Role of Bone-Targeted Therapy in the Treatment of Prostate Cancer

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  • This slide lists the faculty who were involved in the production of these slides.
  • BMD, bone mineral density; GnRH, gonadotropin-releasing hormone.
  • Curatio PowerPoint Template 10/15/12 07:14 Curatio PowerPoint Template ADT, androgen-deprivation therapy.
  • FDA, US Food and Drug Administration.
  • BMD, bone mineral density. Curatio PowerPoint Template 10/15/12 07:14
  • Curatio PowerPoint Template 10/15/12 07:14 BMD, bone mineral density; GnRH, gonadotropin-releasing hormone.
  • Curatio PowerPoint Template 10/15/12 07:14 BMD, bone mineral density; GnRH, gonadotropin-releasing hormone.
  • Curatio PowerPoint Template 10/15/12 07:14 BMD, bone mineral density; GnRH, gonadotropin-releasing hormone; IV, intravenous.
  • q6m, every 6 months.
  • Curatio PowerPoint Template 10/15/12 07:14 BMD, bone mineral density.
  • Curatio PowerPoint Template 10/15/12 07:14 ADT, androgen-deprivation therapy; BMD, bone mineral density; BMI, body mass index.
  • PSA, prostate-specific antigen; PSADT, prostate-specific antigen doubling time.
  • BMFS, bone metastasis–free survival; CRPC, castration-resistant prostate cancer; M0, nonmetastatic; OS, overall survival; PSA, prostate-specific antigen; PSADT, prostate-specific antigen doubling time; q4w, every 4 weeks; SC, subcutaneous.
  • CI, confidence interval; HR, hazard ratio.
  • CI, confidence interval; HR, hazard ratio.
  • CI, confidence interval; CRPC, castration-resistant prostate cancer; HR, hazard ratio; M0, nonmetastatic; OS, overall survival.
  • PSADT, prostate-specific antigen doubling time.
  • CI, confidence interval; HR, hazard ratio; PSADT, prostate-specific antigen doubling time.
  • CI, confidence interval; HR, hazard ratio; PSADT, prostate-specific antigen doubling time.
  • CI, confidence interval; HR, hazard ratio; PSADT, prostate-specific antigen doubling time.
  • CRPC, castration-resistant prostate cancer.
  • CRPC, castration-resistant prostate cancer; q3w, every 3 weeks; SRE, skeletal-related event.
  • q3w, every 3 weeks; SRE, skeletal-related event.
  • OS, overall survival; QoL, quality of life; SRE, skeletal-related event; ZOL, zoledronic acid.
  • AUC, area under the curve; CrCl, creatinine clearance.
  • CRPC, castration-resistant prostate cancer; IV, intravenous; q4w, every 4 weeks; SC, subcutaneous.
  • CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier; SRE, skeletal-related event.
  • ONJ, osteonecrosis of the jaw.
  • ADT, androgen-deprivation therapy; CALGB, Cancer and Leukemia Group B; OS, overall survival; PC, prostate cancer; PFS, progression-free survival; q4w, every 4 weeks; SRE, skeletal-related event.
  • OS, overall survival; PO, orally; PSA, prostate-specific antigen; QD, once daily.
  • OS, overall survival; SRE, skeletal-related event.
  • AA, abiraterone acetate; CI, confidence interval; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival.
  • AA, abiraterone acetate; OS, overall survival; PFS, progression-free survival; SRE, skeletal-related event; TTP, time to palliation.
  • CI, confidence interval; CRPC, castration-resistant prostate cancer; HR, hazard ratio; NR, not reached; OS, overall survival.
  • CI, confidence interval; CRPC, castration-resistant prostate cancer; HR, hazard ratio; NYR, not yet reached; SRE, skeletal-related event.
  • CRPC, castration-resistant prostate cancer; VEGFR, vascular endothelial growth factor receptor.
  • ALP, alkaline phosphatase; BSC, best supportive care; CRPC, castration-resistant prostate cancer; OS, overall survival; PSA, prostate-specific antigen; QoL, quality of life; SRE, skeletal-related event. David I. Quinn, MD, PhD: The ALSYMPCA phase III trial evaluated injected radioisotopes (radium-223) in patients with symptomatic castration-resistant prostate cancer, at least 2 bone metastases, and who were not eligible for docetaxel. Of note, patients who are not fit for docetaxel represent approximately 40% of castration-resistant prostate cancer patients and are typically excluded from clinical trials that incorporate docetaxel. In this study, both sets of patients were offered best standard-of-care treatment, which included a number of secondary hormonal manipulations. Patients that were receiving bis phosphonates were required to continue them; initiating bisphosphonates on this study was not allowed.
  • CI, confidence interval; HR, hazard ratio; OS, overall survival.
  • CI, confidence interval; HR, hazard ratio; SRE, skeletal-related event.
  • CI, confidence interval; HR, hazard ratio; SRE, skeletal-related event.
  • RTK, receptor tyrosine kinase.
  • AR, androgen receptor; PCa, prostate cancer.
  • ALP, alkaline phosphatase; CTx, C-telopeptide; ULN, upper limit of normal.
  • VEGF, vascular endothelial growth factor.
  • BID, twice daily; CRPC, castration-resistant prostate cancer; IRF, independent review facility; QD, once daily. OS, overall survival.
  • CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors.
