novel therapies and bone targeted therapy daniel p...
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Novel Therapies and Bone Targeted Therapy
Daniel P. Petrylak, MD
Yale University Cancer Center
Skeletal-Related Events
Malignancy Bone Lesions SREs
Breast 65%-75% 68%
Prostate 90% 49%
Lung 30%-40% 48%
MM 95%-100% 51%
Coleman. Cancer. 1997;80:1588; Bubendorf. Hum Pathol. 2007;31:578; Saad. Cancer. 2007;110:
1860; Coleman. Oncologist. 2004;9:14.
• The skeleton is the most common site of metastasis
• SREs: fracture, spinal cord compression, radiation or
surgery to bone, and hypercalcemia
MM=multiple myeloma; SRE=skeletal-related event.
Bone Remodeling
Reproduced with permission from Center for Bone Biology website.
http://bonecenter.mc.vanderbilt.edu/edwardsj/. Accessed 11/23/09.
Bone
Formation
Coupling
Stimulation of
osteoclast
formation
Osteoblasts express
osteoclastogenic
factors
Release of
osteoinductive
factors
Stimulation of
osteoblast
differentiation
Bone
Resorption
Mechanisms of Bone Metastases
Reproduced with permission from Kingsley. Mol Cancer Ther. 2007;6:2609; Guise. Clin Cancer
Res. 2006;12:6213s.
CTGF=connective tissue growth factor; CXCR4=chemokine receptor 4; IGF=insulin-
like growth factor; IL=interleukin; MMP=matrix metalloproteinase; Obl=osteoblast;
PDGF=platelet-derived growth factor; PTHrP=parathyroid hormone–related protein;
TGF=transforming growth factor; VEGF=vascular endothelial growth factor.
Growth Factors
IL-6
Mechanisms of Bone Metastases (Cont)
• DKK1 is secreted by
some cancer cells
• DKK1 inhibits Wnt
signaling, leading to
osteoblast inactivation
• DKK1 enhances
osteoclast activation
through decreased
production of
osteoprotegerin and
increased production
of RANKL
DKK1=Dickkopf 1; FRZB and sFRP2=secreted frizzled protein; MIP1α=macrophage-
inflammatory protein 1a; MSC=mesenchymal stem cells; OPG=osteoprotegerin;
RANKL=receptor activator of nuclear factor–κB ligand.
Reproduced with permission from Pinzone. Blood. 2009;113:517.
Zoledronic Acid in HRPC
• Pts on the 8-mg arm are reduced to 4 mg because of renal
toxicity
• Primary outcome: proportion of pts having ≥1 SRE
• Secondary outcomes: time to first on-study SRE, proportion of
pts with SREs, and TTP
•Pts with prostate
cancer
•Hormone
refractory
•Bone
metastases
(N=643)
Zoledronic acid 4 mg q3w
(N=214)
Placebo q3w
(N=208)
R
A
N
D
O
M
I
Z
E
D
Eligibility Criteria
Zoledronic acid 4 mg q3w
(initially 8 mg)
(N=221)
Saad. J Natl Cancer Inst. 2002;94:1458.
Zoledronic Acid in HRPC:
Time to First On-Study SRE
• P=0.011 for 4 mg zoledronic acid vs placebo
Reproduced with permission from Saad. J Natl Cancer Inst. 2002;94:1458.
0 90 180 270 360 450 540
% W
ith
ou
t th
e E
ven
t
Time After the Start of Study Drug (Days)
Zoledronic acid 4 mg
Zoledronic acid 8/4 mg
Placebo
110
100
90
80
70
60
50
40
30
20
10
0
• Tumor cells
– Increase expression of RANKL
– Decrease expression of osteoprotegerin
– Increase bone resorption through osteoclast activity
RANKL Inhibition: Mechanism of Action
CFU-M=colony-forming unit macrophage.
Osteoblast lineage Bone Osteoclast
Osteoblast lineage Bone Osteoclast
CFU-M
Prefusion
osteoclast
Multinucleated
osteoclast Growth factors
Hormones
Cytokines RANKL
RANKL
Rank
OPG
Denosumab
Reproduced with permission from Miller. Curr Osteo Rep. 2009;7:18; Fizazi. J Clin Oncol.
