Transcript Radium-223

Más es posible:
CPRC con Metástasis Óseas
Sintomáticas
Javier Puente, MD, PhD
Hospital Universitario Clinico San Carlos
Medical Oncology Department
Complutense University
Associate Professor of Medicine
Prostate Cancer Disease Landscape:
N=230,000 in USA (some speculation…)
Non – Metastatic Prostate Cancer
Patients at Diagnosis
Localized
Prostate Cancer
Local Disease
with Rising PSA
Post Radical
Therapy
Non-Metastatic
Hormone Sens
N=55,000
ADT
95% of 230,000
~ 220,000
~75% no relapse
Progression
5% relapse
post local Rx
& mets*
~10,000
Newly diagnosed
5% of 230,000
~ 10,000
Non-Metastatic
castration
resistant (M0)
Intermittent
ADT and develop
mets on Rx
break with
normal testo
Metastatic Hormone
Sensitive Prostate Cancer
ADT
*either relapse with mets or
Observe rising PSA and mets
~10,000 M0 CRPC
prior to mCRPC
(25% BCR)
Metastatic
CRPC
N=30,000 in USA
~20,000 M1
HSPC prior to
CRPC
Bone metastases: very common
in prostate cancer
Prostate
~90%
Myeloma
70-95%
Breast
65-75%
Thyroid
60%
Bladder
40%
Lung
30-40%
Renal
20-25%
Melanoma
14-45%
INCIDENCE OF BONE METASTASES
de Bono1 (COU-AA-301)
89-90%
Scher2 (AFFIRM)
91-92%
Tannock3 (TAX 327)
90-92%
Petrylak4 (SWOG 99-16)
84-88%
AFFIRM, A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100; CRPC, castration-resistant prostate cancer;
SWOG, Southwest Oncology Group.
1. de Bono J, et al. N Engl J Med. 2011;364:1995–2005. 2. Scher H, et al. N Engl J Med. 2012;367:1187–1197. [supplemental appendix]
3. Tannock I, et al. N Engl J Med. 2004;351:1502–1512. 4. Petrylak D, et al. N Engl J Med. 2004;351:1513–1520.
Hormonal signals impact bone structure
Boiley WJ, et al. Nature 2003
The “vicious cycle” of bone metastases
Gatrell B & Saad F, Nat Rev Clin Oncol 2014
Osteoclast differentiation and activation
Boiley WJ, et al. Nature 2003
Discovery of the RANK signalling
pathway
Boiley WJ, et al. Nature 2003
“Traditional” drug development strategies
have failed microenvironment targeting drugs
Antonarakis ES, J Clin Oncol 2013
Radiopharmaceuticals
Inhibitors of osteoclast/osteoblast function
reduce SREs but do not prolong survival
Saad F, et al. Nat Rev Clin Oncol 2014
Phase III trial of denosumab in bone
metastases from CRPC
Fizazi K, et al. Lancet 2011; 377(9768): 813-22
Denosumab: Time to first SRE
Fizazi K, et al. Lancet 2011; 377(9768): 813-22
Can the bone tropism of PC be
turned into an Achilles Heel?
• Prostate Cancer is the MOST BONE TROPIC of the
major solid tumors
• Bone/Soft tissue ratios are exceptionally high for metastatic prostate
cancer compared to other solid tumors
• More than 90% of metastatic prostate cancer patients enrolled in
recent mCRPC trials have evidence of bony spread.
• Can we exploit bone tropism for therapeutic benefit?
Proposed Spiral Model for Pca
progression
Logothetis et al. Cancer Discov 2013
Bone stromal targeted therapy:
many attempts and few successes!