  • BAP, bone alkaline phosphatase; CRPC, castration-resistant prostate cancer; PR, partial response; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors; uNTx, urinary N-telopeptide.
  • CRPC, castration-resistant prostate cancer; OS, overall survival; PO, orally; PSA, prostate-specific antigen; SD, stable disease; SRE, skeletal-related event; uNTx, urinary N-telopeptide.
  • Curatio PowerPoint Template 10/15/12 07:14 CRPC, castration-resistant prostate cancer; SREs, skeletal-related events.
  • Role of Bone-Targeted Therapy in the Treatment of Prostate Cancer

    1. 1. Role of Bone-Targeted Therapy in the Treatment of Prostate CancerThis program is supported by an educational donation from
    2. 2. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology 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)DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of theCCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providingeducational grants. The materials may discuss uses and dosages for therapeutic products that have notbeen approved by the United States Food and Drug Administration. A qualified healthcare professionalshould be consulted before using any therapeutic product discussed. Readers should verify all informationand data before treating patients or using any therapies described in these materials.
    3. 3. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Faculty Matthew Raymond Smith, MD, PhD Professor of Medicine Harvard Medical School Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts Evan Y. Yu, MD Associate Professor Department of Medicine/Oncology University of Washington/Fred Hutchinson Cancer Research Center Seattle, Washington
    4. 4. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Faculty Disclosures Matthew Raymond Smith, MD, has disclosed that he has received consulting fees and research contracts from Amgen. Evan Y. Yu, MD, has disclosed that he has received consulting fees from Amgen, Astellas, Medivation, and Janssen and research contracts from Janssen and Bristol-Myers Squibb.
    5. 5. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Overview  Fracture Prevention in Early-Stage Prostate Cancer  Delaying Bone Metastases in Prostate Cancer  Treatment of Bone Metastases Secondary to Castration-Resistant Prostate Cancer  Treatment of Bone Metastases Secondary to Hormone-Sensitive Prostate Cancer  Novel Agents With Bone Protective Effects
    6. 6. Fracture Prevention inEarly-Stage Prostate Cancer
    7. 7. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Fracture Risk by Sex and Age 4000 Men Women Hip Spine Incidence/1,000,000 Person-Yrs 3000 2000 1000 35-39 ≥ 85 35-39 ≥ 85 Age (Yrs)Melton LJ 3rd, et al. J Bone Miner Res. 1992;7:1005-1010.
    8. 8. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology GnRH Agonists Decrease BMD in Men With Prostate Cancer 2 Control 1 GnRH agonist 0 P < .001 for each Percent Change comparison -1 -2 -3 -4 12-mo data -5 Lumbar Total Spine HipMittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661.
    9. 9. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Proportion of Patients With Fractures 1-5 Yrs After Cancer Diagnosis +6.8%; P < .001 21 No ADT (n = 20,035) ADT (n = 6650) 18 19.4 15 Frequency (%) 12 12.6 9 +2.8%; P < .001 6 5.2 3 2.4 0 Any Fracture Fracture Resulting in HospitalizationShahinian VB, et al. N Engl J Med. 2005;352:154-164.
    10. 10. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology National Osteoporosis Foundation Fracture Prevention Guidelines for Men  Consider FDA-approved medical therapies based on the following – A vertebral or hip fracture – Femoral neck or spine T-score ≤ -2.5 – FRAX 10-yr probability of a hip fracture ≥ 3% or 10-yr probability of any major fracture ≥ 20%National Osteoporosis Foundation Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2010.
    11. 11. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology The FRAX Tool: Assessing Fracture Riskhttp://www.sheffield.ac.uk/FRAX
    12. 12. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Alendronate Increases BMD During GnRH Agonist Therapy 5 12-Mo Data 4 BMD Percent Change 3 Placebo 2 Alendronate 1 0 -1 -2 -3 Lumbar Total Spine HipGreenspan SL, et al. Ann Intern Med. 2007;146:416-424.
    13. 13. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Quarterly Zoledronic Acid Increases BMD During GnRH Agonist Therapy 8 Final 12-Mo Data P < .001 for each comparison 6 BMD Percent Change 4 Placebo Zoledronic acid 2 0 -2 -4 Lumbar Total Spine HipSmith MR, et al. J Urol. 2003;169:2008-2012.
    14. 14. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy 6 Final 12-Mo Data P < .005 for each comparison 4 BMD Percent Change 2 Placebo Zoledronic acid 4 mg/yr IV 0 -2 -4 -6 Lumbar Total Spine HipMichaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.
    15. 15. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Denosumab Fracture Prevention Study Current androgen deprivation therapy for prostate cancer for 3 yrs patients older than 70 yrs of age or with T score < -1.0 (N = 1468) for 3 yrs  Primary endpoints: bone mineral density, new vertebral fracturesSmith MR, et al. N Engl J Med. 2009;361:745-755.
