Role of Bone-Targeted Therapy in the Treatment of Prostate Cancer
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Faculty
Matthew Raymond Smith, MD, PhDProfessor of Medicine Harvard Medical SchoolProgram Director, Genitourinary OncologyMassachusetts General Hospital Cancer CenterBoston, Massachusetts
Evan Y. Yu, MDAssociate ProfessorDepartment of Medicine/OncologyUniversity of Washington/Fred Hutchinson Cancer Research CenterSeattle, 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.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Inci
den
ce/1
,000
,000
Per
son
-Yrs
Age (Yrs)
4000
3000
2000
1000
35-39 ≥ 85 ≥ 85
HipSpine
Men Women
Melton LJ 3rd, et al. J Bone Miner Res. 1992;7:1005-1010.
Fracture Risk by Sex and Age
35-39
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
LumbarSpine
TotalHip
P < .001 for each comparison
12-mo data
Per
cen
t C
han
ge
Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661.
GnRH Agonists Decrease BMD in Men With Prostate Cancer
-5
-4
-3
-2
-1
0
1
2
GnRH agonistControl
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Proportion of Patients With Fractures1-5 Yrs After Cancer Diagnosis
0
3
6
9
12
15
18
Any Fracture Fracture Resulting in Hospitalization
Fre
qu
ency
(%
)
+2.8%; P < .001
+6.8%; P < .001
ADT (n = 6650)
No ADT (n = 20,035)
12.6
21
5.2
19.4
2.4
Shahinian VB, et al. N Engl J Med. 2005;352:154-164.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
The FRAX Tool: Assessing Fracture Risk
http://www.sheffield.ac.uk/FRAX
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Alendronate Increases BMD During GnRH Agonist Therapy
Greenspan SL, et al. Ann Intern Med. 2007;146:416-424.
-3
-2
-1
0
1
2
3
4
5
BM
D P
erce
nt
Ch
ang
e
AlendronatePlacebo
LumbarSpine
TotalHip
12-Mo Data
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Quarterly Zoledronic Acid Increases BMD During GnRH Agonist Therapy
LumbarSpine
TotalHip
Smith MR, et al. J Urol. 2003;169:2008-2012.
-4
-2
0
2
4
6
8P < .001 for each comparison
Final 12-Mo Data
Zoledronic acidPlacebo
BM
D P
erce
nt
Ch
ang
e
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy
Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.
-6
-4
-2
0
2
4
6P < .005 for each comparison
Zoledronic acid 4 mg/yr IV Placebo
LumbarSpine
Final 12-Mo Data
BM
D P
erce
nt
Ch
ang
e
TotalHip
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Primary endpoints: bone mineral density, new vertebral fractures
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 q6mfor 3 yrs
Placebo q6mfor 3 yrs
Smith MR, et al. N Engl J Med. 2009;361:745-755.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Denosumab Increased BMD at All Skeletal Sites
1086420
-2-4-6
01 3 6 12 24 36Mos
Ch
an
ge
in
BM
D
Fro
m B
as
eli
ne
(%
)
Femoral Neck
Denosumab
Placebo
Difference at 24 mos,3.9 percentage points
1086420
-2-4-6
01 3 6 12 24 36Mos
Ch
an
ge
in
BM
D
Fro
m B
as
eli
ne
(%
) 86420
-2-4-6
01 3 6 12 24 36Mos
Ch
an
ge
in
BM
D
Fro
m B
as
eli
ne
(%
)
Lumbar Spine
Denosumab
Placebo
Difference at 24 mos,6.7 percentage points
Denosumab
Placebo
Difference at 24 mos,4.8 percentage points
Total Hip
86420
-2-4-6
01 3 6 12 24 36Mos
Ch
an
ge
in
BM
D
Fro
m B
as
eli
ne
(%
)
Placebo
Difference at 24 mos,5.5 percentage points
Distal Third of Radius
Smith MR, et al. N Engl J Med. 2009;361:745-755.
Denosumab
10
10
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Denosumab for Fracture Prevention
12Mos
24 36
P = .004 P = .004 P = .006
1.9
0.3
3.3
1.0
3.9
1.5
0
2
4
6
8
10
New
Ver
teb
ral
Fra
ctu
re (
%) Placebo
Denosumab
13 2 22 7 26 10Patients at Risk, n
Smith MR, et al. N Engl J Med. 2009;361:745-755.