• Bone stromal-targeted radioharmaceutical
• Strontium-89, samarium-153, radium-223
• Bone stromal + tumor targeting with endothelin
antagonism
• ZD4054 and atrasentan
• Bone stromal + tumor targeting with p60src inhibition
• Dasatinib
• Bone stromal tumor targeting via antiRANK ligand
inhibition
• AntiRANK ligand monoclonal (denosumab)
• Bone stroma targeting with biphosphonates
• Clodronate and zoledronic acid
Overview: Radium-223 MOA
• Radium-223 is a targeted alpha emitter that selectively binds to areas of
increased bone turnover in bone metastases and emits high-energy alpha
particles of a short range (<100 μm)1
• As a bone-seeking calcium mimetic, it is bound into newly formed bone
stroma, especially within the microenvironment of osteoblastic or sclerotic
metastases2,3
• The high-energy alpha
particle radiation induces
α
mainly double-stranded
β
DNA breaks that result
γ
in a potent and highly
localized cytotoxic
effect in target areas2,4-6
• The short path of the alpha particles also means that the toxic effects on
adjacent healthy tissue and particularly the bone marrow may be
minimized3,7-8
1. Bruland OS, et al. Clin Cancer Res. 2006;12:6250s–7s. 2. Henriksen G, et al. Cancer Res. 2002;62:3120–3125. 3. Henriksen G, et al. J Nuc Med.
2003;44:252–59. 4. Lewington VJ. J Nucl Med. 2005;46(suppl):38S–47S. 5. Liepe K. Curr Opin Investig Drugs. 2009;10:1346–58. 6. McDevitt MR, et
al. Eur J Nucl Med. 1998;25:1341–51. 7. Kerr C. Lancet Oncol. 2002;3:453. 8. Li Y, et al. Expert Rev Anticancer Ther. 2004;4:459–68.
ALSYMPCA (ALpharadin in SYMptomatic
Prostate CAncer) phase III study design
ALSYMPCA was halted early after the positive efficacy results reported from a planned interim analysis
of 809 patients with 314 deaths occurred. An updated analysis of efficacy and safety was performed
from all 921 enrolled patients when 528 deaths had occurred.
Parker C, et al. N Engl J Med. 2013;369(3):213–223.
ALSYMPCA: Inclusion Criteria
• Histologically confirmed, progressive CRPCa with ≥2 bone metastases (on skeletal
scintigraphy) and no known visceral metastases
• Patients were receiving best standard of care
• Patients had either received docetaxel, were not fit enough or willing to receive
docetaxel, or did not have docetaxel available
• Symptomatic disease, defined as regular use of analgesic medication for cancer-related
bone pain or treatment with EBRT for bone pain within previous 12 weeks
• PSA ≥5 ng/mL with evidence of progressively rising PSA valuesb
• ECOG PS score of 0 to 2c
• Life expectancy of ≥6 months
• Adequate hematologic, renal, and liver function
CRPC, castration-resistant prostate cancer; EBRT, external beam radiation therapy; ECOG PS, Eastern Cooperative Oncology Group Performance
Status; PSA, prostate-specific antigen.
a. Castration-resistant disease was defined as serum testosterone ≤50 ng/dL (≤1.7 nmol/L) after bilateral orchiectomy or during maintenance
on androgen-ablation therapy with luteinizing hormone-releasing hormone agonist or polyestradiol phosphate throughout the study.
b.Two consecutive increases over previous reference value.
c. Score 0 denotes a patient fully active with no functional restriction, and increasing numbers denote greater functional compromise.
18
ALSYMPCA: patient demographics and baseline
characteristics (ITT population)
CHARACTERISTIC
RADIUM-223 (n=614)
PLACEBO (n=307)
71 (49-90)
171 (28)
71 (44-94)
90 (29)
Caucasian race, n (%)
575 (94)
290 (94)
Total ALP, n (%)
<220 U/L
≥220 U/L
348 (57)
266 (43)
169 (55)
138 (45)
Current use of bisphosphonates, n (%)
Yes
No
250 (41)
364 (59)
124 (40)
183 (60)
Any prior use of docetaxel, n (%)
Yes
No
352 (57)
262 (43)
174 (57)
133 (43)
ECOG PS, n (%)
0
1
≥2
165 (27)
371 (60)
77 (13)
78 (25)
187 (61)
41 (13)
WHO ladder for cancer pain, n (%)
1
2
3
257 (42)
151 (25)
194 (32)
137 (45)
78 (25)
90 (29)
Extent of disease, n (%)
<6 metastases
6-20 metastases
>20 metastases
Superscan
100 (16)
262 (43)
195 (32)
54 (9)
38 (12)
147 (48)
91 (30)
30 (10)
EBRT within 12 weeks of screening, n (%)
Yes
No
99 (16)
515 (84)
48 (16)
259 (84)
Age, years, Median (range)
>75 years, n (%)
Parker C, et al. N Engl J Med. 2013;369(3):213–223.