    16. 16. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Denosumab Increased BMD at All Skeletal Sites 10 Lumbar Spine 10 Total Hip 8 8 From Baseline (%) From Baseline (%) Change in BMD Change in BMD 6 Denosumab 6 4 4 Denosumab Difference at 24 mos, 2 6.7 percentage points 2 Difference at 24 mos, 0 0 4.8 percentage points -2 Placebo -2 -4 -4 Placebo -6 -6 01 3 6 12 24 36 01 3 6 12 24 36 Mos Mos 10 Femoral Neck 10 Distal Third of Radius 8 8 From Baseline (%) From Baseline (%) Change in BMD Change in BMD 6 6 4 Denosumab 4 Denosumab 2 Difference at 24 mos, 2 0 3.9 percentage points 0 Difference at 24 mos, 5.5 percentage points -2 -2 Placebo Placebo -4 -4 -6 -6 01 3 6 12 24 36 01 3 6 12 24 36 Mos MosSmith MR, et al. N Engl J Med. 2009;361:745-755.
    17. 17. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Denosumab for Fracture Prevention 10 Denosumab Placebo New Vertebral Fracture (%) 8 P = .004 P = .004 P = .006 6 3.9 4 3.3 1.9 2 1.5 1.0 0.3 0 12 24 36 Mos Patients at Risk, n 13 2 22 7 26 10Smith MR, et al. N Engl J Med. 2009;361:745-755.
    18. 18. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Fracture Risk: Conclusions  Osteoporosis and fractures are an important health problem in men  Various factors increase fracture risk including older age, low BMI, smoking, alcohol use, and low BMD  ADT increases fracture risk  Some but not all men require drug therapy to prevent fractures during ADT  Effective therapies are available – Bisphosphonates increase BMD – Denosumab increases BMD and decreases vertebral fractures
    19. 19. Delaying Bone Metastases in Prostate Cancer
    20. 20. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Natural History of Castration-Resistant Nonmetastatic Prostate Cancer 1.0 Death Bone metastasis Bone metastasis or death 0.8 Proportion With Event 0.6 0.4 0.2 0 0 0.5 1.0 1.5 2.0 2.5 3.0 Yrs Since Random AssignmentSmith MR, et al. J Clin Oncol. 2005;23:2918-2925.
    21. 21. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology PSA and PSADT Are Associated With Shorter Bone Metastasis–Free Survival 1.0 PSA < 7.7 ng/mL 1.0 PSADT < 6.3 mos PSA 7.7-24.0 ng/mL PSADT 6.3-18.8 mosProportion of Patients With Bone PSA > 24.0 ng/mL PSADT > 18.8 mos 0.8 0.8 Metastases or Died 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 0.5 1.0 1.5 2.0 2.5 3.0 0 0.5 1.0 1.5 2.0 2.5 3.0 Yrs Since Random Assignment Yrs Since Random AssignmentSmith MR, et al. J Clin Oncol. 2005;23:2918-2925..
    22. 22. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Phase III Study: BMFS With Denosumab in M0 CRPC With Aggressive PSA Kinetics Bone metastasis or death Double-blind randomization Denosumab 120 mg SC q4w (n = 716) Patients with M0 CRPC at high risk for bone metastases: Calcium and vitamin D Survival PSA ≥ 8.0 ng/mL supplementation follow-up or PSADT ≤ 10.0 mos (N = 1432) Placebo 120 mg SC q4w Off investigational (n = 716) product  Primary endpoint: BMFS  Secondary endpoints: time to first bone metastasis (either symptomatic or asymptomatic), OSSmith MR, et al. Lancet. 2012;379:39-46.
    23. 23. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Denosumab Increases Bone Metastasis– Free Survival 1.0 HR: 0.85 (95% CI: 0.73-0.98; P = .028) Proportion of Patients 0.8 0.6 0.4 Median 0.2 Survival, Mos Events, n Denosumab 29.5 335 Placebo 25.2 370 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Patients at Risk, n Mos Denosumab 716 695 605 521 456 400 368 324 279 228 185 153 111 59 35 Placebo 716 691 569 500 421 375 345 300 259 215 168 137 99 60 36Smith MR, et al. Lancet. 2012;379:39-46.
    24. 24. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Time to First Bone Metastasis With Denosumab 1.0 HR: 0.84 (95% CI: 0.71-0.98; P = .032) 0.8 Proportion of Patients 0.6 0.4 Median 0.2 Time, Mos Events, n Denosumab 33.2 286 Placebo 29.5 319 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 MosSmith MR, et al. Lancet. 2012;379:39-46.
    25. 25. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Denosumab in High-Risk M0 CRPC: Secondary Endpoints  OS: no improvement with denosumab  Time to first bone metastasis prolonged vs placebo with denosumab vs placebo  Fewer symptomatic bone metastases with denosumab vs placebo OS Time to Symptomatic Bone Metastasis Proportion of Patients Alive Without Symptomatic Bone 1.0 1.0 Proportion of Patients 0.8 0.8 Metastases HR: 0.67 (95% CI: 0.49-0.92; 0.6 HR: 1.01 (95% CI: 0.85-1.20; 0.6 P = .013) P = .91) 33% Risk reduction 0.4 0.4 Events, n (%) 0.2 Placebo 0.2 Placebo 96 (13) Denosumab Denosumab 69 (10) 0 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 Study Mo Study MoSmith MR, et al, Lancet. 2012;379:39-46.
