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

Role of Bone-Targeted Therapy in the Treatment of Prostate Cancer. This program is supported by an educational donation from. About These Slides.

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

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  1. Role of Bone-Targeted Therapy in the Treatment of Prostate Cancer This program is supported by an educational donation from

  2. 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 Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) DisclaimerThe materials published on the Clinical Care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 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. Faculty Matthew Raymond Smith, MD, PhDProfessor of MedicineHarvard Medical SchoolProgram Director, Genitourinary OncologyMassachusetts General Hospital Cancer CenterBoston, Massachusetts Evan Y. Yu, MDAssociate ProfessorDepartment of Medicine/OncologyUniversity of Washington/Fred Hutchinson Cancer Research CenterSeattle, Washington

  4. 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. 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. Fracture Prevention in Early-Stage Prostate Cancer

  7. Fracture Risk by Sex and Age Hip 4000 Men Women Spine 3000 Incidence/1,000,000 Person-Yrs 2000 1000 35-39 35-39 ≥ 85 ≥ 85 Age (Yrs) Melton LJ 3rd, et al. J Bone Miner Res. 1992;7:1005-1010.

  8. GnRH Agonists Decrease BMD in Men With Prostate Cancer 2 Control 1 GnRH agonist P < .001 for each comparison 0 -1 Percent Change -2 -3 -4 12-mo data -5 Lumbar Spine Total Hip Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661.

  9. Proportion of Patients With Fractures1-5 Yrs After Cancer Diagnosis +6.8%; P < .001 No ADT (n = 20,035) 21 ADT (n = 6650) 18 19.4 15 12 12.6 Frequency (%) 9 +2.8%; P < .001 6 5.2 3 2.4 0 Any Fracture Fracture Resulting in Hospitalization Shahinian VB, et al. N Engl J Med. 2005;352:154-164.

  10. 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. The FRAX Tool: Assessing Fracture Risk http://www.sheffield.ac.uk/FRAX

  12. Alendronate Increases BMD During GnRH Agonist Therapy 12-Mo Data 5 4 3 Placebo 2 Alendronate BMD Percent Change 1 0 -1 -2 -3 Lumbar Spine Total Hip Greenspan SL, et al. Ann Intern Med. 2007;146:416-424.

  13. Quarterly Zoledronic Acid Increases BMD During GnRH Agonist Therapy Final 12-Mo Data 8 P < .001 for each comparison 6 Placebo 4 Zoledronic acid BMD Percent Change 2 0 -2 -4 Lumbar Spine Total Hip Smith MR, et al. J Urol. 2003;169:2008-2012.

  14. Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy Final 12-Mo Data 6 P < .005 for each comparison 4 Placebo 2 Zoledronic acid 4 mg/yr IV BMD Percent Change 0 -2 -4 -6 Lumbar Spine Total Hip Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.

  15. Denosumab Fracture Prevention Study Denosumab q6mfor 3 yrs Current androgen deprivation therapy for prostate cancer patients older than 70 yrs of age or with T score < -1.0 (N = 1468) Placebo q6mfor 3 yrs • Primary endpoints: bone mineral density, new vertebral fractures Smith MR, et al. N Engl J Med. 2009;361:745-755.

  16. Denosumab Increased BMD at All Skeletal Sites Lumbar Spine Total Hip 10 10 8 8 Denosumab 6 6 Denosumab 4 4 Difference at 24 mos,6.7 percentage points Change in BMD From Baseline (%) Change in BMD From Baseline (%) 2 2 Difference at 24 mos,4.8 percentage points 0 0 -2 -2 Placebo Placebo -4 -4 -6 -6 0 1 3 6 12 24 36 0 1 3 6 12 24 36 Mos Mos Femoral Neck Distal Third of Radius 10 10 8 8 6 6 Denosumab 4 4 Denosumab Change in BMD From Baseline (%) Change in BMD From Baseline (%) 2 2 Difference at 24 mos,3.9 percentage points 0 0 Difference at 24 mos,5.5 percentage points -2 -2 Placebo Placebo -4 -4 -6 -6 0 1 3 6 12 24 36 0 1 3 6 12 24 36 Mos Mos Smith MR, et al. N Engl J Med. 2009;361:745-755.

