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Role of Bone-Targeted Therapy in the Treatment of Prostate Cancer This program is supported by an educational donation from Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email [email protected]) Disclaimer The materials published on the Clinical Care Options Web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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 Fracture Prevention in Early-Stage Prostate Cancer Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Fracture Risk by Sex and Age Incidence/1,000,000 Person-Yrs 4000 Men Hip Spine Women 3000 2000 1000 35-39 ≥ 85 35-39 Age (Yrs) Melton LJ 3rd, et al. J Bone Miner Res. 1992;7:1005-1010. ≥ 85 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology GnRH Agonists Decrease BMD in Men With Prostate Cancer 2 Control GnRH agonist Percent Change 1 P < .001 for each comparison 0 -1 -2 -3 -4 -5 12-mo data Lumbar Spine Total Hip Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Proportion of Patients With Fractures 1-5 Yrs After Cancer Diagnosis +6.8%; P < .001 No ADT (n = 20,035) 21 ADT (n = 6650) Frequency (%) 18 19.4 15 12 12.6 9 +2.8%; P < .001 6 5.2 3 2.4 0 Any Fracture Shahinian VB, et al. N Engl J Med. 2005;352:154-164. Fracture Resulting in Hospitalization Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology The FRAX Tool: Assessing Fracture Risk http://www.sheffield.ac.uk/FRAX Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Alendronate Increases BMD During GnRH Agonist Therapy 5 12-Mo Data BMD Percent Change 4 3 Placebo Alendronate 2 1 0 -1 -2 -3 Lumbar Spine Total Hip Greenspan SL, et al. Ann Intern Med. 2007;146:416-424. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Quarterly Zoledronic Acid Increases BMD During GnRH Agonist Therapy 8 Final 12-Mo Data BMD Percent Change P < .001 for each comparison 6 Placebo Zoledronic acid 4 2 0 -2 -4 Lumbar Spine Smith MR, et al. J Urol. 2003;169:2008-2012. Total Hip Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy 6 Final 12-Mo Data BMD Percent Change P < .005 for each comparison 4 Placebo Zoledronic acid 4 mg/yr IV 2 0 -2 -4 -6 Lumbar Spine Total Hip Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Denosumab Fracture Prevention Study Current androgen deprivation therapy for prostate cancer patients older than 70 yrs of age or with T score < -1.0 (N = 1468) Denosumab q6m for 3 yrs Placebo q6m for 3 yrs Primary endpoints: bone mineral density, new vertebral fractures Smith MR, et al. N Engl J Med. 2009;361:745-755. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology 10 8 6 4 2 0 -2 -4 -6 Lumbar Spine Denosumab Difference at 24 mos, 6.7 percentage points Placebo 01 3 6 12 24 Change in BMD From Baseline (%) Change in BMD From Baseline (%) Denosumab Increased BMD at All Skeletal Sites 10 8 6 4 2 0 -2 -4 -6 36 Total Hip Denosumab Difference at 24 mos, 4.8 percentage points Placebo 01 3 6 12 10 8 6 4 2 0 -2 -4 -6 Femoral Neck Denosumab Difference at 24 mos, 3.9 percentage points Placebo 01 3 6 12 24 36 Mos 24 36 Mos Smith MR, et al. N Engl J Med. 2009;361:745-755. Change in BMD From Baseline (%) Change in BMD From Baseline (%) Mos 10 8 6 4 2 0 -2 -4 -6 Distal Third of Radius Denosumab Difference at 24 mos, 5.5 percentage points Placebo 01 3 6 12 24 Mos 36 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Denosumab for Fracture Prevention New Vertebral Fracture (%) 10 Denosumab Placebo 8 P = .004 P = .004 P = .006 6 4 2 3.9 3.3 1.9 1.5 1.0 0.3 0 Patients at Risk, n 13 12 24 Mos 2 Smith MR, et al. N Engl J Med. 2009;361:745-755. 