ALSYMPCA Updated Analysis:
Radium-223 Significantly Improved OS
The updated analysis confirmed the 30% reduction in risk of death (HR=0.70)
for patients in the radium-223 group compared with placebo.
100
MEDIAN OS (months)
━ Radium-223: 14.9
━ Placebo:
11.3
Survival, %
80
Increase
OS
∆=3.6
mos
60
HR (95% CI): 0.70 (0.58–0.83)
P<0.001
40
20
0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
7
4
1
2
0
1
0
0
Months Since Randomization
━ Radium-223
━ Placebo
614 578 504 369 274 178 105
307 288 228 157 103 67 39
Parker C, et al. N Engl J Med. 2013;369(3):213–223.
60
24
41
14
18
7
ALSYMPCA Updated Analysis:
Radium-223 Improved OS Across All Patient Subgroups
SUBGROUP
All patients
Total ALP
<220 U/L
≥220 U/L
Current use of bisphosphonates
Yes
No
Prior use of docetaxel
Yes
No
Baseline ECOG PS
0 or 1
≥2
Extent of disease
<6 Metastases
6-20 Metastases
>20 Metastases
Superscan
Opioid use
Yesa
Nob
PATIENTS (n)
RADIUM-223
PLACEBO
MEDIAN OS (months)
RADIUM-223
PLACEBO
HR
95% CI
614
307
14.9
11.3
0.70
0.58-0.83
348
266
169
138
17.0
11.4
15.8
8.1
0.82
0.62
0.64-1.07
0.49-0.79
250
364
124
183
15.3
14.5
11.5
11.0
0.70
0.74
0.52-0.93
0.59-0.92
352
262
174
133
14.4
16.1
11.3
11.5
0.71
0.74
0.56-0.89
0.56-0.99
536
77
265
41
15.4
10.0
11.9
8.4
0.68
0.82
0.56-0.82
0.50-1.35
100
262
195
54
38
147
91
30
27.0
13.7
12.5
11.3
NE
11.6
9.1
7.1
0.95
0.71
0.64
0.71
0.46-1.95
0.54-0.92
0.47-0.88
0.40-1.27
345
269
168
139
13.9
16.4
10.4
12.8
0.68
0.70
0.54-0.86
0.52-0.93
0.5
Favors 1.0 Favors
Radium-223
Placebo
2.0
ALP, alkaline phosphatase; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio.
a. Includes patients with a score of 2 or 3 on the World Health Organization (WHO) ladder for cancer pain.
b.Includes patients without pain or opioid use at baseline and patients with a OURCE: Parker C, et al. N Engl J Med. 2013;369(3):213–223.
Parker C, et al. N Engl J Med. 2013;369(3):213–223.
ALSYMPCA Updated Analysis:
Radium-223 Significantly Improved All
Secondary Efficacy Endpoints
The significant improvement in all main secondary efficacy endpoints provided
support for the benefit of radium-223 (+ BSoC) over placebo (+ BSoC).
SECONDARY EFFICACY ENDPOINTS
RADIUM-223
(n=614)
PLACEBO
(n=307)
HAZARD RATIO
(95% CI)
P VALUE
Median time to first SSE (months)
15.6
9.8
0.66 (0.52-0.83)
<0.001
Median time to total ALP progression (months)
7.4
3.8
0.17 (0.13-0.22)
<0.001
Median time to PSA progression (months)
3.6
3.4
0.64 (0.54-0.77)
<0.001
Total ALP response (≥30% reduction), n (%)a
233/497 (47)
7/211 (3)
—
<0.001
Total ALP normalization, n (%)a,b
109/321 (34)
2/140 (1)
—
<0.001
ALP, alkaline phosphatase; BSoC, best standard of care; CI, confidence interval; ITT, intention-to-treat; PSA prostate-specific antigen;
SSE, symptomatic skeletal event.
a. Number of patients without missing values.
b. .In patients who had elevated total ALP at baseline..
Parker C, et al. N Engl J Med. 2013;369(3):213–223.
ALSYMPCA Updated Analysis: Safety
Profiles Were Similar Between the
Radium-223 and Placebo Arms
NUMBER OF PATIENTS WITH AEs OCCURRING IN ≥5% OF PATIENTS IN EITHER TREATMENT GROUP
There were few grade 3 AEs and grade 4 AEs were very low, also comparable to placebo.
