1. Matthew Raymond Smith, MD, PhD Professor of Medicine Harvard Medical School Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts Bone-Modifying Agents to Prevent Bone Metastases in Men With Prostate Cancer This program is supported by an educational donation from

2. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Disclosure Matthew Raymond Smith, MD, PhD, has disclosed that he has received consulting fees from Amgen.

4. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Case Presentation  66-yr-old man with clinical stage T3bNx prostate cancer, Gleason 4+3 in multiple cores, PSA 14  Treated with IMRT + combined ADT for 24 mos  PSA < 0.1 at completion of therapy  2 yrs later, resumed ADT for progressive PSA rise to 23.6; PSA nadir < 0.1  Now, 3 yrs after initiation of salvage ADT, PSA is elevated at 18; estimated PSADT is 6 mos  No detectable metastases by bone scan and abdominal- pelvic CT

5. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer What is your best estimate for median time to detectable bone metastases? A.< 6 mos B.9 mos C.18 mos D.> 30 mos

6. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Natural History of Castration-Resistant Nonmetastatic Prostate Cancer Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. Death Bone metastasis Bone metastasis or death 1.0 0.8 0.6 0.4 0.2 0 00.51.01.52.02.53.0 Yrs Since Random Assignment Proportion With Event

7. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.. PSA and PSADT Are Associated With Shorter Bone Metastasis–Free Survival 1.0 0.8 0.6 0.4 0.2 0 Proportion of Patients With Bone Metastases or Died 00.51.00.52.02.53.0 Yrs Since Random Assignment PSA 24.0 ng/mL 1.0 0.8 0.6 0.4 0.2 0 00.51.00.52.02.53.0 Yrs Since Random Assignment PSADT 18.8 mos

8. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Case  Patient received secondary hormonal therapy with bicalutamide 50 mg PO QD  Best response was PD  PSA is now 33  No detectable metastases on repeat bone scan and abdominal-pelvic CT

9. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer What do you recommend for bone- targeted therapy? A.Monthly zoledronic acid to prevent metastases B.Monthly denosumab to prevent metastases C.Observation until detectable bone metastases D.Other

10. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Smith MR, et al. Lancet. 2012;379:39-46. Patients with M0 CRPC at high risk for bone metastases: PSA ≥ 8.0 ng/mL or PSADT ≤ 10.0 mos (N = 1432) Double-blind randomization Calcium and vitamin D supplementation Off investigational product Denosumab 120 mg SC q4w (n = 716) Placebo 120 mg SC q4w (n = 716) Survival follow-up Bone metastasis or death Phase III Study: BMFS With Denosumab in M0 CRPC With Aggressive PSA Kinetics  Primary endpoint: BMFS  Secondary endpoints: time to first bone metastasis (either symptomatic or asymptomatic), OS

11. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Smith MR, et al. Lancet. 2012;379:39-46. Denosumab Increases Bone Metastasis– Free Survival Proportion of Patients 0 1.0 0.8 0.6 0.4 0.2 0453691215182124273033363942 Mos HR: 0.85 (95% CI: 0.73-0.98; P =.028) Denosumab Placebo Median Survival, Mos 29.5 25.2 Events, n 335 370 Pts at Risk, n Denosumab Placebo 716 35 36 695 691 605 569 521 500 456 421 400 375 368 345 324 300 279 259 228 215 185 168 153 137 111 99 59 60

12. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Time to First Bone Metastasis With Denosumab Smith MR, et al. Lancet. 2012;379:39-46. Proportion of Patients 0 1.0 0.8 0.6 0.4 0.2 0453691215182124273033363942 Mos HR: 0.84 (95% CI: 0.71-0.98; P =.032) Denosumab Placebo Median Time, Mos 33.2 29.5 Events, n 286 319

13. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Smith MR, et al, Lancet. 2012;379:39-46. Denosumab in High-Risk M0 CRPC: Secondary Endpoints  OS: no improvement with denosumab vs placebo  Time to first bone metastasis prolonged with denosumab vs placebo  Fewer symptomatic bone metastases with denosumab vs placebo Study Month 0.2 Study Month 06121824 Proportion of Patients Survived 0 0.4 0.8 1.0 0.6 303642 Placebo Denosumab HR: 1.01 (95% CI: 0.85-1.20; P =.91) OS 0.2 06121824 Proportion of Patients Without Symptomatic Bone Metastases 0 0.4 0.8 1.0 0.6 3036 Placebo Denosumab HR: 0.67 (95% CI: 0.49-0.92; P =.013) Time to Symptomatic Bone Metastasis risk reduction Events, n (%) 96 (13) 69 (10) 33%

14. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Denosumab and Adverse Events Smith MR, et al, Lancet. 2012;379:39-46. Adverse Events, n (%)Placebo (n = 705)Denosumab (n = 720) Any adverse event655 (93)676 (94) Most common adverse events  Back pain156 (22)168 (23)  Constipation119 (17)127 (18)  Arthralgia112 (16)123 (17)  Diarrhea102 (14)111 (15)  Urinary tract infection96 (14)108 (15) Serious adverse events323 (46)329 (46) Most common serious adverse events  Urinary retention31 (4)54 (8)  Hematuria24 (3)35 (5)  Prostate cancer21 (3)15 (2)  Anemia12 (2)22 (3)  Urinary tract infection14 (2)15 (2) Grade 3, 4, or 5 adverse events353 (50)381 (53) Adjudicated positive osteonecrosis of the jaw033 (5) Hypocalcaemia2 (< 1)12 (2)

15. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Relationship Btwn PSADT & Risk for Bone Metastasis or Death: Placebo Arm of 147 Relative Risk for Bone Metastasis or Death 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 PSADT in Mos 2018161412108642 Shorter PSADT Increasing Risk Smith MR, et al. ASCO GU. 2012. Abstract 6.

16. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Bone Metastasis-Free Survival in Patients with PSADT ≤ 10 Months HR = 0.84 (95% CI 0.72, 0.99) P = 0.042 16% Risk Reduction Smith MR, et al. ASCO GU. 2012. Abstract 6. Proportion of Patients With Bone Metastasis-Free Survival 1.0 0.6 0.8 0.4 0.2 0.0 1202436 Study Month 58046033527319912574 57448635128221513877 61830 561 557 398 410 296 306 235 249 159 171 102 109 Placebo Denosumab Median Months Events Delay (Months) 22.4 28.4 6.0 309 273

17. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Bone Metastasis–Free Survival in Patients With PSADT ≤ 6 Mos HR: 0.77 (95% CI: 0.64-0.93; P =.006) 23% risk reduction Smith MR, et al. ASCO GU. 2012. Abstract 6. Proportion of Patients With Bone Metastasis–Free Survival 1.0 0.6 0.8 0.4 0.2 0 1202436 Study Mo 4273232231761227847 4193452381931458946 61830 411 406 274 284 194 207 148 170 99 109 65 67 Placebo Denosumab Median Mos Events, n Delay, Mos 18.7 25.9 7.2 242 97

18. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Bone Metastasis–Free Survival in Patients With PSADT ≤ 4 Mos HR = 0.71 (95% CI 0.56, 0.90) P = 0.004 29% Risk Reduction Proportion of Patients With Bone Metastasis–Free Survival 1.0 0.6 0.8 0.4 0.2 0 1202436 Study Mo 2892091381057146 2632171431178956 61830 279 254 176 117 123 88 102 58 67 35 38 Placebo Denosumab 18.3 25.8 7.5 167 124 Smith MR, et al. ASCO GU. 2012. Abstract 6. Median Mos Events, n Delay, Mos

19. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Conclusions  Bone metastases are a major cause of prostate cancer morbidity  Denosumab is the first bone-targeted therapy to delay bone metastases in men with prostate cancer  In men with high-risk nonmetastatic CRPC, denosumab increases bone metastasis–free survival, time to first bone metastasis, and time to symptomatic bone metastasis  Effects of denosumab on bone metastasis–free survival were maintained in men at particularly high risk

20. Go Online for More Education on Bone Health Interactive Decision Support Tools: Experts make treatment recommendations for patients with prostate or breast cancer Optimizing Bone Health in Patients With Cancer: Proceedings of an Independent Expert Panel Downloadable slides clinicaloptions.com/oncology