22 36 7 26 10 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 Delaying Bone Metastases in Prostate Cancer Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Natural History of Castration-Resistant Nonmetastatic Prostate Cancer Proportion With Event 1.0 Death Bone metastasis Bone metastasis or death 0.8 0.6 0.4 0.2 0 0 0.5 1.0 1.5 2.0 2.5 Yrs Since Random Assignment Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. 3.0 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology PSA and PSADT Are Associated With Shorter Bone Metastasis–Free Survival Proportion of Patients With Bone Metastases or Died 1.0 PSA < 7.7 ng/mL PSA 7.7-24.0 ng/mL PSA > 24.0 ng/mL 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 PSADT < 6.3 mos PSADT 6.3-18.8 mos PSADT > 18.8 mos 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.. 0 0.5 1.0 1.5 2.0 2.5 3.0 Yrs Since Random Assignment Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Phase III Study: BMFS With Denosumab in M0 CRPC With Aggressive PSA Kinetics Double-blind randomization Patients with M0 CRPC at high risk for bone metastases: PSA ≥ 8.0 ng/mL or PSADT ≤ 10.0 mos (N = 1432) Bone metastasis or death Denosumab 120 mg SC q4w (n = 716) Calcium and vitamin D supplementation Placebo 120 mg SC q4w (n = 716) Survival follow-up Off investigational product Primary endpoint: BMFS Secondary endpoints: time to first bone metastasis (either symptomatic or asymptomatic), OS Smith MR, et al. Lancet. 2012;379:39-46. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Denosumab Increases Bone Metastasis– Free Survival Proportion of Patients 1.0 HR: 0.85 (95% CI: 0.73-0.98; P = .028) 0.8 0.6 0.4 0.2 0 Median Survival, Mos Denosumab 29.5 Placebo 25.2 Events, n 335 370 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Mos Patients at Risk, n Denosumab Placebo 716 695 605 521 456 400 368 324 279 228 185 153 111 59 716 691 569 500 421 375 345 300 259 215 168 137 99 60 Smith MR, et al. Lancet. 2012;379:39-46. 35 36 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Time to First Bone Metastasis With Denosumab Proportion of Patients 1.0 HR: 0.84 (95% CI: 0.71-0.98; P = .032) 0.8 0.6 0.4 0.2 Denosumab Placebo Median Time, Mos 33.2 29.5 Events, n 286 319 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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology 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 Time to Symptomatic Bone Metastasis 1.0 0.8 0.6 HR: 1.01 (95% CI: 0.85-1.20; P = .91) 0.4 0.2 Placebo Denosumab 0 0 6 12 18 24 30 Study Mo Smith MR, et al, Lancet. 2012;379:39-46. 36 42 Proportion of Patients Without Symptomatic Bone Metastases Proportion of Patients Alive OS 1.0 0.8 HR: 0.67 (95% CI: 0.49-0.92; P = .013) 33% Risk reduction 0.6 0.4 Events, n (%) Placebo 96 (13) Denosumab 69 (10) 0.2 0 0 6 12 18 24 Study Mo 30 36 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Denosumab and Adverse Events Adverse Events, n (%) Placebo (n = 705) Denosumab (n = 720) 655 (93) 676 (94) 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) 323 (46) 329 (46) 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) 353 (50) 381 (53) 0 33 (5) 2 (< 1) 12 (2) Any adverse event Most common adverse events Serious adverse events Most common serious adverse events Grade 3, 4, or 5 adverse events Adjudicated positive osteonecrosis of the jaw Hypocalcaemia Smith MR, et al, Lancet. 2012;379:39-46. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Relationship Between PSADT and Risk for Bone Metastasis or Death* 3.0 Relative Risk for Bone Metastasis or Death Increasing Risk 2.8 2.6 2.4 2.2 2.0 1.8 1.6 *Placebo arm of study (n = 147) 1.4 20 18 16 14 12 10 8 PSADT in Mos Shorter PSADT Smith MR, et al. ASCO GU 2012. Abstract 6. 