  17. Denosumab for Fracture Prevention 10 Denosumab Placebo 8 P = .004 P = .004 P = .006 6 New Vertebral Fracture (%) 3.9 4 3.3 1.9 1.5 2 1.0 0.3 0 12 24 36 Mos 13 2 22 7 26 10 Patients at Risk, n Smith MR, et al. N Engl J Med. 2009;361:745-755.

  18. 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. Delaying Bone Metastases in Prostate Cancer

  20. Natural History of Castration-Resistant Nonmetastatic Prostate Cancer 1.0 DeathBone metastasisBone metastasis or death 0.8 0.6 Proportion With Event 0.4 0.2 0 0 0.5 1.0 1.5 2.0 2.5 3.0 Yrs Since Random Assignment Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.

  21. PSA and PSADT Are Associated With Shorter Bone Metastasis–Free Survival 1.0 PSA < 7.7 ng/mLPSA 7.7-24.0 ng/mLPSA > 24.0 ng/mL 1.0 PSADT < 6.3 mosPSADT 6.3-18.8 mosPSADT > 18.8 mos 0.8 0.8 0.6 0.6 Proportion of Patients With Bone Metastases or Died 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 Assignment Smith MR, et al. J Clin Oncol. 2005;23:2918-2925..

  22. 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 Bone metastasis or death Double-blind randomization Denosumab 120 mg SC q4w(n = 716) Patients with M0 CRPC at high risk for bone metastases: PSA ≥ 8.0 ng/mL or PSADT ≤ 10.0 mos (N = 1432) Survival follow-up Calcium and vitamin D supplementation Placebo 120 mg SC q4w (n = 716) Off investigational product Smith MR, et al. Lancet. 2012;379:39-46.

  23. Denosumab Increases Bone Metastasis– Free Survival 1.0 HR: 0.85 (95% CI: 0.73-0.98; P = .028) 0.8 0.6 Proportion of Patients 0.4 Median Survival, Mos29.525.2 Events, n335370 0.2 DenosumabPlacebo 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Mos Patients at Risk, nDenosumabPlacebo 716716 695691 605569 521500 456421 400375 368345 324300 279259 228215 185168 153137 11199 5960 3536 Smith MR, et al. Lancet. 2012;379:39-46.

  24. Time to First Bone Metastasis With Denosumab 1.0 HR: 0.84 (95% CI: 0.71-0.98; P = .032) 0.8 0.6 Proportion of Patients 0.4 Median Time, Mos33.229.5 Events, n286319 0.2 DenosumabPlacebo 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Mos Smith MR, et al. Lancet. 2012;379:39-46.

  25. 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 OS Time to Symptomatic Bone Metastasis 1.0 1.0 0.8 0.8 HR: 0.67 (95% CI: 0.49-0.92;P = .013) Proportion of Patients Without Symptomatic Bone Metastases 0.6 0.6 HR: 1.01 (95% CI: 0.85-1.20;P = .91) Proportion of Patients Alive 33% Risk reduction 0.4 0.4 Events, n (%)96 (13)69 (10) 0.2 0.2 PlaceboDenosumab PlaceboDenosumab 0 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 Study Mo Study Mo Smith MR, et al, Lancet. 2012;379:39-46.

  26. Denosumab and Adverse Events Smith MR, et al, Lancet. 2012;379:39-46.

  27. Relationship Between PSADT and Risk for Bone Metastasis or Death* 3.0 2.8 2.6 2.4 Relative Risk for Bone Metastasis or Death 2.2 Increasing Risk 2.0 1.8 1.6 *Placebo arm of study (n = 147) 1.4 20 18 16 14 12 10 8 6 4 2 PSADT in Mos Shorter PSADT Smith MR, et al. ASCO GU 2012. Abstract 6.

