Therapeutic Strategies for Patients With Prostate Cancer and Bone Metastases Michael A. Carducci, MD AEGON Professor in Prostate Cancer Research Johns Hopkins Kimmel Cancer Center Baltimore, Maryland This program is supported by educational grants from

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Faculty Disclosure Michael A. Carducci, MD, has disclosed that he has received consulting fees from Amgen, Bristol-Myers Squibb, and Novartis and has served on data and safety monitoring boards for Medivation, Parexel, Pfizer, and sanofi-aventis. This slide lists the faculty who were involved in the production of these slides.

Spectrum of Bone Disease in Prostate Cancer Treatment-related fractures New bone metastases Disease-related skeletal complications Castrate sensitive , nonmetastatic Castrate resistant , nonmetastatic Castrate resistant , metastatic 4

Negative Impact of Bone Complications CORE Negative Impact of Bone Complications Increased medical costs[1] Treatment of bone complications more than doubles the total treatment costs for patients with bone metastases Diminished quality of life[2-4] History of a skeletal complication is associated with lower QoL in breast and prostate cancer Impaired mobility[6] Hip fracture associated with a 50% long-term disability rate; 25% require nursing home care Skeletal Complications QOL, quality of life.   Negative impact on survival[5] Men with prostate cancer without skeletal fracture survived 39 mos longer than those with a fracture 1. Groot MT, et al. Eur Urol. 2003;43:226-232. 2. Weinfurt KP, et al. Ann Oncol. 2005;16:579-584. 3. Weinfurt KP, et al. Med Care. 2004;42:164-175. 4. Saad F, et al. Eur Urol. 2004;46:731-740. 5. Oefelein MG, et al. J Urol. 2002;168:1005-1007. 6. Riggs BL, et al. Bone. 1995;17:505S-511S. References: 1. Weinfurt KP, Li Y, Castel LD, et al. The impact of skeletal-related events on health-related quality of life of patients with metastatic prostate cancer. Ann Oncol. 2002;13 (suppl 5):180. Abstract 662P. 2. Weinfurt KP, Castel LD, Li Y, et al. Health-related quality of life among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone lesions. Med Care. 2004;42:164-175. 3. Saad F, Olsson C, Schulman CC. Skeletal morbidity in men with prostate cancer: quality-of-life considerations throughout the continuum of care. Eur Urol. 2004;46:731-740. 4. Groot MT, Boeken Kruger CG, Pelger RC, et al. Costs of prostate cancer, metastatic to the bone, in The Netherlands. Eur Urol. 2003;43:226-232. 5. Oefelein MG, Ricchiuti V, Conrad W, et al. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol. 2002;168:1005-1007. 5

Prevention of Skeletal-Related Events in Men With Prostate Cancer Metastasized to Bone

Consequences of Prostate Cancer Progression on Bone Metastasis Osteoporosis Osteopenia Worsening bone pain Spinal cord compression Bone marrow compromise Hyper/hypocalcemia Additional therapy such as surgery and radiation

Randomized Controlled Clinical Trials in Metastatic Castrate-Sensitive PC Patients Zoledronic acid vs placebo CALGB/CTSU 90202 trial Planned enrollment of 680 men with prostate cancer and bone mets on ADT within 6 mos Zoledronic acid 4 mg IV every 4 wks Crossover from placebo to zoledronic acid allowed Accrual complete ADT, androgen-deprivation therapy; IV, intravenous; PC, prostate cancer. ClinicalTrials.gov. NCT00079001.

CALGB 90202: ZOL in Hormone-Sensitive Bone Mets PC—No Current Proven Role Randomize PD ADT + placebo q4w Zoledronic acid q3w Goal N = 680; > 2/3 accrued ADT + zoledronic acid q4w Zoledronic acid q3w ADT, androgen-deprivation therapy; OS, overall survival; PC, prostate cancer; PD, progressive disease; q3, every 3; q4, every 4; SRE, skeletal-related event; ZOL, zoledronic acid. Double blinded Open label Primary endpoint: time to SRE; secondary endpoints: OS, toxicity ClinicalTrials.gov. NCT00079001.

Zoledronic Acid in Castration-Resistant Prostate Cancer Zoledronic acid 4 mg q3w (n = 214) Eligibility Criteria R A N D O M I Z E Patients with prostate cancer Castration resistant Bone metastases (N = 643) Zoledronic acid 4 mg q3w (initially 8 mg) (n = 221) Placebo q3w (n = 208) q3, every 3; SRE, skeletal-related event. Patients in 8-mg arm reduced to 4 mg owing to 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.