RADIUM-223 (n=600)
EVENT
Hematologic AEs
Anemia
Thrombocytopenia
Neutropenia
Nonhematologic AEs
Constipation
Diarrhea
Nausea
Vomiting
Asthenia
Fatigue
General physical health deterioration
Peripheral edema
Pyrexia
Pneumonia
PLACEBO (n=301)
ALL GRADES,
n (%)
GRADE 3,
n (%)
GRADE 4,
n (%)
GRADE 5,a
n (%)
ALL GRADES,
n (%)
GRADE 3,
n (%)
GRADE 4,
n (%)
GRADE 5,a
n (%)
187 (31)
69 (12)
30 (5)
65 (11)
20 (3)
9 (2)
11(2)
18 (3)
4 (1)
0
1 (<1)
0
92 (31)
17 (6)
3 (1)
37 (12)
5 (2)
2 (1)
2 (1)
1 (<1)
0
1 (<1)
0
0
108 (18)
151 (25)
213 (36)
111 (19)
35 (6)
154 (26)
27 (5)
76 (13)
38 (6)
18 (3)
6 (1)
9 (2)
10 (2)
10 (2)
5 (1)
21 (4)
9 (2)
10 (2)
3 (1)
9 (2)
0
0
0
0
0
3 (1)
2 (<1)
0
0
0
0
0
0
0
0
0
5 (1)
0
0
4 (1)
64 (21)
45 (15)
104 (35)
41 (14)
18 (6)
77 (26)
21 (7)
30 (10)
19 (6)
16 (5)
4 (1)
5 (2)
5 (2)
7 (2)
4 (1)
16 (5)
8 (3)
3 (1)
3 (1)
5 (2)
0
0
0
0
0
2 (1)
2 (1)
1 (<1)
0
2 (1)
0
0
0
0
0
0
2 (1)
0
0
0
AE, adverse event.
a. Only 1 grade 5 hematologic AE was considered possibly related to study drug: thrombocytopenia in 1 patient in the radium-223 group.
Parker C, et al. N Engl J Med. 2013;369(3):213–223.
Overall Survival was Significantly Improved
with Radium-223, Regardless of Prior
Docetaxel Use
The significant survival benefit observed with radium-223, regardless of prior docetaxel
use, is consistent with that reported n the ALSYMPCA ITT population (radium-223 14.9 vs
11.3 months with placebo (HR=0.695; 95% CI, 0.581-0.832; P=0.00007).
MEDIAN OS, NO PRIOR DTX (months)
━ Radium-223 (n=262):
16.1
━ Placebo (n=133): 11.5
HR (95% CI): 0.75 (0.56–0.99)
P=0.039
100
80
Patients, %
Patients, %
80
60
40
60
40
20
20
0
0
0
4
8
12
16
20
24
28
32
36
Months
━ Ra-223 262 236 168 118
━ PBO 133 113 74 42
70
24
31
14
MEDIAN OS, PRIOR DTX (months)
━ Radium-223 (n=352):
14.4
━ Placebo (n=174): 11.3
HR (95% CI): 0.71 (0.57–0.89)
P=0.003
100
0
4
8
12 16 20 24 28 32 36 40
Months
13
9
7
3
1
1
0
0
Vogelzang NJ, et al. J Clin Oncol. 31, 2013 (suppl; abstr 5068).
━ Ra-223 352 327 238 155 88
━ PBO 174 152 104 61 35
45
15
27
5
5
4
1
1
0
1
0
0
Safety of cytotoxic chemotherapy following
Radium-223
PARAMETER
RADIUM-223 (n=93)
PLACEBO (n=54)
93
54
Median time to chemotherapy, days (range)
80.0 (1-667)
64.5 (2-448)
Median duration of chemotherapy, days (range)
120.0 (1-809)
112.5 (1-863)
Patients receiving chemotherapy* after study drug, n
Overall Survival in the ITT Population
• In the updated ALSYMPCA analysis of all 921 randomized patients prior to placebo crossover,
radium-223, compared with placebo, significantly improved OS in patients with CRPC and bone
metastases (P=0.00007; HR=0.695; 95% CI, 0.581-0.832)
−Median OS was 14.9 months in the radium-223 group vs 11.3 months in the placebo group
PARAMETER
RADIUM-223 (n=93)
PLACEBO (n=54)
Deaths on chemotherapy, %
14
15
Causality:
PC and skeletal metastases (± other mets)
PC with other metastases (or mets not specified)
Cerebral hemorrhage due to trauma
Cardiopulmonary failure
10
3
1
0
13
0
0
2
Deaths within 30 days after chemotherapy, n (%)
6
4
Causality:
PC and skeletal metastases (± other mets)
Bronchopneumonia
Respiratory failure + pulmonary edema
4
1
0
4
1
0
During Chemotherapy Administration
30 Days After Chemotherapy Administration
Sartor O, et al. Ann Oncol 2012 (suppl; abstr 936P).