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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
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Natural History of Castration-Resistant Nonmetastatic Prostate Cancer
Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.
DeathBone metastasisBone metastasis or death
1.0
0.8
0.6
0.4
0.2
00 0.5 1.0 1.5 2.0 2.5 3.0
Yrs Since Random Assignment
Pro
po
rtio
n W
ith
Eve
nt
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Smith MR, et al. J Clin Oncol. 2005;23:2918-2925..
PSA and PSADT Are Associated With Shorter Bone Metastasis–Free Survival
1.0
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n o
f P
atie
nts
Wit
h B
on
e M
etas
tase
s o
r D
ied
0 0.5 1.0 1.5 2.0 2.5 3.0Yrs Since Random Assignment
PSA < 7.7 ng/mLPSA 7.7-24.0 ng/mLPSA > 24.0 ng/mL
1.0
0.8
0.6
0.4
0.2
00 0.5 1.0 1.5 2.0 2.5 3.0Yrs Since Random Assignment
PSADT < 6.3 mosPSADT 6.3-18.8 mosPSADT > 18.8 mos
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Smith MR, et al. Lancet. 2012;379:39-46.
Patients with M0 CRPC at high risk for
bone metastases:PSA ≥ 8.0 ng/mL
or PSADT ≤ 10.0 mos(N = 1432)
Double-blind randomization
Calcium and vitamin D supplementation
Off investigational product
Denosumab 120 mg SC q4w(n = 716)
Placebo 120 mg SC q4w(n = 716)
Survival follow-up
Bone metastasis or death
Phase III Study: BMFS With Denosumab in M0 CRPC With Aggressive PSA Kinetics
Primary endpoint: BMFS
Secondary endpoints: time to first bone metastasis (either symptomatic or asymptomatic), OS
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Smith MR, et al. Lancet. 2012;379:39-46.
Denosumab Increases Bone Metastasis– Free Survival
Pro
po
rtio
n o
f P
atie
nts
0
1.0
0.8
0.6
0.4
0.2
0 453 6 9 12 15 18 21 24 27 30 33 36 39 42Mos
HR: 0.85 (95% CI: 0.73-0.98; P = .028)
DenosumabPlacebo
Median Survival, Mos
29.525.2
Events, n335370
Patients at Risk, nDenosumabPlacebo
716716
3536
695691
605569
521500
456421
400375
368345
324300
279259
228215
185168
153137
11199
5960
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Time to First Bone Metastasis With Denosumab
Smith MR, et al. Lancet. 2012;379:39-46.
Pro
po
rtio
n o
f P
atie
nts
0
1.0
0.8
0.6
0.4
0.2
0 453 6 9 12 15 18 21 24 27 30 33 36 39 42Mos
HR: 0.84 (95% CI: 0.71-0.98; P = .032)
DenosumabPlacebo
Median Time, Mos
33.229.5
Events, n286319
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Smith MR, et al, Lancet. 2012;379:39-46.
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
Study Mo
0.2
Study Mo
0 6 12 18 24Pro
po
rtio
n o
f P
atie
nts
Ali
ve
0
0.4
0.8
1.0
0.6
30 36 42
PlaceboDenosumab
HR: 1.01 (95% CI: 0.85-1.20;P = .91)
OS
0.2
0 6 12 18 24
Pro
po
rtio
n o
f P
atie
nts
W
ith
ou
t S
ymp
tom
atic
Bo
ne
Met
asta
ses
0
0.4
0.8
1.0
0.6
30 36
PlaceboDenosumab
HR: 0.67 (95% CI: 0.49-0.92;P = .013)
Time to Symptomatic Bone Metastasis
Risk reduction
Events, n (%)96 (13)69 (10)
33%
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Denosumab and Adverse Events
Smith MR, et al, Lancet. 2012;379:39-46.
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)
Urinary tract infection 14 (2) 15 (2)
Grade 3, 4, or 5 adverse events 353 (50) 381 (53)
Adjudicated positive osteonecrosis of the jaw 0 33 (5)
Hypocalcaemia 2 (< 1) 12 (2)
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Relationship Between PSADT and Risk for Bone Metastasis or Death*
Rel
ativ
e R
isk
for
Bo
ne
Met
asta
sis
or
Dea
th
1.4
1.6
1.8
2.0
2.2
2.4
2.6
2.8
3.0
PSADT in Mos
20 18 16 14 12 10 8 6 4 2
Shorter PSADT
Incr
easi
ng
Ris
k
Smith MR, et al. ASCO GU 2012. Abstract 6.