  28. Bone Metastasis–Free Survival in Patients With PSADT ≤ 10 Mos 1.0 HR: 0.84 (95% CI: 0.72-0.99;P = .042) 0.8 16% Risk reduction 0.6 Proportion of Patients With Bone Metastasis–Free Survival 0.4 Median Mos Delay, Mos Events, n 0.2 PlaceboDenosumab 22.428.4 309273 6.0 0 0 6 12 18 24 30 36 Study Mo Patients at Risk, n PlaceboDenosumab 580 561 460 335 296 273 235 199 125 74 398 159 102 574 557 486 351 306 282 249 215 138 77 410 109 171 Smith MR, et al. ASCO GU. 2012. Abstract 6.

  29. Bone Metastasis–Free Survival in Patients With PSADT ≤ 6 Mos 1.0 HR: 0.77 (95% CI: 0.64-0.93;P = .006) 0.8 23% Risk reduction 0.6 Proportion of Patients With Bone Metastasis–Free Survival 0.4 Median Mos Delay, Mos 0.2 Events, n PlaceboDenosumab 18.725.9 24297 7.2 0 0 6 12 18 24 30 36 Study Mo Patients at Risk, n PlaceboDenosumab 427 411 323 223 194 176 148 122 78 47 274 99 65 419 406 345 238 207 193 170 145 89 46 284 67 109 Smith MR, et al. ASCO GU. 2012. Abstract 6.

  30. Bone Metastasis–Free Survival in Patients With PSADT ≤ 4 Mos 1.0 HR: 0.71 (95% CI: 0.56-0.90;P = .004) 0.8 29% Risk reduction 0.6 Proportion of Patients With Bone Metastasis–Free Survival 0.4 Median Mos Delay, Mos 0.2 Events, n 18.325.8 167124 PlaceboDenosumab 7.5 0 0 6 12 18 24 30 36 Study Month Patients at Risk, n PlaceboDenosumab 289 279 209 138 117 105 88 71 46 176 58 35 263 254 217 143 123 117 102 89 56 176 38 67 Smith MR, et al. ASCO GU. 2012. Abstract 6.

  31. 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. Treatment of Bone Metastases Secondary to Castration-Resistant Prostate Cancer

  33. Skeletal-Related Events and Clinical Consequences of Bone Metastases Skeletal-Related Events • Pathologic fractures* • Spinal cord compression* • Radiation therapy to bone* • Surgery to bone* • Hypercalcemia • Change in antineoplastic therapy Other Clinical Symptoms • Bone pain • Analgesic usage • Quality-of-life deterioration • Shortened survival *Universally accepted skeletal-related events.

  34. Combined Analysis of 2 Phase III Trials of Pamidronate in Metastatic CRPC Eligibility Criteria R A N D O M I Z E D • Prostate cancer with confirmed skeletal metastases • Bone pain secondary to bone metastases • No previous bisphosphonate Pamidronate 90 mg q3w x 9 (n = 169) Placebo q3w x 9 (n = 181) Small EJ, et al. J Clin Oncol. 2003;21:4277-4284.

  35. Zoledronic Acid in Castration-Resistant Prostate Cancer • 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 progression Zoledronic acid 4 mg q3w (n = 214) R A N D O M I Z E D Eligibility Criteria • Patients with prostate cancer • Castration resistant • Bone metastases • (N = 643) Zoledronic acid 4 mg q3w (initially 8 mg) (n = 221) Placebo q3w (n = 208) Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.

  36. Time to First SRE: Zoledronic Acid vs Placebo • SREs: ZOL 4 mg 38%; placebo 49% (P = .028) • 11% absolute risk reduction in ≥ 1 SRE • Pain/analgesia scores increased less with ZOL • No improvement in tumor progression, QoL, OS 100 80 60 Percent Without Event 40 • Median, Days P Value • ZOL 4 mg 488 .009 • Placebo 321 20 0 0 120 240 360 480 600 720 Days ZOL 4 mg 214 149 97 70 47 35 3Placebo 208 128 78 44 32 20 3 Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. Saad F, et al. ASCO 2003. Abstract 1523. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.