6 4 2 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Bone Metastasis–Free Survival in Patients With PSADT ≤ 10 Mos Proportion of Patients With Bone Metastasis–Free Survival 1.0 HR: 0.84 (95% CI: 0.72-0.99; P = .042) 0.8 16% Risk reduction 0.6 0.4 0.2 Placebo Denosumab Median Mos Delay, Mos 22.4 28.4 6.0 Events, n 309 273 0 0 6 12 18 24 Study Mo 30 36 Patients at Risk, n 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 77 Smith MR, et al. ASCO GU. 2012. Abstract 6. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Bone Metastasis–Free Survival in Patients With PSADT ≤ 6 Mos Proportion of Patients With Bone Metastasis–Free Survival 1.0 HR: 0.77 (95% CI: 0.64-0.93; P = .006) 0.8 23% Risk reduction 0.6 0.4 0.2 Placebo Denosumab Median Mos 18.7 25.9 Delay, Mos Events, n 242 97 7.2 0 0 6 12 18 24 Study Mo 30 Patients at Risk, n Placebo 427 411 323 274 223 194 176 148 122 99 78 Denosumab 419 406 345 284 238 207 193 170 145 109 89 Smith MR, et al. ASCO GU. 2012. Abstract 6. 36 65 67 47 46 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Bone Metastasis–Free Survival in Patients With PSADT ≤ 4 Mos Proportion of Patients With Bone Metastasis–Free Survival 1.0 HR: 0.71 (95% CI: 0.56-0.90; P = .004) 0.8 29% Risk reduction 0.6 0.4 0.2 Placebo Denosumab Median Mos 18.3 25.8 Delay, Mos 7.5 Events, n 167 124 0 0 6 12 18 24 30 Study Month Patients at Risk, n Placebo 289 279 209 176 138 117 105 88 71 Denosumab 263 254 217 176 143 123 117 102 89 Smith MR, et al. ASCO GU. 2012. Abstract 6. 58 46 67 56 36 35 38 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 Treatment of Bone Metastases Secondary to CastrationResistant Prostate Cancer Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Combined Analysis of 2 Phase III Trials of Pamidronate in Metastatic CRPC Eligibility Criteria Prostate cancer with confirmed skeletal metastases Bone pain secondary to bone metastases No previous bisphosphonate R A N D O M I Z E D SRE (Study Wk 27), n (%) Pamidronate 90 mg q3w x 9 (n = 169) Placebo q3w x 9 (n = 181) 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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Zoledronic Acid in Castration-Resistant Prostate Cancer Eligibility Criteria Patients with prostate cancer Castration resistant Bone metastases (N = 643) R A N D O M I Z E D Zoledronic acid 4 mg q3w (n = 214) Zoledronic acid 4 mg q3w (initially 8 mg) (n = 221) Placebo q3w (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 progression Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Time to First SRE: Zoledronic Acid vs Placebo Percent Without Event 100 SREs: ZOL 4 mg 38%; placebo 49% (P = .028) – 80 11% absolute risk reduction in ≥ 1 SRE Pain/analgesia scores increased less with ZOL No improvement in tumor progression, QoL, OS 60 40 20 Median, Days P Value 488 321 .009 ZOL 4 mg Placebo 0 0 ZOL 4 mg Placebo 214 208 120 149 128 240 97 78 360 Days 70 44 480 600 720 47 32 35 20 3 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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Denosumab vs Zoledronic Acid: DoubleBlind, 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 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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Proportion of Subjects Without SRE Time to First On-Study SRE 1.00 HR: 0.82 (95% CI: 0.71-0.95; P = .0002, noninferiority; P = .008, superiority) 18% Risk reduction 0.75 0.50 KM Estimate of Median Mos 20.7 Denosumab 17.1 Zoledronic acid 0.25 0 0 Patients at Risk, n Zoledronic acid 951 Denosumab 950 3 6 9 12 15 18 21 24 27 140 168 93 115 64 70 47 39 Study Mo 733 758 544 582 Fizazi K, et al. Lancet. 