*Placebo arm of study (n = 147)
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Bone Metastasis–Free Survival in Patients With PSADT ≤ 10 Mos
HR: 0.84 (95% CI: 0.72-0.99;P = .042)
16% Risk reduction
Smith MR, et al. ASCO GU. 2012. Abstract 6.
Pro
po
rtio
n o
f P
atie
nts
Wit
h
Bo
ne
Met
asta
sis–
Fre
e S
urv
ival
1.0
0.6
0.8
0.4
0.2
0120 24 36
Study Mo580 460 335 273 199 125 74574 486 351 282 215 138 77
6 18 30
561557
398410
296306
235249
159171
102109
Patients at Risk, nPlaceboDenosumab
PlaceboDenosumab
MedianMos Events, n
Delay,Mos
22.428.4
6.0309273
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Bone Metastasis–Free Survival in Patients With PSADT ≤ 6 Mos
HR: 0.77 (95% CI: 0.64-0.93;P = .006)
23% Risk reduction
Smith MR, et al. ASCO GU. 2012. Abstract 6.
Pro
po
rtio
n o
f P
atie
nts
Wit
h
Bo
ne
Met
asta
sis–
Fre
e S
urv
ival
1.0
0.6
0.8
0.4
0.2
0120 24 36
Study Mo427 323 223 176 122 78 47419 345 238 193 145 89 46
6 18 30
411406
274284
194207
148170
99109
6567
PlaceboDenosumab
MedianMos Events, n
Delay,Mos
18.725.9
7.224297
Patients at Risk, nPlaceboDenosumab
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Bone Metastasis–Free Survival in Patients With PSADT ≤ 4 Mos
HR: 0.71 (95% CI: 0.56-0.90;P = .004)
29% Risk reduction
Pro
po
rtio
n o
f P
atie
nts
Wit
h
Bo
ne
Met
asta
sis–
Fre
e S
urv
ival
1.0
0.6
0.8
0.4
0.2
0120 24 36
Study Month289 209 138 105 71 46263 217 143 117 89 56
6 18 30
279254
176176
117123
88102
5867
3538
PlaceboDenosumab
18.325.8
7.5167124
Smith MR, et al. ASCO GU. 2012. Abstract 6.
MedianMos Events, n
Delay,Mos
Patients at Risk, nPlaceboDenosumab
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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 Castration-
Resistant Prostate Cancer
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Skeletal-Related Events and Clinical Consequences of Bone MetastasesSkeletal-Related Events
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.
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Combined Analysis of 2 Phase III Trials of Pamidronate in Metastatic CRPC
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)
RANDOMIZED
Small EJ, et al. J Clin Oncol. 2003;21:4277-4284.
Eligibility Criteria
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 5 (3) 6 (3)
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Zoledronic Acid in Castration-Resistant Prostate Cancer
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
Patients with prostate cancer
Castration resistant Bone metastases
(N = 643)
Zoledronic acid 4 mg q3w(n = 214)
Placebo q3w(n = 208)
RANDOMIZED
Eligibility Criteria
Zoledronic acid 4 mg q3w(initially 8 mg)
(n = 221)
Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.
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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
0
20
40
60
80
100
0 120 240 360 480 600 720
Days
Median, Days
P Value
ZOL 4 mg 488.009
Placebo 321ZOL 4 mg 214 149 97 70 47 353
Placebo 208 128 78 44 32 203
Per
cen
t W
ith
ou
t E
ven
t
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.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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
CrCl calculated using Cockcroft-Gault formula
*Doses calculated assuming target AUC of 0.66 (mg.hr/L) (CrCl = 75 mL/min)
Starting Dose Recommendations for Patients With Reduced CrCl
Zoledronic acid [package insert]. 2012.
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
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
*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)
Measure serum creatinine prior to each q3- to 4-wk dose
If significant change in creatinine*
Withhold therapy
Resume starting dose when creatinine returns to within 10% of baseline
If no significant change in creatinine
Give the starting dose
For the second and all subsequent doses
Zoledronic acid [package insert]. 2012.
Treatment Algorithm for Continuing Zoledronic Acid
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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)
*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.
