1. Role of Bone-Targeted Therapy in the Treatment of Prostate Cancer
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3. 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
This slide lists the faculty who were involved in the production of these slides.

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

8. GnRH Agonists Decrease BMD in Men With Prostate Cancer2
Control 1
GnRH agonist
P < .001 for each comparison -1
Percent Change -2 -3 -4
BMD, bone mineral density; GnRH, gonadotropin-releasing hormone.
12-mo data -5
Lumbar
Spine
Total
Hip
Mittan D, et al. J Clin Endocrinol Metab. 2002;87:

9. Proportion of Patients With Fractures 1-5 Yrs After Cancer Diagnosis
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Proportion of Patients With Fractures 1-5 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
ADT, androgen-deprivation therapy. 6
5.2 3
2.4
Any Fracture
Fracture Resulting in Hospitalization
Shahinian VB, et al. N Engl J Med. 2005;352: 9 9 9

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%
FDA, US Food and Drug Administration.
National Osteoporosis Foundation Clinician’s Guide to Prevention and Treatment of Osteoporosis 10

11. The FRAX Tool: Assessing Fracture Risk
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The FRAX Tool: Assessing Fracture Risk
BMD, bone mineral density. 11

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

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

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

15. Denosumab Fracture Prevention Study
Denosumab q6m for 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 q6m for 3 yrs
Primary endpoints: bone mineral density, new vertebral fractures
q6m, every 6 months.
Smith MR, et al. N Engl J Med. 2009;361:

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

17. Denosumab for Fracture Prevention10
Denosumab
Placebo 8
P = .004
P = .004
P = .006 6
New Vertebral Fracture (%)
3.9 4
3.3
1.9 2
1.5
1.0
0.3 12 24 36
Mos
Patients at Risk, n 13 2 22 7 26 10
Smith MR, et al. N Engl J Med. 2009;361: 17

18. Fracture Risk: Conclusions
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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
ADT, androgen-deprivation therapy; BMD, bone mineral density; BMI, body mass index. 18

19. Delaying Bone Metastases in Prostate Cancer

20. Natural History of Castration-Resistant Nonmetastatic Prostate Cancer
1.0
Death Bone metastasis Bone metastasis or death
0.8
0.6
Proportion With Event
0.4
0.2
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:

21. PSA and PSADT Are Associated With Shorter Bone Metastasis–Free Survival
1.0
PSA < 7.7 ng/mL PSA ng/mL PSA > 24.0 ng/mL
1.0
PSADT < 6.3 mos PSADT mos PSADT > 18.8 mos
0.8
0.8
0.6
0.6
Proportion of Patients With Bone Metastases or Died
0.4
0.4
PSA, prostate-specific antigen; PSADT, prostate-specific antigen doubling time.
0.2
0.2
0.5
1.0
1.5
2.0
2.5
3.0
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:

22. Patients with M0 CRPC at high risk for bone metastases:
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:
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
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.
Primary endpoint: BMFS
Secondary endpoints: time to first bone metastasis (either symptomatic or asymptomatic), OS
Smith MR, et al. Lancet. 2012;379:39-46. 22

23. Denosumab Increases Bone Metastasis– Free Survival
1.0
HR: 0.85 (95% CI: ; P = .028)
0.8
0.6
Proportion of Patients
0.4
Median Survival, Mos
Events, n
CI, confidence interval; HR, hazard ratio.
0.2
Denosumab Placebo 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Mos
Patients at Risk, n Denosumab Placebo
111 99
59 60
35 36
Smith MR, et al. Lancet. 2012;379:39-46.

24. Time to First Bone Metastasis With Denosumab
1.0
HR: 0.84 (95% CI: ; P = .032)
0.8
0.6
Proportion of Patients
0.4
Median Time, Mos
CI, confidence interval; HR, hazard ratio.
0.2
Events, n
Denosumab Placebo 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: ; P = .013)
0.6
Proportion of Patients Without Symptomatic Bone Metastases
0.6
HR: 1.01 (95% CI: ; P = .91)
Proportion of Patients Alive
CI, confidence interval; CRPC, castration-resistant prostate cancer; HR, hazard ratio; M0, nonmetastatic; OS, overall survival.
33%
Risk reduction
0.4
0.4
Events, n (%) 96 (13) 69 (10)
0.2
Placebo Denosumab
0.2
Placebo Denosumab 6 12 18 24 30 36 42 6 12 18 24 30 36
Study Mo
Study Mo
Smith MR, et al, Lancet. 2012;379:39-46. 25

26. 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)
14 (2)
Grade 3, 4, or 5 adverse events
353 (50)
381 (53)
Adjudicated positive osteonecrosis of the jaw
33 (5)
Hypocalcaemia
2 (< 1)
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
PSADT, prostate-specific antigen doubling time.
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 Abstract 6.