  37. 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 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. 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. Denosumab vs Zoledronic Acid: Double-Blind, Placebo-Controlled Phase III Trial Patients with CRPC and bone metastases, and no current or past IV bisphosphonate treatment (N = 1901) Denosumab 120 mg SC +Placebo IV* q4w (n = 950) Zoledronic acid 4 mg IV* +Placebo SCq4w(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. Time to First On-Study SRE 1.00 HR: 0.82 (95% CI: 0.71-0.95;P = .0002, noninferiority; P = .008, superiority) Risk reduction 18% 0.75 Proportion of Subjects Without SRE 0.50 KM Estimate ofMedian Mos 0.25 20.7 Denosumab 17.1 Zoledronic acid 0 6 0 3 9 12 15 18 21 24 27 Study Mo Patients at Risk, n Fizazi K, et al. Lancet. 2011;377:813-822.

  41. Adverse Events of Interest *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. Treatment of Bone Metastases Secondary to Hormone-Sensitive Prostate Cancer

  43. CALGB 90202: Zoledronic Acid in Hormone-Sensitive PC With Bone Mets Progression to androgen-independent prostate cancer Patients with prostate cancer metastatic to bone who are receiving ADT(Planned N = 680; > 90% accrued as of August 2012) Zoledronic acid IV over 15 mins, Day 1, q4w + ADT Zoledronic acid IV over 15 mins, Day 1, q4w + ADT Placebo IV over 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, toxicity ClinicalTrials.gov. NCT00079001.

  44. 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 disease Dearnaley DP, et al. Lancet Oncol. 2009;10:872-876.

  45. Denosumab and Zoledronic Acid: Indications in Advanced Prostate Cancer

  46. Novel Agents With Bone-Protective Effects

  47. 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 effects 1. Logothetis C, et al. ASCO 2011. Abstract 4520. 2. Scher H, et al. 2012 ASCO GU Cancers Symposium. Abstract LBA1. 3. Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

  48. COU-AA-301: Abiraterone Acetate Improves OS in Metastatic CRPC 100 HR: 0.646 (95% CI: 0.54-0.77; P < .0001) 80 Abiraterone acetate Median OS: 14.8 mos (95% CI: 14.1-15.4) 60 Survival (%) 40 Placebo Median OS: 10.9 mos (95% CI: 10.2-12.0) 20 Median OS with 2 previous chemos:14.0 mos AA vs 10.3 mos placebo Median OS with 1 previous chemo: 15.4 mos AA vs 11.5 mos placebo 0 0 9 15 12 18 21 3 6 Mos Patients at Risk, n de Bono J, et al. N Engl J Med. 2011;364:1995-2005.

  49. 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 60 155/349(44.4%) 80 Median: 10.25 mos 50 44/163(27.0%) 60 40 Pts Experiencing Palliation (%) Pts Not Experiencing Palliation (%) 30 40 Median: 5.55 mos 20 20 10 P = .0010 (log rank) 0 0 0 3 6 9 12 AA (n = 797) Placebo (n = 398) Mos Logothetis C, et al. ASCO 2011. Abstract 4520.

  50. 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)37% reduction in risk of death 100 90 80 Enzalutamide: 18.4 mos(95% CI: 17.3-NYR) 70 60 50 Survival (%) 40 30 Placebo: 13.6 mos(95% CI: 11.3-15.8) 20 10 0 0 3 6 9 12 15 18 21 24 Duration of OS (Mos) Pts at Risk, n MDV3100Placebo 800399 775376 701317 627263 400167 21181 7233 73 00 Scher HI, et al. ASCO GU 2012. Abstract LBA1.

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