    26. 26. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Denosumab and Adverse Events Adverse Events, n (%) Placebo (n = 705) Denosumab (n = 720) Any adverse event 655 (93) 676 (94) Most common adverse events Back pain 156 (22) 168 (23) Constipation 119 (17) 127 (18) Arthralgia 112 (16) 123 (17) Diarrhea 102 (14) 111 (15) Urinary tract infection 96 (14) 108 (15) Serious adverse events 323 (46) 329 (46) Most common serious adverse events Urinary retention 31 (4) 54 (8) Hematuria 24 (3) 35 (5) Prostate cancer 21 (3) 15 (2) Anemia 12 (2) 22 (3) Urinary tract infection 14 (2) 15 (2) Grade 3, 4, or 5 adverse events 353 (50) 381 (53) Adjudicated positive osteonecrosis of the jaw 0 33 (5) Hypocalcaemia 2 (< 1) 12 (2)Smith MR, et al, Lancet. 2012;379:39-46.
    27. 27. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Relationship Between PSADT and Risk for Bone Metastasis or Death* 3.0 2.8 Relative Risk for Bone Metastasis or Death 2.6 2.4 Increasing Risk 2.2 2.0 1.8 1.6 *Placebo arm of 1.4 study (n = 147) 20 18 16 14 12 10 8 6 4 2 PSADT in Mos Shorter PSADTSmith MR, et al. ASCO GU 2012. Abstract 6.
    28. 28. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Bone Metastasis–Free Survival in Patients With PSADT ≤ 10 Mos 1.0 HR: 0.84 (95% CI: 0.72-0.99; P = .042) Bone Metastasis–Free Survival Proportion of Patients With 0.8 16% Risk reduction 0.6 0.4 Median Delay, 0.2 Mos Mos Events, n Placebo 22.4 309 6.0 Denosumab 28.4 273 0 0 6 12 18 24 30 36 Patients at Risk, n Study Mo Placebo 580 561 460 398 335 296 273 235 199 159 125 102 74 Denosumab 574 557 486 410 351 306 282 249 215 171 138 109 77Smith MR, et al. ASCO GU. 2012. Abstract 6.
    29. 29. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Bone Metastasis–Free Survival in Patients With PSADT ≤ 6 Mos 1.0 HR: 0.77 (95% CI: 0.64-0.93; P = .006) Bone Metastasis–Free Survival Proportion of Patients With 0.8 23% Risk reduction 0.6 0.4 Median Delay, 0.2 Mos Mos Events, n Placebo 18.7 242 7.2 Denosumab 25.9 97 0 0 6 12 18 24 30 36 Patients at Risk, n Study Mo Placebo 427 411 323 274 223 194 176 148 122 99 78 65 47 Denosumab 419 406 345 284 238 207 193 170 145 109 89 67 46Smith MR, et al. ASCO GU. 2012. Abstract 6.
    30. 30. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Bone Metastasis–Free Survival in Patients With PSADT ≤ 4 Mos 1.0 HR: 0.71 (95% CI: 0.56-0.90; P = .004) Bone Metastasis–Free Survival Proportion of Patients With 0.8 29% Risk reduction 0.6 0.4 Median Delay, 0.2 Mos Mos Events, n Placebo 18.3 167 7.5 Denosumab 25.8 124 0 0 6 12 18 24 30 36 Patients at Risk, n Study Month Placebo 289 279 209 176 138 117 105 88 71 58 46 35 Denosumab 263 254 217 176 143 123 117 102 89 67 56 38Smith MR, et al. ASCO GU. 2012. Abstract 6.
    31. 31. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Bone Metastasis Delay: 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 – Not approved for this indication  In men with high-risk nonmetastatic CRPC, denosumab increases bone metastasis–free survival, time to first bone metastasis, and time to symptomatic bone metastasis – Dose higher/more frequent (120 mg q4 wks vs 60 mg q6 mos) than what is approved to prevent fractures in men with CTIBL  Effects of denosumab on bone metastasis–free survival were maintained in men at particularly high risk
    32. 32. Treatment of Bone Metastases Secondary to Castration- Resistant Prostate Cancer
    33. 33. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Skeletal-Related Events and Clinical Consequences of Bone Metastases Skeletal-Related Events Other Clinical Symptoms  Pathologic fractures*  Bone pain  Spinal cord compression*  Analgesic usage  Radiation therapy to bone*  Quality-of-life deterioration  Surgery to bone*  Shortened survival  Hypercalcemia  Change in antineoplastic therapy *Universally accepted skeletal-related events.
    34. 34. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Combined Analysis of 2 Phase III Trials of Pamidronate in Metastatic CRPC Eligibility Criteria R A  Prostate cancer with N Pamidronate 90 mg q3w x 9 confirmed skeletal D (n = 169) metastases O  Bone pain secondary to bone M metastases I  No previous bisphosphonate Z Placebo q3w x 9 E (n = 181) D SRE (Study Wk 27), n (%) Pamidronate Placebo Any SRE 42 (25) 46 (25) Radiation to bone (pain relief) 25 (15) 29 (16) Vertebral fracture 11 (7) 10 (6) Spinal cord compression 5 (3) 3 (2) Surgery to bone 5 (3) 6 (3)Small EJ, et al. J Clin Oncol. 2003;21:4277-4284.
    35. 35. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Zoledronic Acid in Castration-Resistant Prostate Cancer Eligibility Criteria R Zoledronic acid 4 mg q3w A (n = 214) N  Patients with prostate D cancer O Zoledronic acid 4 mg q3w  Castration resistant M  Bone metastases (initially 8 mg) I (n = 221) (N = 643) Z E Placebo q3w D (n = 208)  Patients in 8-mg arm reduced to 4 mg because of renal toxicity  Primary outcome: proportion of patients having ≥ 1 SRE  Secondary outcomes: time to first on-study SRE, proportion of patients with SREs, and time to disease progressionSaad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.