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

29. Bone Metastasis–Free Survival in Patients With PSADT ≤ 6 Mos
1.0
HR: 0.77 (95% CI: ; P = .006)
0.8
23% Risk reduction
0.6
Proportion of Patients With Bone Metastasis–Free Survival
0.4
Median
Mos
Events, n
Delay,
7.2
242 97
CI, confidence interval; HR, hazard ratio; PSADT, prostate-specific antigen doubling time.
0.2
Placebo Denosumab 6 12 18 24 30 36
Patients at Risk, n
Placebo Denosumab
Study Mo
427
411
323
274
223
194
176
148
122 99 78 65 47
419
406
345
284
238
207
193
170
145
109 89 67 46
Smith MR, et al. ASCO GU Abstract 6.

30. Bone Metastasis–Free Survival in Patients With PSADT ≤ 4 Mos
1.0
HR: 0.71 (95% CI: ; P = .004)
0.8
29% Risk reduction
0.6
Bone Metastasis–Free Survival
Proportion of Patients With
0.4
Median
Mos
Delay,
Mos
CI, confidence interval; HR, hazard ratio; PSADT, prostate-specific antigen doubling time.
0.2
Events, n
Placebo Denosumab
7.5 6 12 18 24 30 36
Patients at Risk, n
Placebo Denosumab
Study Month
289
279
209
176
138
117
105 88 71 58 46 35
263
254
217
176
143
123
117
102 89 67 56 38
Smith MR, et al. ASCO GU 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
CRPC, castration-resistant prostate cancer.

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

33. Skeletal-Related Events and Clinical Consequences of Bone Metastases
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
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)
CRPC, castration-resistant prostate cancer; q3w, every 3 weeks; SRE, skeletal-related event.
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
6 (3)
Small EJ, et al. J Clin Oncol. 2003;21:

35. 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)
q3w, every 3 weeks; SRE, skeletal-related event.
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:

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
Placebo 321 20
OS, overall survival; QoL, quality of life; SRE, skeletal-related event; ZOL, zoledronic acid.
120
240
360
480
600
720
Days
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:

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
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
AUC, area under the curve; CrCl, creatinine clearance.
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]

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]

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 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)
CRPC, castration-resistant prostate cancer; IV, intravenous; q4w, every 4 weeks; SC, subcutaneous.
*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: 39 39

40. Time to First On-Study SRE
1.00
HR: 0.82 (95% CI: ; 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
Denosumab
20.7
CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier; SRE, skeletal-related event.
Zoledronic acid
17.1 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 39
Fizazi K, et al. Lancet. 2011;377: 40

41. 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)
Cumulative rate of ONJ†
12 (1.3)
22 (2.3)
Yr 1
5 (0.5)
10 (1.1)
Yr 2
8 (0.8)
Hypocalcemia
55 (5.8)
121 (12.8)
New primary malignancy
18 (1.9)
ONJ, osteonecrosis of the jaw.
*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 Abstract LBA4507. Fizazi K, et al. Lancet. 2011;377: 41

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
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.
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. NCT

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
OS, overall survival; PO, orally; PSA, prostate-specific antigen; QD, once daily.
Dearnaley DP, et al. Lancet Oncol. 2009;10:

45. Denosumab and Zoledronic Acid: Indications in Advanced Prostate Cancer
Denosumab 120 mg SC Monthly
Zoledronic Acid 4 mg IV Monthly
Bone metastases from hormone-sensitive disease
Yes No
Bone metastases from CRPC

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

48. COU-AA-301: Abiraterone Acetate Improves OS in Metastatic CRPC
100
HR: (95% CI: ; P < .0001) 80
Abiraterone acetate
Median OS: 14.8 mos (95% CI: ) 60
Survival (%) 40
Placebo
Median OS: 10.9 mos (95% CI: ) 20
Median OS with 2 previous chemos: 14.0 mos AA vs 10.3 mos placebo
Median OS with 1 previous chemo: mos AA vs 11.5 mos placebo
AA, abiraterone acetate; CI, confidence interval; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival. 3 6 9 12 15 18 21
Patients at Risk, n
Mos AA
797
736
657
520
282 68 2
Placebo
398
355
306
210
105 30 3
de Bono J, et al. N Engl J Med. 2011;364:

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 50
Median: mos
Pts Experiencing Palliation (%) 40
44/163 (27.0%) 60
Pts Not Experiencing Palliation (%) 30 40 20
Median: 5.55 mos 20 10
P = (log rank)
AA (n = 797)
Placebo (n = 398) 3 6 9 12
Mos
Efficacy Measure
Abiraterone (n = 797)
Placebo (n = 398)
P Value
Median OS, mos
14.8
10.9
< .0001
Median radiographic PFS, mos
5.6
3.6
Time to first SRE* (25th percentile), days
301
150
AA, abiraterone acetate; OS, overall survival; PFS, progression-free survival; SRE, skeletal-related event; TTP, time to palliation.
Logothetis C, et al. ASCO Abstract 4520.