ALSYMPCA Updated Analysis:
Radium-223 Significantly Improved Time to
SSE
Patients Without SSE, %
100
80
Increase
TTSSE
∆=5.8
mos
60
MEDIAN TIME TO SSE (months)
━ Radium-223: 15.6
━ Placebo:
9.8
HR (95% CI): 0.66 (0.52–0.83)
P<0.001
40
20
0
0
3
6
9
12
15
18
21
24
27
30
8
4
1
1
0
0
Months Since Randomization
━ Radium-223
━ Placebo
614
307
496
211
342
117
199
56
129
36
63
20
31
9
BSoC, Best standard of care; CI, confidence interval; HR, hazard ratio; SSE, symptomatic skeletal event.
.
Parker C, et al. N Engl J Med. 2013;369(3):213–223.
8
7
Radium-223 Reduced the Overall Risk of SSEs
Regardless of Baseline Stratification Factors:
Bisphosphonate Use at Study Entry (Yes/No)
BISPHOSPHONATE USE AT STUDY ENTRY
100
100
NO BISPHOSPHONATE USE AT STUDY ENTRY
80
Patients Without
Symptomatic Skeletal Events, %
Patients Without
Symptomatic Skeletal Events, %
MEDIAN TIME TO FIRST SSE (months)
━ Radium-223 (n=364):
11.8
━ Placebo (n=183): 8.4
60
40
MEDIAN TIME TO FIRST SSE (months)
━ Radium-223 (n=250):
19.6
━ Placebo (n=124): 10.2
20
80
HR (95% CI): 0.77 (0.58–1.02)
P=0.07
60
40
20
HR (95% CI): 0.49 (0.33–0.74)
Treatment
Period
Treatment
Period
P=0.00048
0
0
0
━ Radium-223 250
━ Placebo 124
4
8
12
193
71
115
29
61
17
16 20
Month
25
10
8
3
24
28
32
3
3
1
1
0
0
0
━ Radium-223 364
━ Placebo 183
4
8
12
16
20
24
28
32
247
103
120
41
68
19
30
9
12
4
5
1
0
0
0
0
CI, confidence interval. HR, hazard ratio. SSE, symptomatic skeletal event.
NOTE: ALSYMPCA was not powered to detect differences between subgroups; P values are for descriptive purpose only and are not adjusted for
multiplicity. Very few placebo patients were still evaluable at later time points on the curve; the hazard ratio is the best interpretation of
radium-223 effect over the complete observed time frame.
.
Parker C, et al. N Engl J Med. 2013;369(3):213–223.
Exploratory Post Hoc Analysis of Overall
Survival by Tertiles of Baseline tALP in
the Radium-223 and Placebo Cohorts
• There was a trend showing improvement in OS with radium-223 treatment compared
with placebo in each tALP tertile*
100
100
RADIUM-223
MEDIAN OS [months (95%CI)]
━ Tertile 1 (N=205): 23.9 (17.5-33.8)
tALP min-max: 32-131
━ Tertile 2 (N=207): 14.1 (12.0-15.9)
tALP min-max: 132-333
━ Tertile 3 (N=202): 10.2 (9.1-11.7)
tALP min-max: 334-6431
60
80
Percentage of Patients
Percentage of Patients
80
40
60
40
20
20
0
0
0
10
20
Months
30
PLACEBO
MEDIAN OS [months (95%CI)]
━ Tertile 1 (N=102): 18.8 (13.9-24.5)
tALP min-max: 29-153
━ Tertile 2 (N=104): 11.5 (9.3-13.5)
tALP min-max: 154-353
━ Tertile 3 (N=101): 7.5 (6.5-9.1)
tALP min-max: 360-4805
40
*tALP ranges in the tertiles are slightly different between radium-223 and placebo cohorts.