    36. 36. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Time to First SRE: Zoledronic Acid vs Placebo  SREs: ZOL 4 mg 38%; placebo 49% (P = .028) 100 – 11% absolute risk reduction in ≥ 1 SRE  Pain/analgesia scores increased less with ZOL Percent Without Event 80  No improvement in tumor progression, QoL, OS 60 40 Median, Days P Value 20 ZOL 4 mg 488 .009 Placebo 321 0 0 120 240 360 480 600 720 Days ZOL 4 mg 214 149 97 70 47 35 3 Placebo 208 128 78 44 32 20Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. Saad F, et al. ASCO 2003. Abstract 1523. Saad F,et3 J Natl Cancer Inst. 2004;96:879-882. al.
    37. 37. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Treatment Guidelines for Zoledronic Acid and Renal Dysfunction  Calculate baseline CrCl to determine patient-specific starting dose  For patients with CrCl > 60 mL/min, the recommended starting dose is 4 mg infused over no less than 15 mins every 3-4 wks  For patients with reduced CrCl the following schedule is recommended Starting Dose Recommendations for Patients With Reduced CrCl Baseline CrCl, mL/min Recommended Dose,* mg 50-60 3.5 mg 40-49 3.3 mg 30-39 3.0 mg < 30 Not recommended CrCl calculated using Cockcroft-Gault formula *Doses calculated assuming target AUC of 0.66 (mg .hr/L) (CrCl = 75 mL/min)Zoledronic acid [package insert]. 2012.
    38. 38. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Treatment Algorithm for Continuing Zoledronic Acid For the second and all subsequent doses Measure serum creatinine prior to each q3- to 4-wk dose If significant change in creatinine* If no significant change in creatinine Withhold therapy Give the starting dose Resume starting dose when creatinine returns to within 10% of baseline *An increase of 0.5 mg/dL for patients with normal baseline serum creatinine (< 1.4 mg/dL) or an increase of 1.0 mg/dL for patients with abnormal baseline serum creatinine (≥ 1.4 mg/dL)Zoledronic acid [package insert]. 2012.
    39. 39. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Denosumab vs Zoledronic Acid: Double- Blind, Placebo-Controlled Phase III Trial Denosumab 120 mg SC + Placebo IV* q4w Patients with CRPC and bone (n = 950) metastases, and no current or past IV bisphosphonate treatment (N = 1901) Zoledronic acid 4 mg IV* + Placebo SC q4w (n = 951)  Calcium and vitamin D supplemented in both treatment groups  Primary endpoint: time to first on-study SRE (fracture, radiation or surgery to bone, spinal cord compression) *Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine.Fizazi K, et al. Lancet. 2011;377:813-822.
    40. 40. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Time to First On-Study SRE 1.00 HR: 0.82 (95% CI: 0.71-0.95; Risk Proportion of Subjects Without SRE P = .0002, noninferiority; 18% reduction P = .008, superiority) 0.75 0.50 KM Estimate of 0.25 Median Mos Denosumab 20.7 Zoledronic acid 17.1 0 0 3 6 9 12 15 18 21 24 27 Study Mo Patients at Risk, n Zoledronic acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39Fizazi K, et al. Lancet. 2011;377:813-822.
    41. 41. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Adverse Events of Interest Subject Incidence, n (%) Zoledronic Acid Denosumab (n = 945) (n = 943) Infectious adverse events 375 (39.7) 402 (42.6) Infectious serious adverse events 108 (11.4) 130 (13.8) Acute-phase reactions (first 3 days) 168 (17.8) 79 (8.4) Renal adverse events* 153 (16.2) 139 (14.7) Cumulative rate of ONJ† 12 (1.3) 22 (2.3) Yr 1 5 (0.5) 10 (1.1) Yr 2 8 (0.8) 22 (2.3) Hypocalcemia 55 (5.8) 121 (12.8) New primary malignancy 10 (1.1) 18 (1.9) *Includes renal failure, increased blood creatinine, acute renal failure, renal impairment, increased blood urea, chronic renal failure, oliguria, hypercreatinemia, anuria, azotemia, decreased creatinine renal clearance, decreased urine output, abnormal blood creatinine, proteinuria, decreased glomerular filtration rate, and nephritis. † P = .09 Fizazi K, et al. ASCO 2010. Abstract LBA4507. Fizazi K, et al. Lancet. 2011;377:813-822.
    42. 42. Treatment of Bone MetastasesSecondary to Hormone-Sensitive Prostate Cancer
    43. 43. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology CALGB 90202: Zoledronic Acid in Hormone-Sensitive PC With Bone Mets Progression to androgen-independent prostate cancer Zoledronic acid IVPatients with prostate over 15 mins, Day 1,cancer metastatic to q4w + ADT bone who are Zoledronic acid IV receiving ADT over 15 mins, Day 1, (Planned N = 680; q4w + ADT> 90% accrued as of Placebo IV over August 2012) 15 mins, Day 1, q4w + ADT  Currently, there is no proven role for zoledronic acid in this setting  Primary endpoint: time to first SRE  Secondary endpoints: OS, PFS, toxicityClinicalTrials.gov. NCT00079001.
