Download Fracture Prevention - Research To Practice

Bone Directed Therapy in Prostate Cancer
Matthew R. Smith, M.D., Ph.D.
Program Director, Genitourinary Oncology
Massachusetts General Hospital Cancer Center
Associate Professor of Medicine
Harvard Medical School
Spectrum of Bone Disease in Prostate Cancer
Castrate-sensitive
nonmetastatic
Castrate-resistant
nonmetastatic
Castrate-resistant
metastatic
Spectrum of Bone Disease in Prostate Cancer
Treatment-Related
Fractures
Castrate-sensitive
nonmetastatic
Castrate-resistant
nonmetastatic
Castrate-resistant
metastatic
Spectrum of Bone Disease in Prostate Cancer
Disease-Related
Skeletal Complications
Treatment-Related
Fractures
Castrate-sensitive
nonmetastatic
Castrate-resistant
nonmetastatic
Castrate-resistant
metastatic
Clinical Complications of
Osteoblastic Metastases

pain

fractures

spinal cord compression

myelophthisis
Markers of Osteoblast (BAP) and Osteoclast (NTx)
Activity in Men with Metastatic Prostate Cancer
BAP (U/L)
Correlation coefficient = 0.67
Normal
NTx (nmol/mmol creatinine)
Adapted and reprinted by permission from the American Association for Cancer Research: Cook RJ et al.
Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin
Cancer Res 2006;12(11 Pt 1):3361-7.
Bisphosphonates: Contemporary Phase 3 Trials in
Castration-Resistant Metastatic Prostate Cancer
STUDY
POPULATION
TREATMENT
ENDPOINT
NCIC Pr06
(n= 204)
Symptomatic
Mitoxantrone/prednisone
±clodronate
Palliative response
032/INT 05
(n= 350)
Symptomatic
IV pamidronate vs
placebo
Pain score
Analgesic use
Zoledronic acid 039
(n= 643)
Asymptomatic
IV zoledronic acid vs
placebo
SRE
Zoledronic Acid Study 039
randomize
placebo q3w
Castrate-resistant,
bone metastases
(n=643)
zoledronic acid q3w
Primary Endpoint: Skeletal Related Events (SRE)
Saad F et al. J Natl Cancer Inst 2002;94(19):1458-68.
Cumulative Incidence of Skeletal-Related Events
Placebo
Events/100 patients
100
P = 0.002
50
Zoledronic acid
Skeletal Related Events
 Radiation to bone
 Pathologic fracture
 Spinal cord compression
 Surgery to bone
 Change in antineoplastic
therapy
0
0
12
24
Time (months)
With permission from Cook RJ and Lawless JF. Proc ASCO 2003;Abstract 3062.
Denosumab–Targeting RANKL
•
•
•
•
Fully human monoclonal antibody to RANKL
IgG2
High affinity for human RANKL (Kd 3x10–12 M)
Does not bind to human TNFα, TNFß, TRAIL, or
CD40L
• Approved to treat osteoporosis
• In development to treat and prevent bone metastases
Bekker PJ et al. J Bone Miner Res 2004;19:1059–66.
Boyle WJ et al. Nature 2003;423:337–42.
Phase 3 RCT of Denosumab versus Zoledronic Acid to
Prevent Skeletal Related Events
Castrate-resistant,
Bone metastases,
No prior bisphosphonate
(n=1870)
R
A
N
D
O
M
I
Z
E
Primary Endpoint:
Skeletal-related events
Fizazi K et al. Proc ASCO 2010;Abstract LBA4507.
Denosumab monthly
Zoledronic acid monthly
Phase 3 RCT of Denosumab versus Zoledronic Acid to
Prevent Skeletal Related Events
Castrate-resistant,
Bone metastases,
No prior bisphosphonate
(n=1870)
R
A
N
D
O
M
I
Z
E
Denosumab monthly
Zoledronic acid monthly
Primary Endpoint:
Skeletal-related events
Accrual complete 2008 Q4
Final analyses 2010
Fizazi K et al. Proc ASCO 2010;Abstract LBA4507.
Proportion of Subjects Without SRE
Time to First On-Study SRE
HR 0.82 (95% CI: 0.71, 0.95)
P = 0.0002 (Non-inferiority)
P = 0.008 (Superiority)
18%
Risk
Reduction
KM Estimate of
Median Months
Denosumab
Zoledronic acid
20.7
17.1
Study Month
Subjects at risk:
Zoledronic Acid
951
733
544
407
299
207
140
93
64
47
Denosumab
950
758
582
472
361
259
168
115
70
39
With permission from Fizazi K et al. Proc ASCO 2010;Abstract LBA4507.
Cumulative Mean Number of
SREs per Patient
Time to First and Subsequent On-Study SRE*
(Multiple Event Analysis)
Rate Ratio = 0.82 (95% CI: 0.71, 0.94)
P = 0.008
*Events occurring at least 21 days apart
18%
Risk
Reduction
Events
Denosumab
Zoledronic acid
Study Month
With permission from Fizazi et al. Proc ASCO 2010;Abstract LBA4507.
494
584
Conclusions–Treatment of Bone Metastases
•
Disease-related skeletal complications are common in men with metastatic
prostate cancer
•
Zoledronic acid decreases risk of SRE in men with castrate-resistant