2009;27:1564.
RANKL Inhibition: Denosumab
• Fully human monoclonal antibody
• Specifically inhibits RANKL
• Prevents osteoclast-mediated bone resorption
• Adverse events
– ONJ and renal toxicity
• Similar incidence to IV bisphosphonates in randomized trials
– Susceptibility to new tumors
• Approximately 5% of pts developed new primary tumors (in
denosumab and placebo groups)
• July 2010: FDA priority review status for the treatment of
bone metastases to reduce SREs in pts with advanced
cancers
Fizazi. J Clin Oncol. 2009;27:1564; Smith. N Engl J Med. 2009;361:745; Stopeck. ESMO. 2009
(abstr 2LBA); Amgen press releases. Amgen Inc. website. http://www-
ext.amgen.com/media/media_pr_detail.jsp?year=2010&releaseID=1448739. Accessed 8/25/10.
FDA=United States Food and Drug Administration.
Phase III Trial of
Denosumab vs Zoledronic Acid in HRPC
• All pts received supplemental calcium and vitamin D
• Primary endpoint: (non-inferiority) time to first on-study
SRE
• Secondary endpoints: superiority
•Hormone-refractory (castration resistant)
•≥1 bone metastasis
(N=1901)
Zoledronic acid 4 mg IV +
Placebo s.c. q4wk
(N=951)
Denosumab 120 mg s.c. +
Placebo IV q4wk
(N=950)
R
A
N
D
O
M
I
Z
E
D
Eligibility Criteria
Fizazi. ASCO. 2010 (abstr LBA4507).
s.c.=subcutaneous.
Phase III Trial of Denosumab vs
Zoledronic Acid in HRPC: Efficacy
Fizazi. ASCO. 2010 (abstr LBA4507).
Endpoint Denosumab Zoledronic
Acid
HR
P Value
Median time to
first on-study SRE 20.7 mos 17.1 mos
HR=0.82 (0.71-0.95)
P=0.008*
TTP
NR
HR=1.06 (0.95-1.18)
P=0.30
OS HR=1.03 (0.91-1.17)
P=0.65
*P=0.0002 non-inferiority
NR=not reported.
Phase III Trial of Denosumab vs
Zoledronic Acid in HRPC: Adverse Events
Fizazi. ASCO. 2010 (abstr LBA4507).
Adverse Event Denosumab
N=943
Zoledronic
Acid
N=945
HR
P Value
Acute-phase reaction 8.4% 17.8% NR
Hypocalcemia 12.8% 5.8% NR
ONJ, N (%) 22 (2.3) 12 (1.3%) P=0.09
Risk factors
•Tooth extraction, dental appliance,
poor oral hygiene
•Chemotherapy
17
14
10
9
Treatment
•Limited surgery (eg, debridement)
•Bone resection
10
2
3
1
Outcome as of April 2010
•Resolution (mucosal coverage)
4
1
Phase III ’147 Study: Denosumab vs
Placebo in HRPC
• Primary endpoint: time to first occurrence of bone metastasis or
death from any cause
• Secondary endpoints
– Time to first occurrence of bone metastasis (excluding death)
– OS
•HRPC
•No bone
metastases
•PSA ≥8 ng/ml
≤3 mos before
randomization or
PSA doubling time
≤10 mos
•N=1432
Denosumab 120 mg q4wk
Placebo
R
A
N
D
O
M
I
Z
E
D
Eligibility Criteria
US National Institutes of Health website. http://clinicaltrials.gov/ct2/show/NCT00286091?term=
NCT00286091&rank=1. Accessed 01/05/11; Amgen press release.http://wwwext.amgen.com/
media/media_pr_detail.jsp?releaseID=1507379. Accessed 01/05/11.