Heinrich D, et al. Presented at the 29th Annual EAU Congress. Stockholm, Sweden. (Abstract 865).
0
10
20
Months
30
40
Radium-223 Patients with a Confirmed tALP
Decline at Week 12 Had Significantly Longer
Overall Survival
Radium-223 patients with a confirmed tALP decline at week 12 had a significantly longer
median OS versus radium-223 patients with no confirmed tALP decline (median OS: 17.8
months vs 10.4 months; HR=0.45; 95% CI, 0.34-0.61; P <0.0001).
100
MEDIAN OS (months)
━ Confirmed tALP decline (n=400): 17.8
━ No confirmed tALP decline (n=97):
HR (95% CI): 0.45 (0.34-0.61)
P <0.0001
Patients, %
80
10.4
60
40
20
0
0
8
16
24
32
40
Months
*Confirmed tALP decline was defined as any decrease from baseline at week 12, confirmed ≥3 weeks later.
Sartor O, et al. J Clin Oncol. 31, 2013 (suppl; abstr 5080).
29
Sequencing CRPC therapy-2010
Metastatic,
minimally
symptomatic
CRPC
Survival
benefit
Symptomatic
or poorprognosis
CRPC
Progresssion
after docetaxel
chemotherapy
Secondary
hormonal Rx
Docetaxel
Mitoxantrone
BSC
Not Known
3 months
Not Known
Zoledronic acid with CRPC (M1 ddisease)
Daniel Petrylak at 2014 ASCO Annual Meeting
Sequencing CRPC therapy-2015
Metastatic,
minimally
symptomatic
CRPC
2010
Survival
benefit
2015
Survival
benefit
Symptomatic
or poorprognosis
CRPC
Progresssion
after docetaxel
chemotherapy
Secondary
hormonal Rx
Docetaxel
Mitoxantrone
BSC
Not Known
3 months
Not Known
Sipuleucel-T (4 m)
Abiraterone (5.2 m)
Enzalutamide (NA)
Docetaxel
Abiraterone (4 m)
Cabazitaxel (2.5 m)
Enzalutamide (4.8 m)
3 months
Radium 223 (3.6 m)
Denosumab or Zoledronic acid with CRPC (M1 ddisease)
Daniel Petrylak at 2014 ASCO Annual Meeting
Disease-modifying agents and skeletal
outcomes
Gatrell B & Saad F, Nat Rev Clin Oncol 2014
Radium-223 and treatment algorithm
Phase 2a Study Evaluating Quantified Bone Scan Response After
Treatment With Ra-223 Alone or in Combination With Abiraterone Acetate
or Enzalutamide in CRPC Patients with Bone Metastases
A randomized, open-label phase 2a study evaluating quantified bone scan response following treatment with
radium-223 dichloride alone or in combination with abiraterone acetate or enzalutamide in CRPC patients with bone
metastases
PATIENTS (N=66)
•Histologically or cytologically
confirmed adenocarcinoma of the
prostate
•Known castration-resistant disease
•Serum PSA ≥ 2 ng/mL (μg/L)
•≥2 bone metastases on bone scan
assessed within 12 weeks prior to
randomization
•ECOG PS 0 to 2
•Visceral and CNS metastases
excluded.
Radium-223 50 kBq/kg IV every 4 wk ×
6
R
1:1:1
Radium-223 50 kBq/kg IV every 4 wk ×
6
+ abiraterone 1000 mg qd PO and
prednisone 5 mg bid × 2 yrs following
last radium-223 dose
Radium-223 50 kBq/kg IV every 4 wk ×
6
+ enzalutamide 160 mg qd PO × 2 yrs
following last radium-223 dose
PRIMARY OBJECTIVE
Test bone scan response at
week 24 based on quantified
BSLA for each regimen
SECONDARY OBJECTIVES
Safety, rPFS, SSE-FS*, OS, and
time to radiologic bone
progression.
ASSESSMENTS: Imaging assessments will be done at screening and at weeks 8, 16, and 24, then every 12 weeks for 2
years following the last radium-223 dose or until progression.
ENROLMENT: This US-based study with 20 planned sites is currently recruiting patients. As of May 16, 4 patients have
been recruited, 3 have been enrolled; first patient first visit occurred on March 7, 2014.