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)
Fizazi K, et al. Lancet. 2011;377:813-822.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Zoledronic acid 951 733 544 407 299 207 140 93 64 47Denosumab 950 758 582 472 361 259 168 115 70 39
Patients at Risk, nStudy Mo
0
1.00
Pro
po
rtio
n o
f S
ub
ject
s W
ith
ou
t S
RE
0 3 6 9 12 15 18 21 24 27
0.25
0.50
0.75
KM Estimate ofMedian Mos
DenosumabZoledronic acid
20.717.1
HR: 0.82 (95% CI: 0.71-0.95;P = .0002, noninferiority;P = .008, superiority)
18%Risk
reduction
Time to First On-Study SRE
Fizazi K, et al. Lancet. 2011;377:813-822.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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) 22 (2.3)
Hypocalcemia 55 (5.8) 121 (12.8)
New primary malignancy 10 (1.1) 18 (1.9)
Fizazi K, et al. ASCO 2010. Abstract LBA4507. Fizazi K, et al. Lancet. 2011;377:813-822.
*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
Adverse Events of Interest
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
Currently, there is no proven role for zoledronic acid in this setting
Primary endpoint: time to first SRE
Secondary endpoints: OS, PFS, toxicityClinicalTrials.gov. NCT00079001.
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
Placebo IV over 15 mins, Day 1, q4w +
ADT
Zoledronic acid IV over 15 mins, Day 1,
q4w + ADT
Progression to androgen-independent
prostate cancer
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Denosumab and Zoledronic Acid: Indications in Advanced Prostate CancerIndication Denosumab
120 mg SC MonthlyZoledronic Acid 4 mg IV Monthly
Bone metastases from hormone-sensitive disease
Yes No
Bone metastases from CRPC
Yes Yes
Novel Agents With Bone-Protective Effects
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
AA 797 736 657 520 282 68 2 0
Placebo 398 355 306 210 105 30 3 0
HR: 0.646 (95% CI: 0.54-0.77; P < .0001)
Placebo Median OS: 10.9 mos (95% CI: 10.2-12.0)
0 3 6 9 12 15 18 210
20
40
60
80
100
Su
rviv
al (
%)
Mos
Abiraterone acetate Median OS: 14.8 mos (95% CI: 14.1-15.4)
Median OS with 2 previous chemos:14.0 mos AA vs 10.3 mos placebo
de Bono J, et al. N Engl J Med. 2011;364:1995-2005.
Median OS with 1 previous chemo: 15.4 mos AA vs 11.5 mos placebo
COU-AA-301: Abiraterone Acetate Improves OS in Metastatic CRPC
Patients at Risk, n
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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
Logothetis C, et al. ASCO 2011. Abstract 4520.
155/349(44.4%)
44/163(27.0%)
Pts
Ex
per
ien
cin
g
Pal
lia
tio
n (
%)
70605040302010
0AA (n = 797) Placebo (n = 398)
Pts
No
t E
xp
erie
nc
ing
P
alli
ati
on
(%
)
100
80
60
40
20
00 3 6 129
Mos
PlaceboAA
Median: 10.25 mos
P = .0010 (log rank)
Median: 5.55 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 < .0001
Time to first SRE* (25th percentile), days
301 150 < .0001
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Scher HI, et al. ASCO GU 2012. Abstract LBA1.
OS improved with enzalutamide vs placebo
Median follow-up: 14.4 mos
Phase III AFFIRM Trial of Enzalutamide (MDV3100) in Post-Docetaxel CRPC: OS
HR: 0.631 (95% CI: 0.529-0.752; P < .0001)37% reduction in risk of death
Placebo: 13.6 mos(95% CI: 11.3-15.8)
Enzalutamide: 18.4 mos(95% CI: 17.3-NYR)
Duration of OS (Mos)0 3 6 9 12 15 18 21 24
Su
rviv
al (
%)
010
2030
40
5060
70
80
90
100
MDV3100Placebo
800399
775376
701317
627263
400167
21181
7233
73
00
Pts at Risk, n
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AFFIRM Trial of Enzalutamide in Post-Docetaxel CRPC: Time to First SRE
De Bono JS, et al. ASCO 2012. Abstract 4519^.