Phase 3 Trial of Docetaxel +/- Dasatinib
• Primary endpoint: Overall survival
• Stratification factors
– Performance status
– Baseline bisphosphonate use
– Urine N-telopeptide level
•Patients with
metastatic CRPC
•Evidence of
progression
Docetaxel 75 mg/m2 q3w +
Dasatinib 100 mg po qd +
Prednisone 5 mg po bid
Docetaxel 75 mg/m2 q3w +
Placebo po qd +
Prednisone 5 mg po bid
R
A
N
D
O
M
I
Z
E
Eligibility
Criteria
N=1,500
Characteristics of Radioisotopes
Alpha Particles1 Beta Particles2
Size
Definition
Consists of helium nuclei
High LET
Do not penetrate a sheet
of paper
Consists of electrons
Relatively low LET
May be halted by an
aluminum plate
DNA hits to kill cells 1-10 100-1000
Type of DNA
Damage
Double-strand breaks
(Lethal, more difficult to
repair)3
Single-strand breaks
(More repairable) 3
LET = linear energy transfer
1. Henriksen G, et al. J Nucl Med. 2003;44(2):252-259; 2. Bruland OS, et al. Clin Cancer Res. 2006;12(20):6250s–6257s.
FDA-Approved Bone-Targeting Radionuclides
for the Treatment of Bone Metastases
FDA
Approval Bone Agent Indication
March
1997
Samarium-153-
lexidronam
Relief of bone pain in patients
with painful skeletal
metastases
June 1993 Strontium-89
Relief of pain in patients with
confirmed osteoblastic
metastatic bone lesions
Sartor. Urology. 2004;63:940; Porter. Int J Radiation Oncology Biol Phys. 1993;25:805; Quadramet
[package insert]. Princeton, NJ: EUSA Pharma, Inc.; 2008; Metastron [package insert]. Arlington Heights,
IL: Medi-Physics, Inc.; 1998; U.S. Food and Drug Administration.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed
September 15, 2010; U.S. Food and Drug Administration.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed
September 15, 2010.
Bone-Targeting Radionuclides for Patients
With Prostate Cancer Bone Metastases
Sartor. Urology. 2004;63:940; Nilsson. Lancet Oncol. 2007;8:587; Porter. Int J Radiation Oncology Biol
Phys. 1993;25:805.
Trial Bone Agent No.
of Pts Results
Sartor, 2004
phase III
Samarium-153-
lexidronam 101
Improvement over placebo:
VAS: 2-4 wks (P≤0.05)
PDS: 1-4 wks (P≤0.05)
Analgesic use: 3-4 wks (P<0.0284) Placebo 51
Porter, 1993
phase III
Strontium-89 +
EBR 126
Strontium-89 vs placebo:
New painful sites: 0.587 vs 1.213 (P<0.002)
Analgesic free at 3 mos: 17.1% vs 2.4% (P<0.05)
Time to further RT: 35.3 vs 20.3 wks (P=0.006) Placebo + EBR
Nilsson, 2007
phase II
Radium-223 +
EBR 33
Radium-223 vs placebo:
Change in bone ALP: -65.6% vs 9.3% P<0.0001
Median time to PSA progression: 26 vs 8 wks
(P=0.048)
Median OS: 65.3 vs 46.4 weeks (P=0.066) Placebo + EBR 31
ALP=alkaline phosphatase; PDS=pain descriptor scale (nonlinear); RT=radiotherapy;
VAS=100-mm pain intensity visual analog scale (linear).
Mechanisms of Bone Targeting
• Strontium-89: A calcium homologue, tracks
deposition of calcium
• Samarium-153 EDTMP: Samarium does not
track to bone, but when chelated with EDTMP
the phosphonic acid groups target to areas of
newly deposited bone
• Phosphorus-32: Tracks inorganic phosphorus
in the body
Optimizing Combinations of
Radiopharmaceuticals and Additional Anti-
Cancer Therapies in HRPC
• Strontium-89/External Radiation Therapy
• Strontium-89/Doxorubicin
• Strontium-89/Cis-Platinum
• Samarium-153/Docetaxel
• Alpharadin + Docetaxel
Strontium89 + Doxorubicin:
Bone Targeted Consolidation Therapy Tu et al, Lancet 357: 336-341
• Prospective randomized trial comparing doxorubicin
+ strontium89 in HRPC patients with bone metastases
• Inclusion criteria
– patients with stable or responding disease after
“induction therapy” of 2-3 cycles of KAVE
chemotherapy
• Exclusion criteria
– Prior radiation to >1 focus of bone disease
– Patients with predominantly visceral disease
Strontium89 + Doxorubicin: Bone Targeted Consolidation Therapy
Tu et al, Lancet 357: 336-341
• Patient Characteristics
– 105 HRPC received “induction” chemotherapy
– 33 not randomized (progressive disease, toxicity,
etc.)