50. Enzalutamide: 18.4 mos (95% CI: 17.3-NYR)
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: (95% CI: ; P < .0001) 37% reduction in risk of death
100 90 80
Enzalutamide: 18.4 mos (95% CI: 17.3-NYR) 70 60
Survival (%) 50 40 30
CI, confidence interval; CRPC, castration-resistant prostate cancer; HR, hazard ratio; NR, not reached; OS, overall survival. 20
Placebo: 13.6 mos (95% CI: ) 10 3 6 9 12 15 18 21 24
Pts at Risk, n
Duration of OS (Mos)
MDV3100 Placebo
211 81
72 33
7 3
0 0
Scher HI, et al. ASCO GU Abstract LBA1. 50

51. AFFIRM Trial of Enzalutamide in Post-Docetaxel CRPC: Time to First SRE
HR: (P < .0001)
100 90
Enzalutamide: 16.7 mos (95% CI: ) 80 70 60
SRE Free (%) 50 40 30 20
Placebo: 13.3 mos (95% CI: 5.5-NYR)
CI, confidence interval; CRPC, castration-resistant prostate cancer; HR, hazard ratio; NYR, not yet reached; SRE, skeletal-related event. 10 3 6 9 12 15 18 21 24
Time to Event (Mos)
Pts at Risk, n
Enzalutamide Placebo
209 68
87 33
19 11
2 0
0 0
De Bono JS, et al. ASCO Abstract 4519^.

52. Other Novel Agents Targeting Bony Metastases in 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:

53. 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.

54. 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
Radium kBq/kg + BSC
Patients with symptomatic CRPC and ≥ 2 bone metastases with no known visceral metastases, either post-docetaxel or unfit for docetaxel (N = 921)
Placebo (saline) +
BSC
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 bisphosphonates were required to continue them; initiating bisphosphonates on this study was not allowed.
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 Abstract 8. 54

55. 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.

56. ALSYMPCA: Time to First SRE
100
HR: (95% CI: ; P = ) 90 80 70
Radium-223 (n = 541)
Median: 13.5 mos 60
Pats 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
Sartor O, et al. ASCO GU Abstract 9.

57. Radium-223: Effect on Specific SREs
Time to first SRE HR: (P = )
Median: 13.6 vs 8.4 mos for placebo
SRE
Patients, n (%)
Time to First Event (Radium-223 vs Placebo)
Radium-223
(n = 541)
Placebo
(n = 268)
P Value*
HR (95%CI)
External beam radiotherapy
122 (23)
72 (27)
.0038
0.65
( )
Spinal cord compression
17 (3)
16 (6)
.016
0.44
( )
Pathologic bone fracture
20 (4)
18 (7)
.013
0.45
( )
Surgical intervention
9 (2)
5 (2)
.69
0.80
( )
CI, confidence interval; HR, hazard ratio; SRE, skeletal-related event.
3 of 4 SRE components improved
Sartor AO, et al. ASCO Abstract 4551.

58. 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.

59. Cabozantinib (XL184): Target Profile
Kinase
IC50, nM
MET
1.8
VEGFR2
0.035
RET
5.2
KIT
4.6
AXL
7.0
TIE2 14
FLT3
S/T Ks (47)
>200
RTK
Cellular IC50, nM, Autophosphorylation
MET 8
VEGFR2 4
Cabozantinib, mg/kg
pMET
MET V
VEGFR2
pVEGFR2
H441
tumors*
RTK, receptor tyrosine kinase.
Mouse
lung†
ATP competitive, reversible
*No growth factor stimulation.
†VEGF-A administered 30 min prior to harvest.
Data courtesy of Ron Weitzman and Dana Aftab.

60. Role of MET in Prostate Cancer and Bone Metastases
Androgen Deprivation Activates MET Signaling
Stromal HGF
HGF
(autocrine + paracrine)
Androgen deprivation X AR
MET AR
MET
Activated MET Is Highly Expressed in Bone Metastases
AR, androgen receptor; PCa, prostate cancer.
Zhang S, et al. Mol Cancer. 2010;9:9. 60

61. Cabozantinib (cMET/VEGFR2 Inhibitor) Demonstrates Significant Bone Effects
Docetaxel pretreated
Baseline
Wk 12
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 80 80
Bisphosphonate naive 60 60 40 40
ALP, alkaline phosphatase; CTx, C-telopeptide; ULN, upper limit of normal. 20 20
% Best Change From Baseline
-20
-20
-40
-40
-60
-60
-80
-80
-100
-100
Pts With Baseline t-ALP Levels ≥ 2 x ULN and ≥ 12 Wks of Follow-up (N = 28)
Samples From Wk 6 and 12 (N = 118)
Hussain M, et al. ASCO Abstract 4516.