SSE-FS, symptomatic skeletal event–free survival. SSE-FS will be calculated from time of randomization to date of first SSE or
death.
*SSEs include time to EBRT use for bone pain or occurrence of new pathologic fracture (vertebral and non-vertebral), spinal cord
compression,
or tumor-related orthopedic surgery.
Petrylak D, et al. J Clin Oncol. 32:5s, 2014 (suppl; abstr TPS5103).
ERA 223: A Phase III Trial of Ra-223 Plus Abiraterone Acetate and
Prednisone in the Treatment of Asymptomatic or Mildly Symptomatic
Chemotherapy-Naïve Patients With Bone-Predominant mCRPC
This international, randomized, double-blind, placebo-controlled, phase III study (ERA 223, NCT02043678) is being
conducted in North America, Europe, Asia, Australia, Brazil, and Israel at 168 investigative sites.
PATIENTS (N=800)
•Chemo-naïve bone metastatic CRPC
•Asymptomatic or mildly symptomatic
•>2 bone metastases
•No known brain or visceral metastasis
•ECOG PS 0 or 1
STRATIFICATION
•Geography (EU, NA, AUS vs Asia vs ROW
•Concurrent use of bisphosphonates or
denosumab alone
•Total ALP <90 U/L or >90 U/L
R
1:1
Radium-223 50 kBq/kg IV every 4 wk × 6
+ abiraterone (100 mg once daily) and
prednisone/prednisolone (5 mg BID)
Matching placebo every 4 wk × 6
+ abiraterone (100 mg once daily) and
prednisone/prednisolone (5 mg BID)
PRIMARY OBJECTIVE
SSE-free survival (SSE-FS)*
SECONDARY OBJECTIVES
OS, time to opiate use for
cancer pain, pain progression,
cytotoxic chemotherapy, rPFS
safety
EXPLORATORY OBJECTIVES**
ENROLMENT: This study is currently recruiting patients. As of September 5, 2014, 74 patients have been screened,
43 have been enrolled.
ANALYSIS: 800 patients expected to provide 389 SSE-FS events are needed to detect a 39% increase in SSE-FS; i.e.,
an overall 0.05 level 2-sided log-rank test has approximately 90% power to detect a difference between the 2 SSE-FS
curves if the alternative hypothesis HR is 0.72, assuming the median SSE-FS is 29.2 months for radium-223 versus
21.0 months for control.
*SSE-FS defined as the time from randomization to occurrence of on-study SSE (defined as EBRT for skeletal symptoms, new
symptomatic pathologic non-vertebral bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention), or death
from any cause.
**Time to first on-study SSE, ALP progression, PSA progression; percentage change in total ALP from baseline; time to increase in
physical symptoms based on the FACT Prostate Symptom Index: Disease-Related Subscale—Physical (FPSI-DRS-P) score.
Smith MR, et al.. Ann Oncol. 2014;25 (Suppl 4): iv1 - mdu438.66. abstr 803TiP.
Modeling Clinical Prostate Cancer
Wan X, et al. Sci Trans Med 2014
FGFR1: Cross-species analysis PC BM
Wan X, et al. Sci Trans Med 2014
Conclusions I
• mCPRC is associated with complications in bone known as
skeletal-related events (SREs) that are associated with decreases
QoL and increased mortality.
• Osteoclas-targeted agents including the bisphosphonate
zoledronic acid and the monoclonal antibody denosumab are
used to reduce incidence of SREs and to decrease loss of BMD.
• Recently approved agents included pathway inhibitors
abiraterone, enzalutamide and radium-223 have been shown to
increase survival and to decrease skeletal morbidity in mCPRC.
Conclusions II
ALSYMPCA conclusions:
In CRPC patients with bone metastases:
• Only one compound, radium-223 significantly prolongs overall
survival
• P value=0.00185; HR=0.695; 95% IC: 0.552-0.875
• Radium-223 significantly prolonged time to first clinically relevant
SRE
• P value=0.00046; HR=0.610; 95%IC: 0.461-0.807
• Radium-223 was very well tolerated
THANK YOU
Javier Puente, MD, PhD
Hospital Universitario Clinico San Carlos
Medical Oncology Department
Complutense University
Associate Professor of Medicine