– 72 patients randomized
• Randomized treatment
– Weekly 20 mg/m2 doxorubicin (X6 weeks) + ~4
mCi strontium89
• End Points
– Time to progression and survival
Tu et al, Lancet 357:336-41
Samarium-153 + Docetaxel in HRPC Massard et al., ASCO-Prostate 2007 #227
• Docetaxel (70 mg/m2 day) and estramustine (10 mg/kg days 1-5) q 3 weeks (average of 4 cycles) as induction therapy (n=43)
• Consolidation with docetaxel at 20 mg/m2 weekly X 6 with 6 weeks + samarium-153 EDTMP at 1 mCi/Kg during week one (n=43)
• Endpoints: PFS at 7 months and survival at one year
Samarium-153 + Docetaxel in HRPC
Massard et al., ASCO-Prostate 2007 #227
• Survival 71% at one year
• 48% were progression free at 7 months
• Pain response: 60% had a >2/10 VAS score
pain improvement
• Toxicity limited in consolidation treatment
– Grade 3-4 neutropenia (14%) and
thrombocytopenia (5%)
References: 1. Henriksen G, et al. Cancer Res. 2002;62:3120–3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-4928.
Bone
Short range of α-particles could reduce bone marrow exposure1
Marrow
Tumor
Range of an α-emitting Radiopharmaceutical
Compared to a β-emitter
Bone Mineral
(Hydroxyapatite)
Range of β-particle
(long range
– 10 to 1000 cell diameters2)
Radionuclide Range of α-particle
(short range – ~2 to 10
cell diameters2)
6 injections at 4-week intervals
Radium-223 dichloride
(50 kBq/kg) +
best standard of care†
Placebo (saline) +
best standard of care†
•Total ALP:
< 220 U/L vs. ≥ 220
U/L
•Bisphosphonate use:
Yes vs. No
•Prior docetaxel:
Yes vs. No
• Confirmed Symptomatic CRPC
• ≥2 bone metastases
• No known visceral metastases
• Post-docetaxel or unfit for docetaxel*
ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design1
Reference: 1. Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
*Unfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable †Best standard of care defined as a routine standard of care at each center, eg. local external beam radiotherapy, corticosteroids, anti-androgens, estrogens (e.g., stilbestrol), estramustine, or ketaconazole
PATIENTS STRATIFICATION
R
A
N
D
O
M
I
Z
E 2:1
N=921
TREATMENT PHASE
>100 centers in 19 countries Planned follow-up is 3 years
ALSYMPCA Endpoints
Primary endpoint
• Overall survival
Secondary endpoints
• Time to occurrence of first SRE
• Time to total ALP progression
• Total ALP response
• Total ALP normalization
• Time to PSA progression
• Safety
• Quality of life
Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
ALSYMPCA
Major Inclusion/Exclusion Criteria
Inclusion criteria
• Symptomatic CRPC with ≥2
bone metastases
– Confirmed by bone
scintigraphy
– No known visceral metastases
• Regular analgesic medication
use for cancer-related bone pain
or treatment with EBRT for
bone pain within previous 12
weeks
• Life expectancy of ≥6 months
Exclusion criteria
• Eligible for first course of docetaxel
(i.e., fit, willing, and where
docetaxel is available)
• Treatment with cytotoxic
chemotherapy within previous 4
weeks or planned during the
treatment period
• Failure to recover from AEs due to
cytotoxic chemotherapy
• Prior use of systemic
radiopharmaceuticals for bone
metastases
EBRT, external beam radiation therapy. Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
ALSYMPCA : Patient Demographics and Baseline