HR: 0.621 (P < .0001)
Placebo: 13.3 mos(95% CI: 5.5-NYR)
Enzalutamide: 16.7 mos(95% CI: 14.6-19.1)
Time to Event (Mos)0 3 6 9 12 15 18 21 24
SR
E F
ree
(%)
0
10
2030
40
5060
70
80
90
100
Enzalutamide Placebo
800399
676278
548196
379128
20968
8733
1911
20
00
Pts at Risk, n
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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
Ra
Ca
Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.
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Parker C, et al. ASCO GU 2012. Abstract 8.
Patients with symptomatic CRPC and ≥ 2 bone metastases with no
known visceral metastases, either
post-docetaxel or unfit for docetaxel
(N = 921)
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
Radium-223 50 kBq/kg + BSC
Placebo (saline) + BSC
Stratified by total ALP, previous docetaxel, and bisphosphonate use; randomized 2:1
Up to 6 treatments at 4-wk intervals
ALSYMPCA: Phase III Trial of Radium-223 in Symptomatic Prostate Cancer
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ALSYMPCA: Overall Survival
Radium-223 541 450 330 213 120 72 30 15 3 0
Placebo 268 218 147 89 49 28 15 7 3 0Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.
OS
(%
) O
S (
%)
Radium-223 (n = 541)Median OS: 14.0 mosRadium-223 (n = 541)Median OS: 14.0 mos
Placebo (n = 268)Median OS: 11.2 mosPlacebo (n = 268)Median OS: 11.2 mos
HR: 0.695 (95% CI: 0.552-0.875;P = .00185)HR: 0.695 (95% CI: 0.552-0.875;P = .00185)
33 66 99 1212 1515 1818 2121 2424 2727
MosMosPts at Risk, nPts at Risk, n
0
10
20
30
40
50
60
70
80
90
100
00
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ALSYMPCA: Time to First SRE
Radium-223 541 379 214 111 51 22 6 0
Placebo 268 159 74 30 15 7 2 0
0
10
20
30
40
50
60
70
80
90
100
Pat
s W
ith
ou
t S
RE
(%
)
HR: 0.610 (95% CI: 0.461-0.807; P = .00046)HR: 0.610 (95% CI: 0.461-0.807; P = .00046)
Radium-223 (n = 541)Median: 13.5 mosRadium-223 (n = 541)Median: 13.5 mos
Placebo (n = 268)Median: 8.4 mosPlacebo (n = 268)Median: 8.4 mos
00 33 66 99 1212 1515 1818 2121
Pts at Risk, nPts at Risk, n MosMos
Sartor O, et al. ASCO GU 2012. Abstract 9.
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Radium-223: Effect on Specific SREs
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) .00380.65
(0.48-0.87)
Spinal cord compression
17 (3) 16 (6) .0160.44
(0.22-0.88)
Pathologic bone fracture
20 (4) 18 (7) .0130.45
(0.24-0.86)
Surgical intervention 9 (2) 5 (2) .690.80
(0.27-2.4)
Sartor AO, et al. ASCO 2012. Abstract 4551.
Time to first SRE HR: 0.610 (P = .00046)
– Median: 13.6 vs 8.4 mos for placebo
3 of 4 SRE components improved
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ALSYMPCA: Adverse Events of Interest
Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.
Adverse Event, n (%)
All Grades Grade 3/4
Radium-223(n = 509)
Placebo(n = 253)
Radium-223(n = 509)
Placebo(n = 253)
HematologicAnemiaNeutropeniaThrombocytopenia
136 (27)20 (4)42 (8)
69 (27)2 (1)
14 (6)
54 (11)9 (2)22 (4)
29 (12)2 (1)4 (2)
NonhematologicBone painDiarrheaNauseaVomitingConstipation
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)
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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 14
S/T Ks (47) >200
Data courtesy of Ron Weitzman and Dana Aftab.
ATP competitive, reversible
RTK Cellular IC50, nM, Autophosphorylation
MET 8
VEGFR2 4
Cabozantinib, mg/kg
pMETMET
V 3 10 30 100
VEGFR2
pVEGFR2
H441tumors*
Mouselung†
*No growth factor stimulation.†VEGF-A administered 30 min prior to harvest.*No growth factor stimulation.†VEGF-A administered 30 min prior to harvest.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Androgen Deprivation Activates MET Signaling
HGF(autocrine + paracrine)
AR MET AR MET
Stromal HGF
Androgen deprivation X
Zhang S, et al. Mol Cancer. 2010;9:9.