Time to First SRE 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 OS, overall survival; QoL, quality of life; SRE, skeletal-related event; Zol, zoledronic acid. 120 240 360 480 600 720 Days Pts at Risk, n ZOL 4 mg 214 149 97 70 47 35 3 Placebo 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.

Study Design: International, Randomized, Double-Blind, Active-Controlled Study Key Inclusion Hormone-refractory (castration-resistant) prostate cancer and bone metastases Key Exclusion Current or previous IV bisphosphonate treatment Denosumab 120 mg SC and Placebo IV* q4w (n = 950) Zoledronic acid 4 mg IV* and Placebo SC q4w (n = 951) IV, intravenous; SC, subcutaneous. Calcium and vitamin D supplemented in both treatment groups Accrual period from May 2006 to December 2008 Analysis cutoff date: October 2009 *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. 12 12

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 of Median Mos 0.25 CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier; SRE, skeletal-related event. Denosumab 20.7 Zoledronic acid 17.1 3 6 9 12 15 18 21 24 27 Study Mo Pts 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 39 Fizazi K, et al. Lancet. 2011;377:813-822. 13

Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) 2.0 Rate ratio: 0.82 (95% CI: 0.71-0.94; P = .008) 18% Risk reduction 1.8 1.6 1.4 1.2 Cumulative Mean Number of SREs per Patient 1.0 0.8 0.6 CI, confidence interval; SRE, skeletal-related event. Events, n 0.4 Denosumab 494 0.2 Zoledronic acid 584 3 6 9 12 15 18 21 24 27 30 33 36 Study Mo *Events occurring at least 21 days apart. Fizazi K, et al. Lancet. 2011;377:813-822. 14

Kaplan-Meier Estimates of OS and TTP Endpoint, Mos Denosumab Zoledronic Acid HR (95% CI) P Value Median OS 19.4 19.8 1.03 (0.91-1.17) .65 Median TTP 8.4 1.06 (0.95-1.18) .30 CI, confidence interval; HR, hazard ratio; OS, overall survival; TTP, time to progression. Fizazi K, et al. Lancet. 2011;377:813-822.

Denosumab vs Zoledronic Acid: Safety Adverse Event, % Zoledronic Acid (n = 945) Denosumab (n = 943) Serious adverse events 60 63 Adverse events causing treatment discontinuation 15 17 Most common adverse events Anemia 36 Back pain 30 32 Decreased appetite 29 28 Nausea 26 Fatigue 23 27 Acute-phase reactions (first 3 days) 18 8 Renal adverse events 16 ONJ 1 2 Hypocalcemia 6 13 ONJ, osteonecrosis of the jaw. Fizazi K, et al. Lancet. 2011;377:813-822.

Recommended Dose and Schedule FDA-Approved Agents for Prevention of SREs in Metastatic Prostate Cancer Agent Drug Class Recommended Dose and Schedule Zoledronic acid Bisphosphonate 4 mg IV q3-4w Denosumab RANKL-targeted MAb 120 mg SQ q4w NCCN recommends either zoledronic acid or denosumab for prevention/delay of SREs in men with CRPC and bone metastases[1] Choice between agents may be guided by Underlying comorbidities Adverse events: renal insufficiency, ONJ, hypocalcemia Logistics: differences in administration (SQ vs IV) Cost considerations CRPC, castration-resistant prostate cancer; FDA, US Food and Drug Administration; IV, intravenous; MAb,monoclonal antibody; NCCN, National Comprehensive Cancer Center; ONJ, osteonecrosis of the jaw; q3w, every 3 weeks; q4w, every 4 weeks; SQ, subcutaneous; SREs, skeletal-related events 1. NCCN. Clinical practice guidelines in oncology: prostate cancer. v.2.2012.

Take-Home Points Bone health is of critical importance for men with advanced prostate cancer Denosumab is approved to reduce SREs and has been shown to be superior to zoledronic acid in this setting Safety of denosumab and zoledronic acid have been better defined by recent studies SRE, skeletal-related event.

Of Note 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 OS, overall survival; SRE, skeletal-related event. 1. Logothetis C, et al. ASCO 2011. Abstract 4520. 2. Scher H, et al. 2012 ASCO GU Cancers Symposium. LBA1. 3. Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

Novel Agents Targeting Bony Metastatic CRPC Radium-223 Cabozantinib MET/VEGFR-targeted agent Dasatinib Src inhibitor CRPC, castration-resistant prostate cancer; VEGFR, vascular endothelial growth factor receptor. Saylor PJ, et al. J Clin Oncol. 2011;29:3705-3714.