Characteristics
Parameter Radium-223 dichloride
(n = 614)
Placebo
(n = 307)
Mean age, y 70.2 70.8
Caucasian, n (%) 575 (94) 290 (95)
Baseline ECOG score, n (%)
≤1
2
536 (87)
76 (12)
265 (86)
40 (13)
Extent of disease, n (%)
<6 metastases
6–20 metastases
>20 metastases/superscan
100 (16)
262 (43)
249 (41)
38 (12)
147 (48)
121 (40)
WHO ladder, cancer pain index ≥2, n
(%) 345 (56) 168 (55)
ITT group (n = 921) WHO pain relief ladder:
1 – Non-opioid analgesic ± adjuvant
2 – Opioid for mild to moderate pain ± non-opioid analgesic ± adjuvant
3 – Opioid for moderate to severe pain ± non-opioid analgesic ± adjuvant
Patients may have also received external-beam radiation therapy for pain
Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
ALSYMPCA: Patient Baseline Characteristics
Parameter
Median (min, max)
Radium-223
dichloride
(n = 614)
Placebo
(n = 307)
Hemoglobin, g/dL 12.2 (8.5-15.7) 12.1 (8.5-16.4)
Albumin, g/L 40 (24-53) 40 (23-50)
Total ALP, µg/L 211 (32-6431) 223 (29-4805)
LDH, U/L 315 (76-2171) 336 (132-3856)
PSA, µg/L 146 (3.8-6026) 173 (1.5-14500)
Current bisphosphonates
Yes, n (%)
250 (40.7)
124 (40.4)
Prior docetaxel
No, n(%)
Yes, n (%)
262 (42.7)
352 (57.3)
133 (43.3)
174 (56.7)
ITT group (n = 921)
Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
Radium-223
dichloride
(n = 614)
Placebo (n = 307)
Median OS
(months) 14.9 11.3
HR 0.695
95% CI 0.581–0.832
P value 0.00007
ALSYMPCA Updated Analysis:
Overall Survival
Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39
Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0
Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0
0
10
20
30
40
50
60
70
80
90
100
Pa
tien
ts (
%)
Treatment Radium-223 dichloride Placebo
3.6 month OS benefit
Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
Prior docetaxel use: 3.1 months OS benefit
Radium-223 352 327 238 155 88 45 27 5 1 0 0
Placebo 174 152 104 61 35 15 5 4 1 1 0
Radium-223 (n = 352)
Median: 14.4 months
Placebo (n = 174)
Median: 11.3 months
HR = 0.710
95% CI, 0.565-
0.891
P = 0.00307
100
90
80
70
60
50
40
30
20
10
0
0 4 8 12 16 20 24 28 32 36 40 Month
%
ALSYMPCA : Overall Survival Stratified by Prior Docetaxel Use
No prior docetaxel use: 4.6 months OS benefit
Radium-223 (n = 262)
Median: 16.1 months Placebo (n = 133)
Median: 11.5 months
HR = 0.745
95% CI, 0.562-
0.987
P = 0.03932
Radium-223 262 236 168 119 70 31 14 7 1 0
Placebo 133 113 74 42 24 14 9 3 1 0
100
90
80
70
60
50
40
30
20
10
0
0 4 8 12 16 20 24 28 32 36
%
Month
42.7% of Radium-223 dichloride arm
43.3% of placebo arm had no prior
docetaxel
Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
ALSYMPCA: Survival Benefit Across Patient
Subgroups
≥
Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
ALSYMPCA: Time to First SRE
Month 0 3 6 9 12 15 18 21 24 27 30
Radium-223 614 487 332 193 125 62 31 8 8 1 0
Placebo 307 207 108 51 33 17 8 6 3 1 0
0
10
20
30
40
50
60
70
80
90
100
Pa
tien
ts (
%)
Radium-
223
dichloride
(n = 614)
Placebo (n = 307)
Median time to
SRE (months) 12.2 6.7
Hazard ratio 0.64
95% CI 0.52–0.78
P value <0.0001
Treatment Radium-223 dichloride Placebo
Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
ALSYMPCA: Time to First SRE
Components
N (%) of Events
Time to Event
(Radium-223 dichloride vs.