disease and bone metastases
•
Denosumab, a human monoclonal antibody targeting RANKL, is superior to
zoledronic acid for prevention of SRE
•
Role of bone-targeted therapy in castrate-sensitive disease has not been
established
Natural History of Castration-Resistant Nonmetastatic
Prostate Cancer
Originally published by the American Society of Clinical Oncology. [Smith MR et al: 23(13), 2005: 2918-25].
PSA and PSA Doubling Time (PSADT) Are Associated
with Shorter Bone Metastasis-Free Survival
Originally published by the American Society of Clinical Oncology. [Smith MR et al: 23(13), 2005: 2918-25].
Denosumab to Prevent Metastases
Castrate-resistant
No bone metastases
PSA≥8 or PSADT ≤10 mos
(n~1500)
Primary Endpoint:
Bone metastasis-free survival
www.clinicaltrials.gov.
R
A
N
D
O
M
I
Z
E
Denosumab monthly
Placebo monthly
Denosumab to Prevent Metastases
Castrate-resistant
No bone metastases
PSA≥8 or PSADT ≤10 mos
(n~1500)
R
A
N
D
O
M
I
Z
E
Denosumab monthly
Placebo monthly
Primary Endpoint:
Bone metastasis-free survival
Accrual complete 2008 Q2
Final analyses 2010
www.clinicaltrials.gov.
ZEUS–Zoledronic Acid to Prevent Metastases
High risk disease:
Gleason sum 8-10, pN+, or
PSA>20 ng/mL at diagnosis
No bone metastases
(n=1433)
R
A
N
D
O
M
I
Z
E
Primary Endpoint:
First bone metastasis
http://www.controlled-trials.com/ISRCTN66626762/zeus.
Zoledronic acid q3 months
for 48 months
Placebo q3 months
ZEUS–Zoledronic Acid to Prevent Metastases
High risk disease:
Gleason sum 8-10, pN+, or
PSA>20 ng/mL at diagnosis
No bone metastases
(n=1433)
R
A
N
D
O
M
I
Z
E
Zoledronic acid q3 months
for 48 months
Placebo q3 months
Primary Endpoint:
First bone metastasis
Anticipated completion date
2011
http://rand.dnsalias.com.
ZEUS–Zoledronic Acid to Prevent Metastases
High risk disease:
Gleason sum 8-10, pN+, or
PSA>20 ng/mL at diagnosis
No bone metastases
(n=1433)
Primary Endpoint:
First bone metastasis
http://rand.dnsalias.com.
R
A
N
D
O
M
I
Z
E
Zoledronic acid q3 months
for 48 months
Placebo q3 months
Study does not control for ADT
1. Some men will develop bone
metastases prior to ADT
2. Dramatic variation in duration
of response to ADT
Conclusions–Metastasis Prevention
•
Prevention of bone metastases is an important unmet clinical need
•
Failure of prior studies is related, at least in part, to poorly defined
natural history of castrate resistant nonmetastatic disease
•
The results of an aborted RCT of zoledronic acid have helped define
the natural history of this disease state
•
An ongoing RCT in high-risk subjects will evaluate whether
denosumab prevents metastases
Consequences of Vertebral Fractures
Pain
• Kyphosis
• Loss of height
• Respiratory problems
•
Netter illustration used with permission of Elsevier, Inc. All rights reserved. www.netterimages.com.
Proportion of Patients with Fractures 1-5 Years After
Cancer Diagnosis
+6.8%; P < 0.001
21
ADT (n = 6650)
18
19.4
15
12
No ADT (n = 20,035)
12.6
+2.8%; P < 0.001
9
6
5.2
3
2.4
0
Any Fracture
Shahinian VB et al. N Engl J Med 2005;352:154-64.
Fracture Resulting
in Hospitalization
Denosumab Fracture Prevention Study
Current androgen deprivation
therapy for prostate cancer;
Age >70 or T score <-1.0
(n=1,468)
R
A
N
D
O
M
I
Z
E
Denosumab q6 months
for 3 years
Placebo q6 months
for 3 years
Primary Endpoint: change in lumbar spine BMD
Key Secondary Endpoint: new vertebral fractures
Smith MR et al. N Engl J Med 2009;361:745-55.
Denosumab Increased BMD at All Skeletal Sites
Smith MR et al. N Engl J Med 2009;361:745-55. © [2009] Massachusetts Medical Society. All rights reserved.
Denosumab Decreased New Vertebral Fractures
Smith MR et al. N Engl J Med 2009;361:745-55. © [2009] Massachusetts Medical Society. All rights reserved.
Conclusions–Fracture Prevention
• Androgen deprivation therapy increases fracture risk
in prostate cancer survivors
• A variety of drugs increase bone mineral density
during androgen deprivation therapy
• Toremifene, a SERM, increases bone mineral
density and decreases incidence of new vertebral
fractures
• Denosumab increases bone mineral density and
decreases incidence of new vertebral fractures