1. Alison T. Stopeck, MD Associate Professor of Medicine Arizona Cancer Center University of Arizona Tucson, Arizona Bone-Targeted Therapy in the Treatment of Bone Metastases This program is supported by an educational donation provided by

2. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Disclosure Alison T. Stopeck, MD, has disclosed that she has received contracted research support from Bayer and Peregrine, consulting fees from Amgen and Genentech, and fees for non-CME activities from Celgene.

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4. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Case Presentation  A 70-yr-old woman presents with severe back pain  Pain persists despite NSAID therapy, x-ray of her spine revealed a compression fracture of T12  MRI confirmed the compression fracture of T12, but also notes a soft-tissue mass associated with the lesion  Past medical history notable for cancer in her left breast diagnosed 10 yrs prior; underwent MRM  Pathology revealed a 6-cm infiltrating lobular cancer: ER > 90%; PR > 90%; HER2 neg; 4 of 22 positive LNs  She was treated with AC x 4 cycles and tamoxifen x 5 yrs  Has been off all hormonal therapy for last 5 yrs

5. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Case Presentation  Bone scan and chest/abdominal/pelvic CT scan reveals additional bone metastases in L2 and L4, but no visceral metastases  Biopsy of the soft-tissue mass at T12 consistent with metastatic breast cancer, ER/PR still strongly positive  She receives radiation therapy to her involved disease from T12-L4  After radiation therapy, pain is markedly improved in her back and she is only taking 1-2 NSAIDs per day for symptoms  You decide to start her on anastrozole as therapy for her MBC and order the following labs: CBC, CMP, CA 27.29

6. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Case Presentation  Labs: normal CBC and plt ct  Calcium: normal  Albumin: normal  CA 27.29: 242 U/mL  Creatinine: 1.2 mg/dL  PMH: HTN, diet-controlled DM  PE: slightly overweight, minimal pain over T12 area, but no other findings –Neurologically intact

7. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer What additional therapy would you recommend for this patient? A.No additional therapy B.Start denosumab monthly C.Start pamidronate monthly D.Start zoledronic acid monthly E.Start vitamin D and calcium daily F.Other

8. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Complications of Bone Metastases  Pain  Fracture  Spinal cord compression  Hypercalcemia  Skeletal complications account for 63% of hospital costs in patients with advanced breast cancer Coleman RE. Cancer. 1997;80:1588-1594. Biermann WA, et al. Bone. 1991;12(suppl 1):S37-S42

9. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer The Natural History of Bone Metastases in Breast Cancer  Pathologic fracture is the most common SRE in patients with breast cancer  Median onset is 11 mos from initial diagnosis of bone metastases  ~ 20% develop hypercalcemia after a median of 14 mos  ~ 10% develop cord compression after a median of 17 mos Lipton A. Cancer. 2003;97:848-853.

10. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Untreated Patients Experience Multiple SREs Breast Cancer [1] Skeletal Morbidity Rate* *Mean number of SRE per patient per yr. 1. Lipton A, et al. Cancer. 2000;88:1082-1090. 2. Saad F. Clin Prostate Cancer. 2005;4:31-37. 3. Rosen LS, et al. Cancer. 2004;100:2613-2621. Prostate CA [2] NSCLC + Other Solid Tumors [3] SRESRE + HCM 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 3.70 4.00 1.47 2.71

11. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Other than a prior SRE, patients with which of the following are at the greatest risk for SREs? A.Visceral metastases B.Elevated uNTX/creatinine ratio C.Blastic lesions D.Bone pain

12. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer FDA-Approved Agents for Prevention of SREs in Metastatic Breast Cancer  Both ASCO and NCCN recommend all 3 agents [1,2] –No agent recommended over another AgentDrug ClassRecommended Dose and Schedule Zoledronic acidBisphosphonate4 mg IV q3-4w PamidronateBisphosphonate90 mg IV q3-4w DenosumabRANKL-targeted MAb120 mg SQ q4w 1. Van Poznak CH, et al. J Clin Oncol. 2011;29:1221-1227. 2. NCCN. Clinical practice guidelines in oncology: breast cancer. v.2.2011.

13. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Bisphosphonates Reduce SREs in Breast Cancer 1. Lipton A, et al. Cancer. 2000;88:1082-1090. 2. Rosen LS, et al. Cancer. 2003;98:1735-1744. 3. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. StudyTreatment Duration, Mos Patients With SRE, % P Value Lipton et al [1] * 24  Placebo 64 <.001  Pamidronate 51 Rosen et al [2] 24  Pamidronate 49 NS  Zoledronic acid 46 Kohno et al [3] 12  Placebo 50.003  Zoledronic acid 30 *Includes HCM.

14. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Zoledronic Acid vs Placebo in Stage IV Breast Cancer With Bone Metastases Events at 12 Mos Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. 0 10 30 50 80 30.7 52.2 All SREs 8.8 17.7 Radiation to bone 25.4 38.9 Fractures 3.5 11.5 Spinal cord compression 2.6 8.8 HCM Patients (%) Zoledronic acid 4 mg (n = 114) Placebo (n = 113) 100 90 70 60 40 20

15. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. *P <.05 Zoledronic Acid vs Placebo in Stage IV BC: Pain Scores (Brief Pain Inventory) 1.0 0.8 0.6 0.4 0.2 0 -0.2 -0.4 -0.6 -0.8 BPI Mean Change From Baseline 4-mg zoledronic acid Placebo Time on Study (Wks) 05224812162024283236404448 * * * * * * * * * * * * *

16. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer 3 Identical International, Randomized, Double-Blind, Active-Controlled Trials Zoledronic Acid 4 mg IV* and Placebo SC q4w (n = 2861) Denosumab 120 mg SC and Placebo IV* q4w (n = 2862) Enrollment Criteria  Adults with breast, prostate, or other solid tumors and bone metastases or multiple myeloma  No current or previous IV bisphosphonate administration for treatment of bone metastases *Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine. Supplemental Calcium and Vitamin D Recommended 1° Endpoint  Time to first on-study SRE (noninferiority) 2° Endpoints  Time to first on-study SRE (superiority)  Time to first and subsequent on-study SRE (superiority)

17. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Breast Cancer Trial (136): Baseline Characteristics CharacteristicZoledronic Acid (n = 1020) Denosumab (n = 1026) Women, n (%)1011 (99)1018 (99) Median age, yrs5657 ECOG status of 0 or 1, n (%)932 (91)955 (93) Hormone receptor positive, n (%)726 (71)740 (72) Median time from initial diagnosis of bone metastasis to randomization, mos 2.02.1 Previous SRE,* n (%)373 (37)378 (37) Previous oral bisphosphonate use,* n (%)38 (4)42 (4) Presence of visceral metastases, n (%)525 (51)552 (54) *Based on randomization stratification. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

18. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Time to First On-Study SRE Zoledronic acid10208296765844984272961919429 Denosumab10268396976025144373061899926 Patients at Risk, n *Adjusted for multiplicity. KM Estimate of Median Mos Denosumab Zoledronic acid Not reached 26.4 HR: 0.82 (95% CI: 0.71-0.95; P <.001 noninferiority; P =.01 superiority*) Mos 0 1.00 Proportion of Subjects Without SRE 036912151821242730 0.25 0.50 0.75 Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

19. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Time to First On-Study SRE: Extended Analysis Zoledronic acid1020831675584498429356265186111384 Denosumab1026834692597510444384280193101389 Patients at Risk, n KM Estimate of Median Mos Denosumab Zoledronic acid 32.7 27.4 HR: 0.82 (95% CI: 0.71-0.95; P =.0096, superiority) Study Mo 0 1.0 Subjects Without SRE (%) 0.2 0.4 0.6 03691215182124273330 0.8 Stopeck A, et al. SABCS 2010. Abstract P6-14-01.

20. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Time to First On-Study SRE or Hypercalcemia: Extended Analysis Zoledronic acid1020831673581492424355263185109384 Denosumab1026834688594506441381276191100378 KM Estimate of Median Mos Denosumab Zoledronic acid 32.4 25.1 HR: 0.82 (95% CI: 0.71-0.95; P =.0076) Study Mo 0 1.0 Proportion of Patients Without SRE or Hypercalcemia 0.2 0.4 0.6 03691215182124273330 0.8 18% Risk Reduction Patients at Risk, n Stopeck A, et al. SABCS 2010. Abstract P6-14-01.

21. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Back to Our Case  Patient is started on zoledronic acid at 3.5 mg monthly secondary to a baseline CrCl of 55 mL/min  8 mos later, she develops severe rib pain and follow-up staging reveals a pathologic left rib fracture  Her antitumor therapy is changed to fulvestrant

22. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer What else would you recommend? A.Stop all bone-modifying therapy B.Continue zoledronic acid C.Switch to monthly denosumab D.Switch to monthly pamidronate E.Combine denosumab with zoledronic acid F.Check her uNTX and then determine therapy

23. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) 036912151821242730 0 0.5 1.0 1.5 Cumulative Mean Number of SRE Mos Total No. of Events Denosumab Zoledronic acid 474 608 Rate ratio: 0.77 (95% CI: 0.66-0.89; P =.001 † ) *Events that occurred at least 21 days apart. † Adjusted for multiplicity. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

24. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer n = number of patients randomized Lipton A, et al. ASCO 2010. Abstract 9015. Pooled Analysis: Time to First On-Study SRE by Previous SRE History HR: 0.82 (95% CI: 0.70-0.96; P =.015) HR: 0.83 (95% CI: 0.72-0.97; P =.021) HR: 0.83 (95% CI: 0.74-0.92; P <.001) Proportion of Patients Without On-Study SRE 0612182430 1.0 0.8 0.6 0.4 0.2 0 With Previous SRE Zoledronic acid (n = 819) Denosumab (n = 818) 0612182430 Without Previous SRE Zoledronic acid (n = 1091) Denosumab (n = 1094) 0612182430 Overall Zoledronic acid (n = 1910) Denosumab (n = 1912) Study Mo Risk Set, n ZA Dmab 819 818 0101 425 411266 145 144 36 48 1910 19124 1052 1084 692 716 382 402 114 127 1091 1094 4343 627 673 426 450 237 258 78 79

25. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Time to First Radiation to Bone Zoledronic acid102092281772163655538925612443 Denosumab102694884075166256539724713538 Patients at Risk, n KM Estimate of Median Mos Denosumab Zoledronic acid Not reached HR: 0.74 (95% CI: 0.59-0.94; P =.01) Study Mo 0 1.00 Proportion of Subjects Without Radiation to Bone 0.25 0.50 036912151821242730 0.75 26% Risk Reduction Stopeck A, et al. SABCS 2009. Abstract 22.

26. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Denosumab in Pts With Bone Mets and Excess Bone Resorption Despite IV BP Fizazi K, et al. J Clin Oncol. 2009;27:1564-1571. 100 020139212517 Visit Wk Median Change From Baseline in uNTx Corrected by Creatine (%) 80 60 40 20 0 -20 -40 -60 -80 -100 IV BP q4w Denosumab 180 mg q12w Denosumab 180 mg q4w Pooled denosumab group

27. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Percent Decrease in uNTx Levels With Therapy TrialDenosumabZoledronic Acid Breast cancer ↓ 80%↓ 68% Prostate cancer ↓ 40%↓ 28% Solid tumor/MM ↓ 76%↓ 65% Comparing baseline to Wk 13 values Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. Fizazi K, et al. Lancet. 2011;377:813-822. Henry DH et al. JCO 2011; 29:1125.

28. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer What is the best reason to continue bone- targeted therapy in this patient? A.Improvement in pain control B.Improvement in PFS C.Improvement in OS D.Improvement in QoL

29. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Disease Progression and OS from 3 Phase III Trials of Solid Tumor Patients Disease Progression OS HR: 1.00 (95% CI: 0.94-1.07; P =.9166) Events, n ZA2768 Denosumab2776 HR: 0.97 (95% CI: 0.90-1.06; P =.5242) Events, n ZA2768 Denosumab2776 1.0 0.8 0.6 0.4 0.2 0 Proportion of Subjects Without Disease Progression Study Mo 0612182430 Pts at Risk, n ZA Denosumab 2766 2770 17 21 1474 1497 837 850 395 408 134 1.0 0.8 0.6 0.4 0.2 0 Proportion of Subjects Survived Study Mo 0612182430 Pts at Risk, n ZA Denosumab 2768 2776 60 61 2099 2143 1543 1600 919 943 367 379 Richardson G, et al. COSA 2011. Abstract 296.

30. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Time to Experiencing Pain Improvement (  2-Point Decrease in Worst Pain Score of Brief Pain Inventory) Denosumab74535119613810888685133 Zoledronic acid74734420814810688715225 Pts at Risk, n KM Estimate of Median Days Denosumab Zoledronic acid 82 85 HR: 1.02 (95% CI: 0.91-1.15; P =.72) Mos 0 1.00 Proportion of Subjects 0.25 0.50 0369121518212427 0.75 Stopeck A, et al. ASCO 2010. Abstract 1024.

31. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Time to Worsening Pain in Patients With No or Mild Pain (0-4) at Baseline Stopeck A, et al. ASCO 2010. Abstract 1024. Denosumab542369286247197170126 Zoledronic acid50029422418015512895 KM Estimate of Median Mos Denosumab Zoledronic acid 9.7 5.8 HR: 0.78 (95% CI: 0.67-0.92; P =.0024) Mos 0 1.00 Proportion of Subjects 0.40 0.60 BL369121518 0.80 0.20 Pts at Risk, n

32. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Health-Related Quality-of-Life Outcomes  Functional Assessment of Cancer Therapy-General (FACT-G) –Total score –Physical well-being –Functional well-being –Social well-being –Emotional well-being  Higher scores indicate better health-related quality of life

33. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Quality of Life: FACT-G Mean Change From Baseline Health-related QoL was higher with dmab than ZA throughout the study -3 -2 0 1 1369121518 Zoledronic acid Denosumab 890845768700640592467 913878787709640575460 Mos Pts at risk, n From Baseline Mean Change in FACT-G Score Zoledronic acid Denosumab Fallowfield L, et al. ASCO 2010. Abstract 1025.

34. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer A.Acute phase reactions B.Hypocalcemia C.Infusion reactions D.ONJ E.Renal toxicity Which of the following AEs are more commonly seen with denosumab therapy compared with IV bisphosphonates?

35. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer *P =.2861 † No cases of hypocalcemia were grade 5 (fatal). ‡ In the first 3 days after initial treatment. Stopeck A, et al. SABCS 2010. Abstract P6-14-01. Adverse Events: From Extended Analysis Event, n (%)Zoledronic Acid (n = 1013) Denosumab (n = 1020) All adverse events987 (97.4)961 (96.2) Serious adverse events509 (50.2)489 (47.9) Adverse events related to renal toxicity95 (9.4)55 (5.4) Osteonecrosis of the jaw*18 (1.8)26 (2.5) Hypocalcemia (any)37 (3.7)62 (6.1)  Hypocalcemia of grade 3 or 4 † 12 (1.2)18 (1.8) Acute-phase reactions ‡ 286 (28.2)109 (10.7)

36. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Between-Group Differences in AEs With Unadjusted P <.05 Favors denosumabFavors zoledronic acid Hypocalcemia Toothache Renal failure acute Blood urea increased Bronchospasm Hyperthermia Skin hyperpigmentation Metastases to spine Hypercalcemia Edema Alanine aminotransferase increased Lumbar vertebral fracture Dyspepsia Renal failure Pain Chills Anemia Arthralgia Bone pain Pyrexia Risk Difference -1010-550 Zoledronic Acid, n (%) (n = 1013) Denosumab, n (%) (n = 1020) 247(24.4)170(16.7) 238(23.5)186(18.2) 291(28.7)250(24.5) 232(22.9)192(18.8) 58(5.7)29(2.8) 97(9.6)72(7.1) 25(2.5)2(0.2) 74(7.3)52(5.1) 56(5.5)35(3.4) 47(4.6)28(2.7) 40(3.9)22(2.2) 35(3.5)17(1.7) 21(2.1)9(0.9) 19(1.9)7(0.7) 15(1.5)4(0.4) 10(1.0)2(0.2) 8(0.8)0(0.0) 7(0.7)1(0.1) 37(3.7)57(5.6) 34(3.4)56(5.5) Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

37. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Back to Our Case  Our patient is switched from zoledronic acid to denosumab  6 mos after switching to denosumab, she develops dental pain  On examination, she has an area of exposed bone in her mandible

38. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Regarding her ONJ, what would you advise our patient? A.ONJ is often reversible B.Discontinue denosumab therapy C.See an oral surgeon for resection D.Avoid eating sweets

39. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Associated Oral Events n (%)Zoledronic Acid (n = 37) Denosumab (n = 52) All (N = 89) Tooth extraction24 (65)30 (58)54 (61) Jaw pain25 (68)46 (88)71 (80) Local infection17 (46)26 (50)43 (48) n (%)Zoledronic Acid (n = 37) Denosumab (n = 52) All (N = 89) Mandible31 (84)34 (65)65 (73) Maxilla5 (14)15 (29)20 (22) Both1 (3)3 (6)4 (4) Location of ONJ Saad F, et al. Ann Oncol. 2011 Oct 10. [Epub ahead of print]

40. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Systemic Risk Factors Subjects With ONJSubjects Without ONJ* n (%) ZA (n = 37) Denosumab (n = 52) All (N = 89) ZA (n = 2824) Denosumab (n = 2810) All (N = 5634) Diabetes † 11 (30)9 (17)20 (22)431 (15)443 (16)874 (16) Anemia (Hg <10) ‡ 17 (46)23 (44)40 (45)1185 (42)1119 (40)2304 (41) Chemotherapy agents 27 (73)36 (69)63 (71)1950 (69)1921 (68)3871 (69) Antiangiogenics8 (22)6 (12)14 (16)236 (8)214 (8)450 (8) Corticosteroids28 (76)39 (75)67 (75)1786 (63)1762 (63)3548 (63) *Includes subjects without oral events and subjects negatively adjudicated. † History or on study. ‡ Hg values centrally determined. Saad F, et al. Ann Oncol. 2011 Oct 10. [Epub ahead of print]

41. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Treatment n (%)Zoledronic Acid (n = 37) Denosumab (n = 52) All (N = 89) Limited surgery16 (43)21 (40)37 (42) Bone resection1 (3)3 (6)4 (4) Median or n (%)Zoledronic Acid (n = 37) Denosumab (n = 52) All (N = 89) Resolved*11 (30)21 (40)32 (36) Time to resolution †, mos8.78.08.2 Ongoing, present at time of death, or unknown 26 (70)31 (60)57 (64) Outcomes * Complete mucosal coverage of exposed bone; † Among subjects with ONJ resolution Saad F, et al. Ann Oncol. 2011 Oct 10. [Epub ahead of print]

42. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer What is the major factor that guides your choice among the available bone-targeted agents for your patients with bone metastases? A.Route of administration B.Adverse effect profile C.Efficacy in preventing SREs and HCM D.Efficacy in palliating pain from bone mets E.Cost F.Lytic vs blastic disease G.Life expectancy of the patient

43. clinicaloptions.com/oncology Preventing and Managing Skeletal-Related Events in Breast Cancer Conclusions  Bisphosphonates and denosumab are both effective at –Preventing SREs and HCM –Palliating pain from bone mets –Preventing the development of pain  2 distinct choices –Different toxicity profiles –Zoledronic acid: flulike symptoms, fevers, bone pains, renal toxicity –Denosumab: hypocalcemia –Subcutaneous vs intravenous administration

44. Go Online to Access More Education on Bone Health! Downloadable slides from the symposium Expert Insight tools Proceedings of an Independent Expert Panel on Bone Health Interactive Virtual Presentations on bone health for patients with cancer clinicaloptions.com/oncology