Placebo)
SRE Component
Radium-223
dichloride
(n = 614)
Placebo
(n = 307) P value
HR
(95% CI)
External-beam
radiotherapy 186 (30.3) 105 (34.2) 0.00117
0.67
(0.52-0.85)
Spinal cord
compression 25 (4.1) 21 (6.8) 0.025
0.51
(0.28-0.93)
Pathologic bone
fracture 32 (5.2) 20 (6.5) 0.09
0.62
(0.35-1.09)
Surgical
intervention 12 (2) 7 (2.3) 0.479
0.71
(0.28-1.8)
Reference: Sartor et al. J Clin Oncol. 2012;30 (suppl): abstract 4551. Presented at ASCO 2012.
ALSYMPCA: Overall Safety Data
Radium-223
dichloride
(n = 600)
Placebo
(n = 301)
All AEs 558 (93) 290 (96)
Grade 3 or 4 AEs 349 (58) 197 (66)
Serious AEs (SAEs) 281 (47) 181 (60)
Discontinuation due to AEs 99 (17) 62 (21)
Deaths due to AEs 96 (16) 67 (23)
Patients with adverse events (AEs), n (%)
Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
ALSYMPCA: Median Number of Injections
Radium-223
dichloride
(n = 614)
Placebo
(n = 307)
Patients treated, n 599 302
Median number of
injections, range 6 (1-6) 5 (1-6)
Received all 6 injections, n (%) 387 (63) 145 (47)
ITT group (n = 921)
Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
ALSYMPCA: Adverse Events of Interest
All Grades Grades 3 or 4
Radium-223
dichloride
(n = 600)
Placebo
(n = 301)
Radium-223
dichloride
(n = 600)
Placebo
(n = 301)
Hematologic
Anemia 187 (31.2) 92 (31) 77 (13) 40(13)
Neutropenia 30 (5) 3 (1) 13 (2) 2 (1)
Thrombocytopenia 69 (11.5) 17 (5.6) 39 (6.5) 6 (2)
Non-hematologic
Bone pain 300 (50) 187 (62) 125 (21) 77 (26)
Diarrhea 151 (25) 45 (15) 9 (1.5) 5 (1.7)
Nausea 213 (35.5) 104 (35) 10 (2) 5 (2)
Vomiting 111 (18.5) 41 (14) 10 (2) 7 (2)
Constipation 108 (18) 64 (21) 6 (1) 4 (1)
Patients with AEs, n (%)
Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
Functional Assessment of Cancer Therapy for
Patients with Prostate Cancer (FACT-P)
• The FACT-P is a validated questionnaire used to assess QoL in men with
prostate cancer1
• Items are rated on a 0 to 4 Likert-type scale where higher sum scores, after
transforming the scores for negatively worded items, represent better QoL
• The FACT-P has 39 items and is composed of 5 subscales2
– Physical well-being (PWB) (7 items)
– Social/family well-being (SWB) (7 items)
– Emotional well-being (EWB) (6 items)
– Functional well-being (FWB) (7 items)
– Prostate cancer (PCS) (12 items)
• Total score (PWB + SWB + EWB+ FWB + PCS) has a range of 0 to 1562
– Minimally important difference (MID) is 10 points
• Trial outcome index (TOI; PWB + FWB +PCS) has a range of 0 to 1042
– MID is 9 points
Functional Assessment of Cancer
Therapy General Version (FACT-G)
Prostate cancer-specific module
Reference: 1. ESPER et al. Urology 1997;50:920 2. Parker et al. Ann Oncol. 2012 (suppl; abstr 898PD).
Percent of Patients with QoL Measurements
Based on FACT-P: Post-baseline Visits
Patients represented in chart must have baseline quality of life
measurements
Responder Analysis Based on Changes
in FACT-P Summary Scores
Responder Analysis Based on Changes
in FACT-P Subscale Scores
QoL Responder Analysis: FACT-P Summary Scores
and Subscale Scores at Week 16 and/or Week 24
MID, minimally important difference; NS, Not significant; †For each subscale, MID = 3
Radium-223 ( n = 434) Placebo (n = 191)
P < 0.1 P < 0.05
P < 0.05
Reference: Parker et al. Ann Oncol. 2012 (suppl; abstr 898PD).