    44. 44. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Do Bisphosphonates Prolong Survival?  MRC PR05 study – Hormone-sensitive metastatic prostate cancer – Clodronate 2080 mg PO QD vs placebo – Endpoints – Primary: progression of symptomatic bone metastases or death – Secondary: OS, safety  PR05: OS benefit (P = .032) with early separation of curves  MRC PR04: no benefit in PSA detectable–only diseaseDearnaley DP, et al. Lancet Oncol. 2009;10:872-876.
    45. 45. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Denosumab and Zoledronic Acid: Indications in Advanced Prostate Cancer Indication Denosumab Zoledronic Acid 120 mg SC Monthly 4 mg IV Monthly Bone metastases Yes No from hormone- sensitive disease Bone metastases Yes Yes from CRPC
    46. 46. Novel Agents WithBone-Protective Effects
    47. 47. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Novel Agents With Both Antitumor and Bone-Protective Effects  Recent study reports of benefits of abiraterone,[1] enzalutamide (MDV-3100),[2] and radium-223[3] describe reduction in SREs  These studies demonstrate an OS benefit and report SREs as supportive measure of clinical benefit  Hypothesized to be related to direct antitumor effects1. Logothetis C, et al. ASCO 2011. Abstract 4520. 2. Scher H, et al. 2012 ASCO GU CancersSymposium. Abstract LBA1. 3. Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.
    48. 48. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology COU-AA-301: Abiraterone Acetate Improves OS in Metastatic CRPC 100 HR: 0.646 (95% CI: 0.54-0.77; 80 P < .0001) Abiraterone acetate Median OS: 14.8 mos Survival (%) 60 (95% CI: 14.1-15.4) 40 Placebo Median OS: 10.9 mos 20 (95% CI: 10.2-12.0) Median OS with 2 previous Median OS with 1 previous chemos: chemo: 0 14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo 0 3 6 9 12 15 18 21 Patients at Risk, n Mos AA 797 736 657 520 282 68 2 0 Placebo 398 355 306 210 105 30 3 0de Bono J, et al. N Engl J Med. 2011;364:1995-2005.
    49. 49. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology COU-AA-301: Effect of Abiraterone Acetate on Pain Palliation and SREs  Nearly one half of COU-AA-301 patients report significant pain at baseline 70 100 AA Placebo Pts Not Experiencing 60 Pts Experiencing 155/349 80 Palliation (%) Palliation (%) 50 (44.4%) Median: 10.25 mos 40 44/163 60 30 (27.0%) 40 20 Median: 5.55 mos 10 20 P = .0010 (log rank) 0 0 AA (n = 797) Placebo (n = 398) 0 3 6 9 12 Mos Efficacy Measure Abiraterone Placebo P Value (n = 797) (n = 398) Median OS, mos 14.8 10.9 < .0001 Median radiographic PFS, mos 5.6 3.6 < .0001 Time to first SRE* 301 150 < .0001 (25th percentile), daysLogothetis C, et al. ASCO 2011. Abstract 4520.
    50. 50. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Phase III AFFIRM Trial of Enzalutamide (MDV3100) in Post-Docetaxel CRPC: OS  OS improved with enzalutamide vs placebo  Median follow-up: 14.4 mos HR: 0.631 (95% CI: 0.529-0.752; P < .0001) 100 37% reduction in risk of death 90 80 Enzalutamide: 18.4 mos 70 (95% CI: 17.3-NYR) Survival (%) 60 50 40 30 20 Placebo: 13.6 mos (95% CI: 11.3-15.8) 10 0 0 3 6 9 12 15 18 21 24 Pts at Risk, n Duration of OS (Mos) MDV3100 800 775 701 627 400 211 72 7 0 Placebo 399 376 317 263 167 81 33 3 0Scher HI, et al. ASCO GU 2012. Abstract LBA1.
    51. 51. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology AFFIRM Trial of Enzalutamide in Post- Docetaxel CRPC: Time to First SRE HR: 0.621 (P < .0001) 100 90 Enzalutamide: 16.7 mos 80 (95% CI: 14.6-19.1) 70 SRE Free (%) 60 50 40 30 20 Placebo: 13.3 mos 10 (95% CI: 5.5-NYR) 0 0 3 6 9 12 15 18 21 24 Time to Event (Mos) Pts at Risk, n Enzalutamide 800 676 548 379 209 87 19 2 0 Placebo 399 278 196 128 68 33 11 0 0De Bono JS, et al. ASCO 2012. Abstract 4519^.
    52. 52. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Other Novel Agents Targeting Bony Metastases in CRPC  Radium-223  Cabozantinib: MET/VEGFR-targeted agent  Dasatinib: Src inhibitorSaylor PJ, et al. J Clin Oncol. 2011;29:3705-3714.
    53. 53. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Radium-223 Targets Bone Metastases  Radium-223 functions as a calcium mimic  Targets sites of new bone growth Ca within and around bone metastases Ra  Excreted by the small intestineParker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.
    54. 54. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology ALSYMPCA: Phase III Trial of Radium-223 in Symptomatic Prostate Cancer Stratified by total ALP, previous docetaxel, and bisphosphonate use; randomized 2:1 Up to 6 treatments at 4-wk intervals Patients with symptomatic Radium-223 50 kBq/kg + CRPC and ≥ 2 bone BSC metastases with no known visceral metastases, either post-docetaxel or unfit for docetaxel Placebo (saline) + (N = 921) BSC  Primary endpoint: OS  Secondary endpoints: time to first SRE, time to total ALP progression, total ALP response, ALP normalization, time to PSA progression, safety, QoLParker C, et al. ASCO GU 2012. Abstract 8.
