1. 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

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These slides may not be published or posted online without permission from Clinical Care Options (
Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. 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.

4. 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

5. 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: Weinfurt KP, et al. Ann Oncol. 2005;16: Weinfurt KP, et al. Med Care. 2004;42: Saad F, et al. Eur Urol. 2004;46: Oefelein MG, et al. J Urol. 2002;168: 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:
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:
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:
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: 5

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

7. 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

8. Randomized Controlled Clinical Trials in Metastatic Castrate-Sensitive PC Patients
Zoledronic acid vs placebo
CALGB/CTSU 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. NCT

9. 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. NCT

10. 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:

11. 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
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 Placebo
Saad F, et al. J Natl Cancer Inst. 2002;94: Saad F, et al. ASCO Abstract Saad F, et al. J Natl Cancer Inst. 2004;96:

12. 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: 12 12

13. Time to First On-Study SRE
1.00
HR: 0.82 (95% CI: ) P = (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: 13

14. Time to First and Subsequent On-Study SRE* (Multiple Event Analysis)
2.0
Rate ratio: 0.82 (95% CI: ; 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: 14

15. 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 ( )
.65
Median TTP
8.4
1.06 ( )
.30
CI, confidence interval; HR, hazard ratio; OS, overall survival; TTP, time to progression.
Fizazi K, et al. Lancet. 2011;377:

16. 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:

17. 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

18. 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.

19. 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 Abstract Scher H, et al ASCO GU Cancers Symposium. LBA Parker C, et al ASCO GU Cancers Symposium. Abstract 8.

20. 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:

21. Radium-223 Targets Bone Metastases
Radium 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 ASCO GU Cancers Symposium. Abstract 8.

22. 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 ASCO GU Cancers Symposium. Abstract 8. Perez CA, et al. Principles and practice of radiation oncology. 5th ed

23. 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 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. NCT Parker C, et al ASCO GU Cancers Symposium. Abstract 8.

24. ALSYMPCA: Overall Survival
100
HR: (95% CI: ; P = ) 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 ASCO GU Cancers Symposium. Abstract 8.

25. ALSYMPCA: Time to First Skeletal-Related Event
100
HR (95% CI: ; P = ) 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 ASCO GU Cancers Symposium. Abstract 8.

26. 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 ASCO GU Cancers Symposium. Abstract 8.

27. 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: Verras M, et al. Cancer Res. 2007;67: Zhang S, et al. Mol Cancer. 2010;9:9. 27

28. 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 ASCO GU Cancers Symposium. Abstract Knudsen BS, et al. Urology. 2002;60: Morrissey C, et al. J Cell Biochem. 2007;101: Zhang S, et al. Mol Cancer. 2010;9:9. 5. Grano M, et al. Proc Natl Acad Sci U S A. 1996;93: Inaba M, et al. Blood. 1993;82: Zelzer E, et al. Curr Top Dev Biol. 2005;65: Street J, et al. J Orthop Surg Res. 2009;4:19.

29. 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 ASCO GU Cancers Symposium. Abstract 127.

30. 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. NCT

31. 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. NCT

32. 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)

33. 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: Yu EY, et al. Clin Cancer Res. 2009;15: ClinicalTrials.gov. NCT

34. 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

35. 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.

36. Go Online for More CCO Coverage of Bone Health in Prostate Cancer!
Interactive Virtual Presentation: On-demand PowerPoint presentation narrated by one of our experts Expert Insight Tool: Expert faculty help guide choice of bone-targeted therapy based on your patients’ specific characteristics Downloadable slidesets for your own noncommercial presentations
clinicaloptions.com/oncology clinicaloptions.com/urology