NS NS
P < 0.05
P < 0.1
• For improvement in quality of life, as measured by FACT-P total
score, treatment with radium-223 dichloride resulted in a
significantly higher percentage of responders vs. placebo (27%
vs. 18% P = 0.024), and the difference in responder rates based
on TOI was trending toward significance
• There was a trend toward improvement in all subscales of the
FACT-P, with P < 0.05 for the PCS and EWB subscales
Quality of Life Responder Analysis
Mean Changes From Baseline in FACT-P Total
and TOI Scores
Ch
an
ge
from
Base
lin
e
-2 -1 0 1
-6 -5 -4 -3
-10 -9 -8 -7
-13 -12 -11
Week 0 Week 16 Week 24 Week 42
Visit Assessment Visit Assessment
-2 -1 0 1
-6 -5 -4 -3
-10 -9 -8 -7
Ch
an
ge
from
Base
lin
e
-13 -12 -11
Week 0 Week 16 Week 24 Week 42
FACT-P Total
Score
TOI Score
Radium-223 dichloride Placebo
TOI, trial outcome index
Reference: Parker et al. Ann Oncol. 2012 (suppl; abstr 898PD).
• Mean change scores for both FACT-P Total score and TOI score
appear to decline relative to baseline over time, however, rate of
decline appears faster for the placebo group compared with the
radium-223 dichloride
Chemotherapy Post-Radium-223
Dichloride Treatment Subgroup
Analysis
Patients Treated with Chemotherapy After
Radium-223 Dichloride*
*Post-hoc analysis
Reference: Sartor et al. Ann Oncol. 2012 (suppl; abstr 936P).
The proportion of patients receiving chemotherapy following
ALSYMPCA
• 90 out of 615 patients (15%) in the radium-223 dichloride
group
• 54 out of 307 patients (18%) in the placebo group
The most common chemotherapeutic agents administered after study drug
treatment were docetaxel (n = 105), mitoxantrone (n = 23), and
cyclophosphamide (n = 19)
Patient Demographics and Baseline
Characteristics*
Radium-223
(n = 93)
Placebo
(n = 54)
Mean age, years 67.2 68.2
Caucasian race, n (%) 86 (93) 50 (93)
Baseline ECOG PS, n (%)
≤ 1
2
88 (95)
5 (5)
47 (87)
7 (13)
WHO ladder, cancer pain index, ≥ 2, n (%) 48 (52) 29 (54)
Total ALP, n (%)
< 220 U/L
≥ 220 U/L
59 (63)
34 (37)
38 (70)
16 (30)
Current use of bisphosphonates, n (%)
Yes
No
45 (48)
48 (52)
24 (44)
30 (56)
Median number of study drug injections, range 6 (2–6) 5.5 (1–6)
Patients receiving all 6 injections of study drug, n (%) 66 (71) 27 (50)
Any prior use of docetaxel, n (%)
Yes
No
63 (68)
30 (32)
32 (59)
22 (41)
ALP = alkaline phosphatase; ECOG = Eastern Cooperative Oncology Group *Post-hoc
analysis Reference: Sartor et al. Ann Oncol. 2012 (suppl; abstr 936P).
Cytotoxic Chemotherapy Following ALSYMPCA Participation: Safety*
Month
Med
ian
pla
tele
t
co
un
t (x
10
9/L
)
Radium, n 93 51 42 24 13 14 8
Placebo, n 54 34 20 14 7 9 6 M
edia
n h
emo
glo
bin
cou
nt
g/d
L
Month Radium, n 93 51 42 24 13 14 8
Placebo, n 54 34 20 14 7 9 6
Platelets Hemoglobin
Reference: Sartor et al. Ann Oncol. 2012 (suppl; abstr 936P).
*Post-hoc analysis
Radium-223 dichloride Placebo
Cytotoxic Chemotherapy Following ALSYMPCA Participation: Safety*
Month
Med
ian
ab
solu
te
neu
tro
ph
il c
ou
nt
(x1
09/L
)
Radium, n 91 47 42 23 12 13 8
Placebo, n 49 30 19 12 7 8 6
Neutrophils
Reference: Sartor et al. Ann Oncol. 2012 (suppl; abstr 936P).
