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

Role of Bone-Targeted Therapy in the
Treatment of Prostate Cancer
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Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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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
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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.
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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
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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
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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.
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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)
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
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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.
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The FRAX Tool: Assessing Fracture Risk
http://www.sheffield.ac.uk/FRAX
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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.
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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
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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.
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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.
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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
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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
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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
Delaying Bone Metastases in
Prostate Cancer
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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
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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
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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.
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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.
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36
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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.
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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
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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.
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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
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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.
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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
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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
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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
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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.
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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.
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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
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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.
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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
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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.
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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
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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
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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.
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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.
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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.
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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
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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
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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)
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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.
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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.
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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.
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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)
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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.
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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
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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
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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
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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
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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.
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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
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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
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