Transcript Advances in the management of skeletal related events

Advances in the Management of Skeletal
Related Events/Bone Metastases in
Prostate Cancer
Robert Dreicer, M.D., M.S., FACP, FASCO
Chair Dept of Solid Tumor Oncology
Taussig Cancer Institute
Cleveland Clinic
Professor of Medicine
Cleveland Clinic Lerner College of Medicine
Clinical States In Prostate Cancer (circa
Winter 2014)
Sipuleucel-T
Organ
Confined
Denosumab
Rising PSA
Hormone
Naive
Locally
Advanced
Disease
Metastatic
Disease
(De novo)
Metastases
Castrate
Resistant
Asymptomatic
Cabazitaxel
Metastases
Castrate
Resistant
Symptomatic
Metastases
Castrate
Resistant
Post Docetaxel
Rising PSA
Castrate
Metastases
Castrate
Resistant
Post
Cabazitaxel
Enzalutamide
Abiraterone
Radium 223
Modified from Scher H, et al. Urology
2000
Bone Issues in Prostate Cancer
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A major bone tropic neoplasm
Bone issues vary along the disease spectrum
Impact of ADT
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Osteoporosis
Increase in osteoporotic related fx
Prevention/delay of bone metastases
Castration resistant metastatic disease
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SRE (SSE) prevention
Bone Events Defined
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Skeletal Related Event (SRE)
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Radiation to bone
Pathologic fracture
Surgery to bone
Spinal cord compression
Hypercalcemia of malignancy
Symptomatic Skeletal Event (SSE)
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EBRT to relieve skeletal symptoms
New symptomatic pathologic bone fracture
Occurrence of spinal cord compression
Tumor-related orthopedic surgical intervention
Denosumab versus zoledronic acid for treatment of bone
metastases in men with castration-resistant prostate cancer:
a randomised, double-blind study
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1904 men with metastatic CRPC were
randomized to receive denosumab (human
monoclonal antibody against RANKL) or
zolendronic acid
The primary endpoint was time to first on-study
SRE (pathological fracture, radiation therapy,
surgery to bone, or spinal cord compression),
and was assessed for non-inferiority
The same outcome was further assessed for
superiority as a secondary endpoint
Fizazi K, et al. Lancet. 2011
377:813-22
Fizazi K, et al. Lancet.
2011 377:813-22
COU-AA-301: Abiraterone Acetate Improves Overall
Survival in mCRPC
HR = 0.646 (0.54-0.77) P< 0.0001
100
Abiraterone acetate:
14.8 months (95%CI: 14.1, 15.4)
Survival (%)
80
60
40
Placebo:
10.9 months (95%CI: 10.2, 12.0)
20
2 Prior Chemo OS:
14.0 mos AA vs 10.3 mos placebo
1 Prior Chemo OS
15.4 mos AA vs 11.5 mos placebo
0
0
100
200
300
400
500
Days from Randomization
de Bono J et al: N Engl J Med 364:19952005, 2011
600
700
Ryan CJ, et al. N Engl J
Med 2013;368:138-48
Logothetis CJ, et al. Lancet Oncol 2012; 13: 1210–17
Scher H, et al. n engl j med 367:1187 2012
Impact of Enzalutamide, an androgen receptor signaling
inhibitor, on time to first skeletal related event (SRE) and pain
in the phase 3 AFFIRM Study
• Median time to first SRE for enzalumatide treated
patients: 16.7 months versus 13.3 months for patients
receiving placebo (hazard ratio [HR] = 0.69; P =
.0001) 9
• Pain palliation: as > 30% reduction in mean pain score
at week 13 versus baseline without a > 30% increase in
analgesic use was achieved by 45% of patients on
enzalutamide compared with only 7% of patients in the
placebo group (P = .0079)
Fizazi K, et al. ESMO 2012 Abstract 896O
ALSYMPCA (ALpharadin in SYMptomatic Prostate
CAncer) Phase III Study Design
TREATMENT
PATIENTS
• Confirmed
symptomatic
CRPC
• ≥ 2 bone
metastases
• No known
visceral
metastases
• Postdocetaxel or
unfit for
docetaxel
6 injections at
4-week intervals
STRATIFICATION
• Total ALP:
< 220 U/L vs ≥ 220 U/L
• Bisphosphonate use:
Yes vs No
• Prior docetaxel:
Yes vs No
R
A
N
D
O
M
I
S
E
D
2:1
N = 922
Radium-223 (50 kBq/kg)
+ Best standard of care
Placebo (saline)
+ Best standard of care
Parker C, et al. N Engl J Med 2013;369:213-23
Questions
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Does the addition of “standard” bone targeted
agents to next generation therapies “add”,
“synergize” or “add nothing” to more effective
therapies ?
Does the introduction of more potent agents
earlier mitigate the effect of older agents?
Pharmacoeconomics
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Bone targeted agent with drugs that already impact on
SRE?