Radium-223 Targets Bone Metastases Radium-223 functions as a calcium mimic Targets sites of new bone growth within and around bone metastases Excreted by the small intestine Ca Ra Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

Radium-223 Targets Bone Metastases Range of α-particle Radium-223 Bone surface α-particles cause double-strand DNA breaks in nearby tumour cells Limited penetration of α emitters (~ 2-10 cell diameters) results in highly localized killing of tumor cells with minimal collateral damage to normal tissue in surrounding area Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8. Perez CA, et al. Principles and practice of radiation oncology. 5th ed. 2007.

ALSYMPCA: Phase III Study Design Randomized 2:1 and stratified by total ALP (< vs ≥ 220 U/L), bisphosphonate use (yes vs no), and previous docetaxel (yes vs no) Patients with: Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel (N = 921) Radium-223 50 kBq/kg + Best Standard of Care Placebo (saline) + Best Standard of Care ALP, alkaline phosphatase; CRPC, castration-resistant prostate cancer. 6 injections at 4-wk intervals Planned follow-up: 3 yrs Clinicaltrials.gov. NCT00699751. Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

ALSYMPCA: Overall Survival 100 HR: 0.695 (95% CI: 0.552-0.875; P = .00185) 90 80 70 60 Radium-223 (n = 541) Median OS: 14.0 mos OS (%) 50 40 30 Placebo (n = 268) Median OS: 11.2 mos 20 CI, confidence interval; HR, hazard ratio; OS, overall survival. 10 3 6 9 12 15 18 21 24 27 Pts at Risk, n Mos Radium-223 541 450 330 213 120 72 30 15 3 Placebo 268 218 147 89 49 28 7 Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

ALSYMPCA: Time to First Skeletal-Related Event 100 HR 0.610 (95% CI: 0.461-0.807; P = .00046) 90 80 70 Radium-223 (n = 541) Median: 13.5 mos 60 % Without SRE 50 40 Placebo (n = 268) Median: 8.4 mos 30 20 CI, confidence interval; HR, hazard ratio; SRE, skeletal-related event. 10 3 6 9 12 15 18 21 Pts at Risk, n: Mos Radium-223 541 379 214 111 51 22 6 Placebo 268 159 74 30 15 7 2 Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

ALSYMPCA Adverse Events of Interest Adverse Event, n (%) All Grades Grade 3/4 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) 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) 6 (1) 8 (2) 10 (2) 59 (23) 3 (1) 6 (2) Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

Role of MET in Prostate Cancer and Bone Metastases Androgen deprivation activates MET signaling[1,2] Stromal HGF HGF (autocrine + paracrine) Τ X Τ AR Androgen deprivation MET AR MET Activated MET is highly expressed in bone metastases[3] AR, androgen receptor; HGF, hepatocyte growth factor; PCa, prostate cancer. 1. Humphrey PA, et al. Am J Pathol. 1995;147:386-396. 2. Verras M, et al. Cancer Res. 2007;67:967-975. 3. Zhang S, et al. Mol Cancer. 2010;9:9. 27

Role for MET and VEGFR in Tumor-Bone Interactions in CRPC[1] Bone metastases in CRPC are associated with high levels of MET expression[2-4] Osteoblasts and osteoclasts express MET and VEGFRs and respond to HGF and VEGF[5-8] HGF and VEGF may be important factors directing crosstalk between tumor cells and bone cells Simultaneous inhibition of MET and VEGFR may block the progression of osteolytic and osteoblastic bone lesions Stroma Angiogenesis VEGF Proliferation Differentiation Survival HGF Osteoblast VEGF HGF VEGF HGF NP-1 MET Migration Proliferation Survival HGF VEGF Tumor Cell Migration Proliferation Survival CRPC, castration-resistant prostate cancer; HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. Osteoclast 1. Smith DC, et al. 2011 ASCO GU Cancers Symposium. Abstract 127. 2. Knudsen BS, et al. Urology. 2002;60:1113-1117. 3. Morrissey C, et al. J Cell Biochem. 2007;101:873-886. 4. Zhang S, et al. Mol Cancer. 2010;9:9. 5. Grano M, et al. Proc Natl Acad Sci U S A. 1996;93:7644-7648. 6. Inaba M, et al. Blood. 1993;82:53-59. 7. Zelzer E, et al. Curr Top Dev Biol. 2005;65:169-187. 8. Street J, et al. J Orthop Surg Res. 2009;4:19.