2011;377:813-822. 407 472 299 361 207 259 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Adverse Events of Interest Subject Incidence, n (%) Zoledronic Acid (n = 945) Denosumab (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) 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) Cumulative rate of ONJ† *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. Treatment of Bone Metastases Secondary to Hormone-Sensitive Prostate Cancer Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology CALGB 90202: Zoledronic Acid in Hormone-Sensitive PC With Bone Mets 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 Progression to androgen-independent prostate cancer 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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 disease Dearnaley DP, et al. Lancet Oncol. 2009;10:872-876. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Denosumab and Zoledronic Acid: Indications in Advanced Prostate Cancer Indication Denosumab 120 mg SC Monthly Zoledronic Acid 4 mg IV Monthly Bone metastases from hormonesensitive disease Yes No Bone metastases from CRPC Yes Yes Novel Agents With Bone-Protective Effects Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology COU-AA-301: Abiraterone Acetate Improves OS in Metastatic CRPC 100 HR: 0.646 (95% CI: 0.54-0.77; P < .0001) Survival (%) 80 Abiraterone acetate Median OS: 14.8 mos (95% CI: 14.1-15.4) 60 40 Placebo Median OS: 10.9 mos (95% CI: 10.2-12.0) Median OS with 2 previous chemos: Median OS with 1 previous chemo: 14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo 20 0 0 3 6 9 12 Patients at Risk, n AA 797 736 657 520 Mos 282 Placebo 355 306 210 105 398 de Bono J, et al. N Engl J Med. 2011;364:1995-2005. 15 18 21 68 2 0 30 3 0 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology COU-AA-301: Effect of Abiraterone Acetate on Pain Palliation and SREs 70 60 50 40 30 20 10 0 Pts Not Experiencing Palliation (%) Nearly one half of COU-AA-301 patients report significant pain at baseline Pts Experiencing Palliation (%) 155/349 (44.4%) 44/163 (27.0%) AA (n = 797) 100 80 Placebo Median: 10.25 mos 60 40 Median: 5.55 mos 20 P = .0010 (log rank) 0 0 Placebo (n = 398) Efficacy Measure AA 3 6 Mos 9 12 Abiraterone (n = 797) Placebo (n = 398) P Value Median OS, mos 14.8 10.9 < .0001 Median radiographic PFS, mos 5.6 3.6 < .0001 Time to first SRE* (25th percentile), days 301 150 < .0001 Logothetis C, et al. ASCO 2011. Abstract 4520. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 Survival (%) 100 90 80 70 HR: 0.631 (95% CI: 0.529-0.752; P < .0001) 37% reduction in risk of death Enzalutamide: 18.4 mos (95% CI: 17.3-NYR) 60 50 40 30 20 10 0 Placebo: 13.6 mos (95% CI: 11.3-15.8) 0 3 6 Pts at Risk, n MDV3100 800 775 701 Placebo 399 376 317 Scher HI, et al. ASCO GU 2012. Abstract LBA1. 9 12 15 18 Duration of OS (Mos) 627 400 211 72 263 167 81 33 21 24 7 3 0 0 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology AFFIRM Trial of Enzalutamide in PostDocetaxel CRPC: Time to First SRE SRE Free (%) HR: 0.621 (P < .0001) 100 90 80 70 Enzalutamide: 16.7 mos (95% CI: 14.6-19.1) 60 50 40 30 20 10 0 Placebo: 13.3 mos (95% CI: 5.5-NYR) 0 Pts at Risk, n Enzalutamide 800 Placebo 399 3 6 676 278 548 196 9 12 15 Time to Event (Mos) 379 128 De Bono JS, et al. ASCO 2012. Abstract 4519^. 209 68 87 33 18 21 24 19 11 2 0 0 0 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Other Novel Agents Targeting Bony Metastases in CRPC Radium-223 Cabozantinib: MET/VEGFR-targeted agent Dasatinib: Src inhibitor Saylor PJ, et al. J Clin Oncol. 2011;29:3705-3714. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Radium-223 Targets Bone Metastases Radium-223 functions as a calcium mimic Targets sites of new bone growth within and around bone metastases Ca Ra Excreted by the small intestine Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 CRPC and ≥ 2 bone metastases with no known visceral metastases, either post-docetaxel or unfit for docetaxel (N = 921) Radium-223 50 kBq/kg + BSC Placebo (saline) + 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, QoL Parker C, et al. ASCO GU 2012. Abstract 8. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology ALSYMPCA: Overall Survival 100 HR: 0.695 (95% CI: 0.552-0.875; P = .00185) 90 80 OS (%) 70 60 Radium-223 (n = 541) Median OS: 14.0 mos 50 40 30 Placebo (n = 268) Median OS: 11.2 mos 20 10 0 0 3 6 9 12 15 18 21 24 27 Mos Pts at Risk, n Radium-223 541 450 330 213 120 72 Placebo 268 218 147 89 49 28 Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8. 30 15 15 7 3 3 0 0 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology ALSYMPCA: Time to First SRE 100 HR: 0.610 (95% CI: 0.461-0.807; P = .00046) Pats Without SRE (%) 90 80 70 Radium-223 (n = 541) Median: 13.5 mos 60 50 40 Placebo (n = 268) Median: 8.4 mos 30 20 10 0 0 3 6 Pts at Risk, n Radium-223 541 379 214 Placebo 268 159 74 Sartor O, et al. ASCO GU 2012. Abstract 9. 9 12 15 18 21 51 15 22 7 6 2 0 0 Mos 111 30 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 (%) SRE Time to First Event (Radium-223 vs Placebo) Radium-223 (n = 541) Placebo (n = 268) P Value* 122 (23) 72 (27) .0038 0.65 (0.48-0.87) Spinal cord compression 17 (3) 16 (6) .016 0.44 (0.22-0.88) Pathologic bone fracture 20 (4) 18 (7) .013 0.45 (0.24-0.86) Surgical intervention 9 (2) 5 (2) .69 0.80 (0.27-2.4) External beam radiotherapy 3 of 4 SRE components improved Sartor AO, et al. ASCO 2012. Abstract 4551. HR (95%CI) Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology ALSYMPCA: Adverse Events of Interest Adverse Event, n (%) All Grades Grade 3/4 Radium-223 (n = 509) Placebo (n = 253) Radium-223 (n = 509) Placebo (n = 253) Hematologic Anemia Neutropenia Thrombocytopenia 136 (27) 20 (4) 42 (8) 69 (27) 2 (1) 14 (6) 54 (11) 9 (2) 22 (4) 29 (12) 2 (1) 4 (2) Nonhematologic Bone pain Diarrhea Nausea Vomiting Constipation 217 (43) 112 (22) 174 (34) 88 (17) 89 (18) 147 (58) 34 (13) 80 (32) 32 (13) 46 (18) 89 (18) 6 (1) 8 (2) 10 (2) 6 (1) 59 (23) 3 (1) 4 (2) 6 (2) 2 (1) Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Cabozantinib (XL184): Target Profile RTK Cellular IC50, nM, Autophosphorylation MET 8 VEGFR2 4 Kinase IC50, nM MET 1.8 VEGFR2 0.035 RET 5.2 KIT 4.6 AXL 7.0 TIE2 14 pMET FLT3 14 MET S/T Ks (47) >200 ATP competitive, reversible Cabozantinib, mg/kg V pVEGFR2 VEGFR2 3 10 30 100 H441 tumors* Mouse lung† *No growth factor stimulation. †VEGF-A administered 30 min prior to harvest. Data courtesy of Ron Weitzman and Dana Aftab. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Role of MET in Prostate Cancer and Bone Metastases Androgen Deprivation Activates MET Signaling Stromal HGF AR MET Androgen deprivation HGF AR X MET (autocrine + paracrine) Activated MET Is Highly Expressed in Bone Metastases Zhang S, et al. Mol Cancer. 2010;9:9. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Cabozantinib (cMET/VEGFR2 Inhibitor) Demonstrates Significant Bone Effects Baseline Bone Scan Evaluable (N = 108) Wk 12 n (%) Complete resolution 21 (19) Partial resolution 61 (56) Stable 23 (21) Progressive disease 3 (3) Docetaxel pretreated Hussain M, et al. ASCO 2011. Abstract 4516. % Best Change From Baseline Effects on Osteoblast (t-ALP) and Osteoclast (CTx) Activity 100 80 60 40 20 0 -20 -40 -60 -80 -100 Pts With Baseline t-ALP Levels ≥ 2 x ULN and ≥ 12 Wks of Follow-up (N = 28) 100 80 60 40 20 0 -20 -40 -60 -80 -100 Bisphosphonate treated Bisphosphonate naive Samples From Wk 6 and 12 (N = 118) Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology n (%) Bone metastases and bone pain at baseline (n = 83): pain improvement at Wk 6 or 12 56 (67) Narcotics for bone pain at baseline (n = 67): pain improvement at Wk 6 or 12 47 (70) Evaluable for narcotics change (n = 55): decrease or discontinuation of narcotics 31 (56) 7/27 (26%) patients discontinued narcotics entirely Worst Pain ≥ 4 at Baseline 0 ** * Improved Randomized Discontinuation Trial; Post Hoc Investigator Survey % Change in Average Worst Pain From Baseline Cabozantinib: Effects on Bone Pain and Nonrandomized Expansion Trial Narcotic Use 20 Prospective: Pts With Average -20 -40 -60 -80 -100 Previous docetaxel Previous docetaxel + abiraterone and/or cabazitaxel *Previous radionuclide therapy 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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology MET and VEGFR Interactions in Bone Tumors MET is activated in bone metastases Stroma Angiogenesis VEGF – Tumor cells express MET – Autocrine and paracrine activation of MET by HGF Proliferation differentiation survival HGF Osteoblast VEGF – Express MET and VEGFRs Zhang S, et al. Mol Cancer. 2010;9:9. VEGF NP-1 MET – VEGF activation of MET via neuropilin-1 Osteoblasts and osteoclasts HGF HGF HGF Migration proliferation survival Osteoclast VEGF Migration proliferation survival Tumor Cell Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Cabozantinib: Randomized Phase III Trials Patients with bonemetastatic CRPC, moderate to severe bone pain, and previous treatment with docetaxel, abiraterone, or enzalutamide (Planned N = 246) Patients with bonemetastatic CRPC, and previous treatment with docetaxel, abiraterone, or enzalutamide (Planned N = 246) 1. ClinicalTrials.gov. NCT01522443. 2. ClinicalTrials.gov. NCT01605227. Cabozantinib 60 mg QD + Pain Endpoint Trial[1] Mitoxantrone Placebo Mitoxantrone/Prednisone + Cabozantinib Placebo Primary endpoint: durable pain response at Wk 12 Secondary endpoints: bone scan response by IRF, OS Cabozantinib 60 mg QD + OS Endpoint Trial[2] Placebo Prednisone 5 mg BID + Placebo Primary endpoint: OS Secondary endpoints: bone scan response by IRF Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Maximum PSA Change From Baseline (%) 200 Tumor Size (by RECIST) PSA 150 100 50 0 -50 -100 -150 Yu EY, et al. Clin Cancer Res. 2009;15:7421-7428. Maximum uNTx Change From Baseline (%) 50 40 30 20 10 0 -10 -20 -30 -40 -50 160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 100 Maximum BAP Change From Baseline (%) Maximum Tumor Size Change From Baseline (%) Phase II Study: Dasatinib Monotherapy in Metastatic CRPC With No Previous Chemo Urine N-Telopeptide Bisphosphonate No bisphosphonate Bone Alkaline Phosphatase 80 60 40 20 0 -20 -40 -60 -80 Bisphosphonate No bisphosphonate Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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. Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.com/oncology Docetaxel/Prednisone ± Dasatinib in CRPC: Phase III Study Patients with metastatic CRPC and evidence of progression (Planned N = 1500) Docetaxel + Prednisone + Placebo daily 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/tolerability ClinicalTrials.gov. NCT00744497 Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer clinicaloptions.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 Go Online for More CCO Coverage of Bone Health! 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