*Post-hoc analysis
Radium-223 dichloride Placebo
Conclusions
• Alpha emitting isotope therapy improves
survival in men with castration resistant
prostate cancer
• Minimal toxicity
• Combination studies with
hormonal/chemothearpeutic agents are
underway
Cabozantinib is a Potent Targeted Therapy That
Inhibits MET and VEGFR2
Clinical activity in mCRPC1
• High rates of bone scan improvement
• Reduction in bone markers
• Regression of soft tissue disease
• PFS improvement
• Pain improvement and narcotics reduction
• PSA changes discordant with other
measures of antitumor activity
1 M. Hussain et al. ASCO 2011 (Abstract #4516)
Bone scan images
Baseline Follow-up
Bone Scan Response By Independent Radiology Review
Computer-assisted evaluation of BSLA
Bone scan evaluable (N=93)a n (%)
Bone scan response 62 (67)
Complete (100% reduction of BSLA) 4 (4)
Partial (≥30% reduction of BSLA) 58 (62)
Stable 15 (16)
Progressive disease 7 (8)
Median duration of response, months (range) 5.4 (5.0 – 6.9)
BSLA, bone scan lesion area a Bone metastases at baseline and ≥1 post-baseline scan available for 84 patients
Median change in bone scan lesion area: 60% reduction
Change in Bone Scan Lesion Area Patients with ≥1 post-baseline bone scan (n=84)
+++
CCC
CC
C C CC CC CC CC C C C C* * **
*
Docetaxel + Abiraterone or MDV3100
Radionuclide
Docetaxel
Cabazitaxel
Prior therapies:
C
% C
ha
ng
e f
rom
Ba
se
lin
e
-100
-80
-60
-40
-20
0
20
40
60
80
100
+: >100% increase
• Evidence of tumor regression in 80% of patients
• Overall RECIST response: PR = 1 (3%); SD = 25 (66%); PD = 9 (24%); UE = 3 (8%)
• PSA declines observed in 36% of patients − PSA changes do not always correlate with other parameters of clinical benefit
Change in Measurable Soft Tissue Lesions Patients with ≥1 post-baseline assessment (n=35)
-60
-40
-20
0
20
40
60
80
*
Docetaxel + Abiraterone or MDV3100
Radionuclide
Docetaxel
Cabazitaxel
Prior therapies:
C
% C
ha
ng
e f
rom
Ba
se
lin
e
C
C C C C C C C C C *
Change in Circulating Tumor Cells Baseline CTCs ≥5 and Week 6 and/or Week 12 assessment (n=62)
• 92% demonstrated best CTC decrease ≥30%
• Median best CTC change: 86% decrease
• Conversion to <5 CTCs: 39% at Week 6
-100
-80
-60
-40
-20
0
20
40
60
80
100
Be
st
% C
ha
ng
e in
CT
Cs
300
C
C CC C C C CC C C C C**
* *
C
*
Docetaxel + Abiraterone or MDV3100
Radionuclide
Docetaxel
Cabazitaxel
Prior therapies:
C
Change in Pain Scores Patients with baseline score ≥4 (n=39)
• 64% had a pain decrease ≥30%
• Median change in pain: 46% reduction
• 56% decreased narcotics use, including 31% who discontinued narcotics
-100
-80
-60
-40
-20
0
20
40
% C
ha
ng
e f
rom
Ba
se
lin
e
* * **C
C C C C C C C C
*
Docetaxel + Abiraterone or MDV3100
Radionuclide
Docetaxel
Cabazitaxel
Prior therapies:
C
Effects on Bone Biomarkers
Median change in CTx at Week 12: 37% reduction
-100
-50
0
50
100
Be
st
% C
ha
ng
e
286
Bisphosphonate/Denosumab-Treated
Bisphosphonate/Denosumab-Naïve
CTx BSAP
Patients with Week 12+ assessment
of serum bone-specific ALP (n = 73)
Patients with quantifiable baseline serum CTx
and Week 12 assessment (n = 50)
120
-100
-50
0
50
100
% C
ha
ng
e a
t w
ee
k 1
2
Conclusions
• Alpha emitting isotope therapy improves
survival in men with castration resistant
prostate cancer
• Minimal toxicity
• Combination studies with
hormonal/chemotherapeutic agents are
underway
• New agents are targeting bone and have
promising activity