Activated MET Is Highly Expressed in Bone Metastases
Role of MET in Prostate Cancer and Bone Metastases
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Cabozantinib (cMET/VEGFR2 Inhibitor) Demonstrates Significant Bone Effects
Bone Scan Evaluable (N = 108) n (%)
Complete resolution 21 (19)
Partial resolution 61 (56)
Stable 23 (21)
Progressive disease 3 (3)
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 2011.
Abstract 4516.
% B
es
t C
ha
ng
e F
rom
Ba
se
lin
e
-100
-80
-60
-40
-20
0
20
40
60
80
100
-100
-80
-60
-40
-20
0
20
40
60
80
100 Bisphosphonate treated
Bisphosphonate naive
Effects on Osteoblast (t-ALP) and Osteoclast (CTx) Activity
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Cabozantinib: Effects on Bone Pain and Narcotic UseRandomized 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)
Nonrandomized Expansion Trial Prospective: Pts With Average
Worst Pain ≥ 4 at Baseline
Hussain M, et al. ASCO 2011. Abstract 4516. Basch EM, et al. 2011 AACR-NCI-EORTC Abstract B57.
7/27 (26%) patients discontinuednarcotics entirely
Imp
rove
d
20
0
-20
-40
-60
-80
-100%
Ch
ang
e i
n A
vera
ge
Wo
rst
Pai
n F
rom
Bas
elin
e
** *
Previous docetaxelPrevious docetaxel + abiraterone and/or cabazitaxel*Previous radionuclide therapy
Median best pain reduction from baseline: 46%
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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
Zhang S, et al. Mol Cancer. 2010;9:9.
Stroma
AngiogenesisVEGF
HGF
VEGF HGFHGF
HGF
VEGF
VEGFOsteoblast
Tumor Cell
Osteoclast
Migrationproliferation
survival
Proliferationdifferentiation
survival
Migrationproliferation
survival
MET
NP-1
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Patients with bone-metastatic CRPC, moderate
to severe bone pain, and previous treatment with
docetaxel, abiraterone, or enzalutamide
(Planned N = 246)
Pain Endpoint Trial[1]
Primary endpoint: durable pain response at Wk 12
Secondary endpoints: bone scan response by IRF, OS
Cabozantinib 60 mg QD +Mitoxantrone Placebo
Mitoxantrone/Prednisone +Cabozantinib Placebo
Patients with bone-metastatic CRPC, and previous treatment with
docetaxel, abiraterone, or enzalutamide
(Planned N = 246)
OS Endpoint Trial[2]
Primary endpoint: OS
Secondary endpoints: bone scan response by IRF
Cabozantinib 60 mg QD +Placebo
Prednisone 5 mg BID +Placebo
1. ClinicalTrials.gov. NCT01522443.2. ClinicalTrials.gov. NCT01605227.
Cabozantinib: Randomized Phase III Trials
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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
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Tumor Size (by RECIST)
PSA
Urine N-Telopeptide
Bone Alkaline Phosphatase
50403020
10
0-10
-20
-30-40-50
Max
imu
m T
um
or
Siz
eC
han
ge
Fro
m B
asel
ine
(%)
200
150
100
50
0
-50
-100
-150
Max
imu
m P
SA
Ch
ang
e F
rom
Bas
elin
e (%
)
160140120100
604020
-20-40
-80-100
Max
imu
m u
NT
xC
han
ge
Fro
m B
asel
ine
(%)
100
80
60
20
0
-20
-60
-80
Max
imu
m B
AP
Ch
ang
e F
rom
Bas
elin
e (%
)
Yu EY, et al. Clin Cancer Res. 2009;15:7421-7428.
80
0
-60
Bisphosphonate No bisphosphonate
Bisphosphonate No bisphosphonate
40
-40
Phase II Study: Dasatinib Monotherapy in Metastatic CRPC With No Previous Chemo
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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.
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
Docetaxel/Prednisone ± Dasatinib in CRPC: Phase III Study
ClinicalTrials.gov. NCT00744497
Docetaxel +Prednisone +Placebo daily
Docetaxel +Prednisone +
Dasatinib 100 mg/day PO
Patients with metastatic
CRPC and evidence of progression
(Planned N = 1500)
Primary endpoint: OS Secondary endpoints: ∆ uNTx, time to first SRE, ∆ pain intensity, time to PSA
progression, tumor response rate, PFS, safety/tolerability
clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
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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