2 Placebo 162 107 162 107 162 107 Exemestane 164 109 164 109 164 103 DXA 0 Lumbar spine areal BMD Total hip areal BMD Femoral neck areal BMD -2-4 -6 0 1 2 Placebo Exemestane 0 1 2 Number assessed Years from baseline Years from baseline Years from baseline Placebo 165 108 164 107 164 107 Exemestane 165 111 164 111 164 111 Effects of AIs on bone strength are underestimated by DXA. 0 1 2 Cortical bone is more affected than trabecular bone (Cheung et al., Lancet Oncol 2012)

Fractures (%) Steroidal and nonsteroidal AIs increase fracture risk compared with Tamoxifen 14 12 P <.0001 11.0 Tamoxifen Anastrozole Exemestane Letrozole 10 8 7.7 P =.003 7.0 P <.001 6 4 5.0 4.0 5.7 2 0 ATAC [1] (68) IES [2] (58) BIG 1-98 [3] (26) Treatment (months) 1. Howell A, et al. Lancet 2005;365:60-62. 2. Coleman RE, et al. Lancet Oncol 2007;8:119-127. 3. Thürlimann B, et al. N Engl J Med 2005;353:2747-2757.

Oral BPs for preventing AI-induced bone loss in post-menopausal women with early breast cancer Rizzoli, Body et al.; OI 2012 Antiresorptive Refer BMD Dosing Follow-up Mean change, agent study n years % BMD (trial) Lumbar spine Total hip Clodronate Saarto 61 1600 mg 5-1.0-0.1 2001 PO / d Risedronate Singh 59 35 mg 1 + 0.3 + 0.7 (IBIS II) 2007 PO / wk Risedronate Confavreux 11 35 mg 1 + 4.1 + 1.8 2007 PO / wk Risedronate Greenspan 87 35 mg 2 + 0.4 + 0.9 2008 PO / wk Risedronate Markopoulos 70 35 mg 2 + 5.7 + 1.6 (ARBI) 2010 PO / wk Risedronate Van Poznak 111 35 mg 2 + 2.2 + 1.8 (SABRE) 2010 PO / wk Ibandronate Lester 50 150 mg 2 + 3.0 + 0.6 (AREBON) 2008 PO / d

Prevention of bone loss in PostMP women treated with AIs Z(O)-FAST trial R A N D O M I Z E D Zoledronic acid 4 mg q 6 mo UP FRONT + Letrozole (2.5 mg/day) Zoledronic acid 4 mg q 6 mo DELAYED* + Letrozole (2.5 mg/day) 0 1 year 3 years 5 years Final analysis Stage I to IIIa ER+ and/or PR+ breast cancer Baseline lumbar spine and total hip T score 2.0 *Initiation of zoledronic acid determined by postbaseline T-score < 2, any clinical fracture, or an asymptomatic fracture at 36 months.

BMD least squares means change from baseline, % Bone loss in PostMP women treated with AIs 36-month results of the ZO-FAST Study n = 1060 (524 immediate-zol group; 536 delayed-zol group) 110 pts (21%) in the delayed-zol group initiated ZOL Eidtmann, Ann Oncol 2010 6 4 Immediate ZOL Delayed ZOL 2 0 n = 489 Δ 5.27 496 393 n = Δ 7.94 299 Δ 9.29 474 Δ 3.37 383 Δ 4.72 305 Δ 5.41 391 303 486 387 309-2 -4-6 12 24 36 12 24 36 Lumbar Spine (L2-L4) Time, months Total Hip

Phase 3 Study of Denosumab in Women With Non- Metastatic Breast Cancer Receiving AI Therapy Study Design: Multi-center, randomized, double-blind, placebo-controlled study conducted in the United States and Canada Women Receiving Aromatase Inhibitor Therapy For Hormone-Receptor- Positive, Non- Metastatic Breast Cancer N = 127 Denosumab 60 mg SC every 6 months (x 4 doses) N = 125 Placebo SC every 6 months (x 4 doses) Baseline 12 month 24 month Ellis G, et al. J Clin Oncol 2008

Percentage Change (± 95% CI) From Baseline in Lumbar Spine Bone Mineral Density Effect of Denosumab on Lumbar Spine Bone Mineral Density 8 7 6 5 4 3 2 1 0-1 -2-3 * * Placebo (N = 122) * P < 0.0001 versus Placebo Months * * 5.5% Difference at Month 12 Denosumab (N = 123) 1 3 6 12 24 * 7.6% Difference at Month 24 Ellis G, et al. J Clin Oncol 2008

% change from baseline (± 95 % CI) Effects of denosumab on BMD at the hip and the radius (one-third) Total hip 5 4 3 2 1 0-1 -2 * Placebo (n = 106) Placebo (n = 122) 4 Denosumab (n = 115) Denosumab (n = 123) 3 * * * * 4.7 % difference at 24 months Radius 2 1 0-1 -2-3 -4-5 * 6.1 % difference at 24 months 1 3 6 12 24 Time, months 12 24

Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-contr. trial Gnant et al., Lancet 2015 n = 3240 (ITT) post MP women on AIs (84%; median 1 m.) or starting AIs (16%) Randomly assigned to denosumab 60 mg sc q6m (n = 1711) placebo sc q6m (n = 1709) treated until the prespecified number of 247 first clinical fractures (except skull, face, fingers, toes) was reached

Adjusted mean change in BMD (%) Bone mineral density 10 Lumbar Spine P < 0.0001 at all timepoints Placebo every 6 months Denosumab 60 mg q6 months 10 Femoral neck P < 0.0001 at all timepoints 8 5.85% 7.27% 8 6 4 3.94% 6 4 2.22% 2.86% 3.41% 2 2 0 =5.75% =8.28% =10.02% 0 =3.30% =5.19% =6.51% -2-2 -1.08% -4-1.81% -2.44% -2.75% -4-2.33% -3.10% -6 n = 986 n = 725 n = 475-6 n = 995 n = 723 n = 469 12 months 24 months 36 months 12 months 24 months 36 months

Risk of fracture (%) First clinical fracture (primary endpoint) 30 25 Placebo Denosumab Nb. Fract. /pts Hazard ratio vs placebo P value 176 / 1709 0.50 (0.39-0.65) <0.0001 92 / 1711 20 15 10 5 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Time, since randomisation (months) Number at risk Placebo 1709 1660 1470 1265 1069 921 785 637 513 384 275 185 112 Denosumab 1711 1665 1488 1297 1118 965 823 688 540 432 305 221 116 Similar reduction in vertebral fractures (X-rays; >20-25%) : HR 0.53 (0.33-0.85; P = 0.009)

First clinical fracture separated by subgroup (Forest plot; hazard ratios) AI before randomisation Fractures (n) / patients (n) Denosumab Placebo No Yes 16/270 29/269 76/1441 147/1440 Baseline bone mineral density T-score < -1 T-score -1 49/773 84/775 43/938 92/934 Age (years) < 60 60-69 70 25/507 41/479 42/782 83/755 25/422 52/475 0.1 0.5 1 2 3 Hazard ratio (denosumab vs placebo)

WHAT ARE THE MOST RECENT GUIDELINES?

Guidelines for osteoporis screening and treatment in cancer receiving AIs, ADT, Source Population Screening Indications for treatment [ Reference ] interval (DXA) ASCO Annual T-score < - 2.5 [Hillner et al.; premp w/ovar. suppr JCO 2003] 65 yrs 60-64 yrs «at high risk» initiating AI Belg.BoneClub - any Every T-score < - 2.5 [Body et al; initiating AI ther. 1-2 yrs History of fragility fract. OI 2007] or GnRH agonist - any T-score < - 1.0 initiating ADT + CRFs NCCN - any Every Any of the following : [Gralow et al; initiating AI ther. 2 yrs - T-score < - 2.0 JNCCN 2009] or GnRH agonist - FRAX 10-yr probab. for - any hip fract 3 % receiving ADT major OP Fract 20%

Source Population Screening Indications for treatment [ référence ] interval (DXA) Intl Exp Panel any Every T-score - 2.0 [Hadji,Aapro,Body..; initiating AI ther. 1-2 yrs T-score > - 2.0 Ann Oncol 2011] with 2 additional CRFs ESCEO-IOF - any Not Any of the following : [Rizzoli,Body, initiating AI ther. specified - age 75 yrs De Censo, ; - premp with - personal frag. Fract. OI 2012] ovarian suppr >50yrs - T-score < - 2.5 - T-score < - 1.5 plus 1 CRF - T-score < - 1.0 plus 2 CRFs - FRAX 10-yr hip fract. 3%

CMCE/XGE/0036c/12(2) January 2015 ESMO-recommended treatment algorithm for managing bone loss during adjuvant cancer treatment T-score > -2.0 and no additional risk factors Patients with cancer receiving chronic adjuvant treatment known to accelerate bone loss T-score < -2.0 Exercise Calcium and vitamin D Monitor risk and BMD at 1 2 yr intervals Any 2 of the following risk factors: Age >65 yrs T-score < -1.5 Smoking (current or history) BMI <20 Family history of hip fracture Personal history of fragility fracture >50 years Oral glucocorticoid use for >6 mo Coleman R, Body JJ, Aapro M, Hadji P, Herrstedt P; Ann Oncol 2014 Adapted from Hadji P, et al. Ann Oncol 2011;22:2546 55; Reid DM, et al. CancerTreat Rev 2008; Body JJ et al., Osteoporos Int 2007

CMCE/XGE/0036c/12(2) January 2015 ESMO-recommended treatment algorithm for managing bone loss during adjuvant cancer treatment T-score > -2.0 and no additional risk factors Patients with cancer receiving chronic adjuvant treatment known to accelerate bone loss T-score < -2.0 Exercise Calcium and vitamin D Monitor risk and BMD at 1 2 yr intervals Any 2 of the following risk factors: Age >65 yrs T-score < -1.5 Smoking (current or history) BMI <20 Family history of hip fracture Personal history of fragility fracture >50 years Oral glucocorticoid use for >6 mo Exercise Calcium and vitamin D Bisphosphonate therapy (zoledronic acid, alendronate, risedronate, ibandronate). Denosumab may be another treatment option in some patients. Coleman R, Body JJ, Aapro M, Hadji P, Herrstedt P; Ann Oncol 2014 Adapted from Hadji P, et al. Ann Oncol 2011;22:2546 55; Reid DM, et al. CancerTreat Rev 2008; Body JJ et al., Osteoporos Int 2007 Monitor BMD every 2 yrs Check compliance with oral therapy