Cabozantinib: Ex. of Pts With Bone Scan Evidence of Mets With ≥ 1 Post-BL Scan Patients With Bone Scan Resolution (Partial or Complete)* Baseline Week 6 Previous docetaxel Yes Maximum tumor change, per mRECIST -17% Improvement in bone pain† No Change in tALP and PSA Bone scans at baseline and during therapy with cabozantinib tALP PSA 1000 400 750 300 BL, baseline; mRECIST, modified Response Evaluation Criteria in Solid Tumors; NE, not evaluated due to no pain at baseline; PSA, prostate-specific antigen; tALP, serum total alkaline phosphatase. tALP 500 200 PSA 250 100 BL 2 6 10 14 Wks on Study *Independent radiologist review. †Post hoc investigator survey of whether pain improved at Wk 6 and/or 12. Smith DC, et al. 2011 ASCO GU Cancers Symposium. Abstract 127.

Cabozantinib 60 mg QD + Mitoxantrone Placebo + Prednisone Placebo COMET-2: CabOzantinib MET Inhibition CRPC Efficacy Trial–2 Study Design Patients with: Confirmed mCRPC with bone metastases Bone pain (BPI ≥ 4) Previously treated with docetaxel and either abiraterone or MDV3100 (N = 246) Cabozantinib 60 mg QD + Mitoxantrone Placebo + Prednisone Placebo (n = 123) Mitoxantrone + Prednisone + Cabozantinib Placebo (N = 123) BPI, bone pain index; IRF, independent review facility; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival. Primary endpoint: durable pain response Secondary endpoint: bone scan response by IRF, OS ClinicalTrials.gov. NCT01522443.

COMET-2 Randomized, controlled, double-blinded Eligibility Endpoints Cabozantinib 60 mg QD vs mitoxantrone/prednisone N = 246 (1:1 randomization) Pain and analgesic use measured similarly to NRE Eligibility mCRPC patients who failed docetaxel and abiraterone or MDV3100 Moderate to severe pain (BPI ≥ 4) despite “optimized” narcotics Endpoints Primary: pain response at Wk 6 confirmed at Wk 12 Secondary: bone scan response and OS Goal of OS analysis: show no decrement (80% power to detect a 0.67 HR) BPI, bone pain index; mCRPC, metastatic castration-resistant prostate cancer; NRE, non-randomized expansion cohort; OS, overall survival. ClinicalTrials.gov. NCT01522443.

Cabozantinib 60 mg QD + Placebo COMET-1: CabOzantinib MET Inhibition CRPC Efficacy Trial–1 (Planned Design) Arm A (n = 640) Patients with: Confirmed mCRPC with bone metastases Previously treated with docetaxel Previously treated with either abiraterone or MDV3100 No limit to prior treatments Cabozantinib 60 mg QD + Placebo N = 960 Placebo + Prednisone 5 mg BID Arm B (n = 320) IRF, independent review facility; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival. Primary endpoint: OS Secondary endpoint: bone scan response (IRF assessed)

Dasatinib in CRPC Oral TKI approved for Ph+ CML and Ph+ ALL Separate mechanism: Src inhibition Phase I/II study of dasatinib plus docetaxel in mCRPC showed PSA responses and clinical benefit[1] Phase II study in chemotherapy-naive mCRPC showed disease stabilization and reduction in bone biomarkers (regardless of bisphosphonate use)[2] Bone alkaline phosphatase Urinary N-telopeptide Ongoing phase III trial of docetaxel ± dasatinib in mCRPC[3] CML, chronic myeloid leukemia; mCRPC, metastatic castration-resistant prostate cancer; Ph+ ALL, Philadelphia chromosome-positive acute lymphoblastic leukemia; PSA, prostate-specific antigen; TKI, tyrosine kinase inhibitor. 1. Araujo JC, et al. Cancer. 2012;118:63-71. 2. Yu EY, et al. Clin Cancer Res. 2009;15:7421-7428. 3. ClinicalTrials.gov. NCT00744497.

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

Prostate Cancer–Related Bone Disease Continuum of bone-related complications has produced greater understanding of biology and natural history RANK ligand inhibitors and bisphosphonates reduce SREs Agents with direct antitumor activity in bone metastases showing survival advantage, with more to come! SRE, skeletal-related event.

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