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

Sipuleucel-T
Organ
Confined
Denosumab
Metastatic
Disease
(De novo)
Cabazitaxel
Rising PSA
Hormone
Naive
Metastases
Castrate
Resistant
Asymptomatic
Metastases
Castrate
Resistant
Symptomatic
Metastases
Castrate
Resistant
Post Docetaxel
Metastases
Castrate
Resistant
Post
Cabazitaxel
Locally
Advanced
Disease
Rising PSA
Castrate
Modified from Scher H, et al. Urology
2000
Enzalutamide
Abiraterone
Radium 223






A major bone tropic neoplasm
Bone issues vary along the disease spectrum
Impact of ADT


Osteoporosis
Increase in osteoporotic related fx
Prevention/delay of bone metastases
Castration resistant metastatic disease

SRE (SSE) prevention

 Skeletal Related Event (SRE)

Radiation to bone


Pathologic fracture
Surgery to bone

Spinal cord compression

Hypercalcemia of malignancy
 Symptomatic Skeletal Event (SSE)


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


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

100
80
COU-AA-301: Abiraterone Acetate Improves Overall
Survival in mCRPC
HR = 0.646 (0.54-0.77) P< 0.0001
Abiraterone acetate:
14.8 months (95%CI: 14.1, 15.4)
60
40
Placebo:
10.9 months (95%CI: 10.2, 12.0)
20
0
0
2 Prior Chemo OS:
14.0 mos AA vs 10.3 mos placebo
100 200 300 400
1 Prior Chemo OS
15.4 mos AA vs 11.5 mos placebo
500
Days from Randomization
600 700 de Bono J et al: N Engl J Med 364:1995-
2005, 2011

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
6 injections at
4-week intervals
• Confirmed symptomatic
CRPC
• ≥ 2 bone metastases
• No known visceral metastases
• Postdocetaxel or unfit for docetaxel
STRATIFICATION
• Total ALP:
< 220 U/L vs ≥ 220 U/L
• Bisphosphonate use:
Yes vs No
• Prior docetaxel:
Yes vs No
O
M
I
S
R
A
N
D
E
D
2:1
Radium-223 (50 kBq/kg)
+ Best standard of care
Placebo (saline)
+ Best standard of care
N = 922

Parker C, et al. N Engl J Med 2013;369:213-23


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
 Bone targeted agent with drugs that already impact on
SRE?