    55. 55. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology ALSYMPCA: Overall Survival 100 HR: 0.695 (95% CI: 0.552-0.875; 90 P = .00185) 80 70 60 OS (%) Radium-223 (n = 541) 50 Median OS: 14.0 mos 40 30 Placebo (n = 268) Median OS: 11.2 mos 20 10 0 0 3 6 9 12 15 18 21 24 27Pts at Risk, n MosRadium-223 541 450 330 213 120 72 30 15 3 0Placebo 268 218 147 89 49 28 15 7 3 0Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.
    56. 56. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology ALSYMPCA: Time to First SRE 100 HR: 0.610 (95% CI: 0.461-0.807; 90 P = .00046) 80 Pats Without SRE (%) 70 60 Radium-223 (n = 541) Median: 13.5 mos 50 40 Placebo (n = 268) 30 Median: 8.4 mos 20 10 0 0 3 6 9 12 15 18 21Pts at Risk, n MosRadium-223 541 379 214 111 51 22 6 0Placebo 268 159 74 30 15 7 2 0Sartor O, et al. ASCO GU 2012. Abstract 9.
    57. 57. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Radium-223: Effect on Specific SREs  Time to first SRE HR: 0.610 (P = .00046) – Median: 13.6 vs 8.4 mos for placebo Patients, n (%) Time to First Event (Radium-223 vs Placebo) SRE Radium-223 Placebo P Value* HR (n = 541) (n = 268) (95%CI) External beam 0.65 122 (23) 72 (27) .0038 radiotherapy (0.48-0.87) Spinal cord 0.44 17 (3) 16 (6) .016 compression (0.22-0.88) Pathologic 0.45 20 (4) 18 (7) .013 bone fracture (0.24-0.86) 0.80 Surgical intervention 9 (2) 5 (2) .69 (0.27-2.4) 3 of 4 SRE components improvedSartor AO, et al. ASCO 2012. Abstract 4551.
    58. 58. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology ALSYMPCA: Adverse Events of Interest All Grades Grade 3/4 Adverse Event, n (%) Radium-223 Placebo Radium-223 Placebo (n = 509) (n = 253) (n = 509) (n = 253) Hematologic Anemia 136 (27) 69 (27) 54 (11) 29 (12) Neutropenia 20 (4) 2 (1) 9 (2) 2 (1) Thrombocytopenia 42 (8) 14 (6) 22 (4) 4 (2) Nonhematologic Bone pain 217 (43) 147 (58) 89 (18) 59 (23) Diarrhea 112 (22) 34 (13) 6 (1) 3 (1) Nausea 174 (34) 80 (32) 8 (2) 4 (2) Vomiting 88 (17) 32 (13) 10 (2) 6 (2) Constipation 89 (18) 46 (18) 6 (1) 2 (1)Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.
    59. 59. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Cabozantinib (XL184): Target Profile Kinase IC50, nM RTK Cellular IC50, nM, Autophosphorylation MET 1.8 MET 8 VEGFR2 0.035 VEGFR2 4 RET 5.2 KIT 4.6 Cabozantinib, mg/kg AXL 7.0 V 3 10 30 100 TIE2 14 pMET H441 tumors* FLT3 14 MET S/T Ks (47) >200 pVEGFR2 Mouse ATP competitive, reversible lung† VEGFR2 *No growth factor stimulation. † VEGF-A administered 30 min prior to harvest.Data courtesy of Ron Weitzman and Dana Aftab.
    60. 60. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Role of MET in Prostate Cancer and Bone Metastases Androgen Deprivation Activates MET Signaling Stromal HGF HGF (autocrine + paracrine) AR MET Androgen deprivation AR X MET Activated MET Is Highly Expressed in Bone MetastasesZhang S, et al. Mol Cancer. 2010;9:9.
    61. 61. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Cabozantinib (cMET/VEGFR2 Inhibitor) Demonstrates Significant Bone Effects Bone Scan Evaluable (N = 108) n (%) Complete resolution 21 (19) Partial resolution 61 (56) Stable 23 (21) Progressive disease 3 (3) Effects on Osteoblast (t-ALP) and Osteoclast (CTx) Activity 100 100 Bisphosphonate treated % Best Change From Baseline 80 80 Bisphosphonate naive 60 60 40 40 20 20 0 0 -20 -20 -40 -40 -60 -60 -80 -80 -100 -100 Pts With Baseline t-ALP Samples From Wk 6 and 12Hussain M, et al. ASCO 2011. Levels ≥ 2 x ULN and (N = 118)Abstract 4516. ≥ 12 Wks of Follow-up (N = 28)
    62. 62. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Cabozantinib: Effects on Bone Pain and Narcotic Use % Change in Average Worst Pain From Baseline Nonrandomized Expansion Trial 20 Prospective: Pts With Average Worst Pain ≥ 4 at Baseline Randomized Discontinuation 0 ** * Trial; Post Hoc Investigator n (%) Improved Survey -20 Bone metastases and bone pain at baseline (n = 83): pain improvement at Wk 6 or 12 56 (67) -40 Narcotics for bone pain at baseline (n = 67): pain improvement at Wk 6 -60 or 12 47 (70) Evaluable for narcotics change -80 (n = 55): decrease or discontinuation of narcotics 31 (56) -100 Previous docetaxel Previous docetaxel + abiraterone and/or cabazitaxel 7/27 (26%) patients discontinued *Previous radionuclide therapy narcotics entirely Median best pain reduction from baseline: 46%Hussain M, et al. ASCO 2011. Abstract 4516. Basch EM, et al. 2011 AACR-NCI-EORTC Abstract B57.