Limitations include CMCE/XGE/0036c/12(2) January 2015 Assessment of risk factors for fracture and treatment recommendations have not been prospectively validated in patients with cancer. Loss of BMD and FRAX score underestimate the deleterious effects of AI therapy on fracture risk Optimal duration of treatment is unknown (as long as that of AI therapy?) None of the proposed guidelines have been validated AND.

Effects Of Bisphosphonate Treatment On Recurrence And Cause-specific Mortality In Women With Early Breast Cancer: A Meta-analysis Of Individual Patient Data From Randomised Trials Early Breast Cancer Trialists Collaborative Group (EBCTCG) The Lancet, Oct 2015.

Breast Cancer Recurrence: Postmenopausal Women* Distant Recurrence Bone Recurrence Non Bone Recurrence 1564 events 508 events 1056 events Significantly Greater Effect on Bone than Other Distant Recurrence * Includes induced menopause and women aged >55 if unknown

Breast Cancer Mortality By Menopausal Status Significantly Improved Survival in Postmenopausal Women

There was no significant heterogeneity between the apparent effects on bone recurrence of the different bisphosphonate regimens tested in these trials. For this outcome, the benefits of the nonaminobisphosphonate (clodronate, n=5053) and of the two most widely tested aminobisphosphonates (zoledronic acid, n=9290, and ibandronate, n=3072) appeared similar. The benefits appeared to be similar in trials of «low-intensity» anti-osteoporosis schedules (eg, 6-monthly iv zoledronic acid) and in trials of more intensive schedules such as those approved for use in metastatic bone disease (eg, monthly zoledronic acid, daily oral ibandronate or clodronate).

ABCSG-18: Study Design Prospective, randomized, double-blind, placebo-controlled phase III trial Postmenopausal pts with early HR+ breast cancer receiving adjuvant AI therapy* (N = 3425) Denosumab 60 mg SC Q6M (n = 1711) Placebo SC Q6M (n = 1709) Primary endpoint: time to first clinical fracture (RR 0.50) Gnant M, et al. Lancet. 2015;386:433-443. Secondary endpoints: % change in BMD, vertebral fractures, DFS *, OS, BMFS, safety * SABCS Dec 2015

? Should current guidelines be changed? Given that AIs increase fracture rate whatever the initial BMD Bone fractures rate appears to be underestimated Products released by increased bone turnover attract cancer cells to bone and stimulate their growth * Denosumab decreases AI and ADT-induced fracture rate Bisphosphonates given to prevent AI-induced bone loss and in the adjuvant setting appear to reduce recurrence rate and prolong survival in postmenopausal women Denosumab prolongs DFS in patients under AIs

Given that AIs increase fracture rate whatever the initial BMD Bone fractures rate appears to be underestimated Products released by increased bone turnover attract cancer cells to bone and stimulate their growth ( vicious cycle ) * Denosumab decreases AI and ADT-induced fracture rate? Should current guidelines be changed? Bisphosphonates given to prevent AI-induced bone loss and in the adjuvant setting appear to reduce recurrence rate and prolong survival in postmenopausal women Denosumab prolongs DFS in patients under AIs Why not give an antiresorptive to all postmp women at moderate or at least high risk of recurrence when they start adjuvant AI therapy?

Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel P. Hadji, R.E. Coleman, C. Wilson, T.J. Powles, P. Clézardin, M. Aapro, L. Costa, J. - J. Body, C. Markopoulos, D. Santini, I. Diel, A. Di Leo, D. Cameron, D. Dodwell, I. Smith, M. Gnant, R. Gray, N. Harbeck, B. Thurlimann, M. Untch, J. Cortes, M. Martin, U.- S. Albert, P.- F. Conte, B. Ejlertsen, J. Bergh, M. Kaufmann & I. Holen. Ann Oncol 2016 The panel recommends that bisphosphonates (either intravenous zoledronic acid or oral clodronate) are considered as part of the adjuvant breast cancer treatment in this population and the potential benefits and risks discussed with relevant patients.

Summary 1. AIs increase bone loss and fracture rate in postmp women. 2. Bisphosphonates and denosumab can prevent AI-induced bone loss. Denosumab has recently been shown to decrease fracture rate.

Summary 1. AIs increase bone loss and fracture rate in postmp women. 2. Bisphosphonates and denosumab can prevent AIinduced bone loss. Denosumab has recently been shown to decrease fracture rate. 3. Prevention of CTIBL in breast cancer has opened the way for the prevention of disease recurrence. 4. Current guidelines for prevention of AI-induced bone loss should probably be reviewed (ABCSG- 18; EBCTG metaanalysis)