62. Cabozantinib: Effects on Bone Pain and Narcotic Use
Nonrandomized Expansion Trial Prospective: Pts With Average
Worst Pain ≥ 4 at Baseline 20
Randomized Discontinuation Trial; Post Hoc Investigator Survey
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) *
Improved
-20
% Change in Average Worst Pain From Baseline
-40
-60
-80
-100
Previous docetaxel
Previous docetaxel + abiraterone and/or cabazitaxel
*Previous radionuclide therapy
7/27 (26%) patients discontinued
narcotics entirely
Median best pain reduction from baseline: 46%
Hussain M, et al. ASCO Abstract Basch EM, et al AACR-NCI-EORTC Abstract B57.

63. MET and VEGFR Interactions in Bone Tumors
MET is activated in bone metastases
Tumor cells express MET
Autocrine and paracrine activation of MET by HGF
VEGF activation of MET via neuropilin-1
Osteoblasts and osteoclasts
Express MET and VEGFRs
Stroma
Angiogenesis
VEGF
Proliferation differentiation survival
HGF
Osteoblast
VEGF
HGF
VEGF
HGF
NP-1
MET
Migration proliferation survival
HGF
Migration proliferation survival
VEGF
Tumor Cell
VEGF, vascular endothelial growth factor.
Osteoclast
Zhang S, et al. Mol Cancer. 2010;9:9. 63

64. Cabozantinib: Randomized Phase III Trials
Patients with bone-metastatic CRPC, moderate to severe bone pain, and previous treatment with docetaxel, abiraterone, or enzalutamide
(Planned N = 246)
Cabozantinib 60 mg QD +
Mitoxantrone Placebo
Pain Endpoint Trial[1]
Primary endpoint: durable pain response at Wk 12
Secondary endpoints: bone scan response by IRF, OS
Mitoxantrone/Prednisone +
Cabozantinib Placebo
Cabozantinib 60 mg QD +
Placebo
Patients with bone-metastatic CRPC, and previous treatment with docetaxel, abiraterone, or enzalutamide
(Planned N = 246)
BID, twice daily; CRPC, castration-resistant prostate cancer; IRF, independent review facility; QD, once daily. OS, overall survival.
OS Endpoint Trial[2]
Primary endpoint: OS
Secondary endpoints: bone scan response by IRF
Prednisone 5 mg BID +
Placebo
1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

65. 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. Phase II Study: Dasatinib Monotherapy in Metastatic CRPC With No Previous Chemo
Tumor Size (by RECIST)
Urine N-Telopeptide 50
160 40
140
120 30
100 20 80 10 60
Maximum Tumor Size Change From Baseline (%)
Maximum uNTx Change From Baseline (%) 40 20
-10
-20
-20
-40
-30
-60
-40
-80
Bisphosphonate
No bisphosphonate
-50
-100
PSA
Bone Alkaline Phosphatase
200
100
150 80
CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors. 60
100 40
Maximum PSA Change From Baseline (%) 50
Maximum BAP Change From Baseline (%) 20
-20
-50
-40
-100
-60
-150
-80
Bisphosphonate
No bisphosphonate
Yu EY, et al. Clin Cancer Res. 2009;15:

67. 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%)
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.
Araujo J, et al. Cancer. 2011;118:63-71.

68. Docetaxel/Prednisone ± Dasatinib in CRPC: Phase III Study
Placebo daily
Patients with metastatic CRPC and evidence of progression
(Planned N = 1500)
Docetaxel +
Prednisone +
Dasatinib 100 mg/day PO
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.
Primary endpoint: OS
Secondary endpoints: ∆ uNTx, time to first SRE, ∆ pain intensity, time to PSA progression, tumor response rate, PFS, safety/tolerability
ClinicalTrials.gov. NCT

69. Curatio PowerPoint Template
4/19/2017 8:09 AM
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
CRPC, castration-resistant prostate cancer; SREs, skeletal-related events. 69

70. Go Online for More CCO Coverage of Bone Health!
Expert perspectives on all the key data, plus interactive activities exploring the clinical implications Interactive Decision Support Tool: expert faculty provide their treatment recommendations based on specific factors from your patients
clinicaloptions.com/oncology