    63. 63. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology MET and VEGFR Interactions in Bone Tumors  MET is activated in bone Stroma metastases Angiogenesis VEGF – Tumor cells express MET Proliferation differentiation HGF survival – Autocrine and paracrine Osteoblast HGF VEGF activation of MET by HGF VEGF HGF NP-1 MET – VEGF activation of MET Migration proliferation via neuropilin-1 HGF survival Migration VEGF Tumor Cell proliferation  Osteoblasts and osteoclasts survival – Express MET and VEGFRs OsteoclastZhang S, et al. Mol Cancer. 2010;9:9.
    64. 64. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Cabozantinib: Randomized Phase III Trials Patients with bone- Cabozantinib 60 mg QD +metastatic CRPC, moderate Pain Endpoint Trial[1] Mitoxantrone Placebo to severe bone pain, and  Primary endpoint: previous treatment with durable pain response docetaxel, abiraterone, or at Wk 12 enzalutamide  Secondary endpoints: (Planned N = 246) Mitoxantrone/Prednisone + bone scan response by Cabozantinib Placebo IRF, OS Cabozantinib 60 mg QD + Patients with bone- OS Endpoint Trial[2] Placebo metastatic CRPC, and  Primary endpoint: OS previous treatment with  Secondary endpoints:docetaxel, abiraterone, or bone scan response by enzalutamide IRF (Planned N = 246) Prednisone 5 mg BID + Placebo1. ClinicalTrials.gov. NCT01522443.2. ClinicalTrials.gov. NCT01605227.
    65. 65. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Dasatinib: Src Inhibition  Src and related kinases are overexpressed in prostate cancer tumor cells  Normal osteoclast function depends on Src kinase  Src inhibition blocks – Tumor cell proliferation – Osteoclast proliferation – Osteoclast activity/osteolysis
    66. 66. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Phase II Study: Dasatinib Monotherapy in Metastatic CRPC With No Previous Chemo 50 Tumor Size (by RECIST) 160 140 Urine N-Telopeptide Change From Baseline (%) Change From Baseline (%) 40 120 Maximum Tumor Size 30 100 Maximum uNTx 20 80 10 60 40 0 20 -10 0 -20 -20 -40 -30 -60 -40 -80 -50 -100 Bisphosphonate No bisphosphonate 200 PSA 100 Bone Alkaline PhosphataseChange From Baseline (%) Change From Baseline (%) 150 80 60 100 Maximum BAP Maximum PSA 40 50 20 0 0 -20 -50 -40 -100 -60 -150 -80 Bisphosphonate No bisphosphonateYu EY, et al. Clin Cancer Res. 2009;15:7421-7428.
    67. 67. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Phase I/II Study: Dasatinib Plus Docetaxel in CRPC  N = 46 patients with CRPC  Responses – Durable 50% PSA declines in 26/46 (57%) patients – 18/30 (60%) RECIST-evaluable patients had a PR – 14 (30%) patients had disappearance of a lesion on bone scan  Bone markers – 33/38 (87%) had decrease in uNTx – 26/34 (76%) had a decrease in BAP  Toxicity: grade 3/4 in 13/46 (28%)Araujo J, et al. Cancer. 2011;118:63-71.
    68. 68. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Docetaxel/Prednisone ± Dasatinib in CRPC: Phase III Study Docetaxel + Prednisone + Patients with Placebo daily metastatic CRPC and evidence of progression (Planned N = 1500) Docetaxel + Prednisone + Dasatinib 100 mg/day PO  Primary endpoint: OS  Secondary endpoints: ∆ uNTx, time to first SRE, ∆ pain intensity, time to PSA progression, tumor response rate, PFS, safety/tolerabilityClinicalTrials.gov. NCT00744497
    69. 69. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancerclinicaloptions.com/oncology Summary  Bisphosphonates increase bone mineral density during androgen-deprivation therapy  Denosumab increases bone mineral density and decreases fractures during androgen-deprivation therapy  In men with high-risk CRPC, denosumab significantly increased bone metastasis–free survival, time to bone metastasis, and time to symptomatic bone metastasis  Disease-related skeletal complications are common in men with metastatic prostate cancer  Zoledronic acid decreases risk of SREs in men with castrate-resistant disease and bone metastases  Denosumab is superior to zoledronic acid for delay in first skeletal-related events and rate of skeletal-related events in this setting  Newer systemic therapies with good antitumor efficacy have also been shown in secondary endpoint analyses to prevent and delay the occurrence of SREs
    70. 70. Go Online for More CCO Coverage of Bone Health!Expert perspectives on all the key data, plus interactive activitiesexploring the clinical implicationsInteractive Decision Support Tool: expert faculty provide theirtreatment recommendations based onspecific factors from your patientsclinicaloptions.com/oncology

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