38 / 59
0
Study Month
1.0
0.8
0.6
0.4
0.2
12
6
No. at risk
Placebo
Denosumab
580
574
460
486
335
351
273
282
199
215
125
138
74
77
561
557
398
410
296
306
235
249
159
171
102
109
18
24
30
36
HR = 0.84 (95% CI, 0.72 to 0.99)
P
= .042
Placebo
Denosumab
Placebo
Denosumab
A
Bone Metastasis–Free
Survival (proportion)
0
1.0
0.8
0.6
0.4
0.2
12
6
18
24
30
36
HR = 0.77 (95% CI, 0.64 to 0.93)
P
= .006
B
Bone Metastasis–Free
Survival (proportion)
0
Study Month
1.0
0.8
0.6
0.4
0.2
12
No. at risk
Placebo
Denosumab
580
574
442
465
320
332
266
273
178
192
106
111
69
65
24
36
HR = 0.85 (95% CI, 0.71 to 1.01)
P
= .065
Placebo
Denosumab
Placebo
Denosumab
A
Proportion of Patients
Without Bone Metastasis
0
1.0
0.8
0.6
0.4
0.2
12
24
36
HR = 0.80 (95% CI, 0.65 to 0.97)
P
= .026
B
Proportion of Patients
Without Bone Metastasis
Smith et al
0
Study Month
0.6
0.4
0.2
12
6
No. at risk
Placebo
Denosumab
580
574
460
486
335
351
273
282
199
215
125
138
74
77
561
557
398
410
296
306
235
249
159
171
102
109
18
24
30
36
Placebo
Denosumab
Placebo
Denosumab
Placebo
Denosumab
Bone Metastasis–Fre
Survival (proportion
0
Study Month
1.0
0.8
0.6
0.4
0.2
12
6
No. at risk
Placebo
Denosumab
427
19
323
345
223
38
176
193
122
145
78
89
47
46
411
406
274
284
194
207
148
170
99
109
65
67
18
24
30
36
HR = 0.77 (95% CI, 0.64 to .93)
P
= .006
B
Bone Metastasis–Free
Survival (proportion)
0
1.0
0.8
0.6
0.4
0.2
12
6
18
24
30
36
HR = 0.71 (95% CI, 0.56 to 0.90)
P
= .004
C
Bone Metastasis–Free
Survival (proportion)
0
Study Month
0.6
0.4
0.2
12
No. at risk
Placebo
Denosumab
580
574
442
465
320
332
266
273
178
192
106
111
69
65
24
36
Placebo
Denosumab
Placebo
Denosumab
Placebo
Denosumab
Proportion of Patient
Without Bone Metasta
0
Study Month
1.0
0.8
0.6
0.4
0.2
12
No. at risk
Placebo
Denosumab
427
419
311
325
210
222
172
186
111
125
69
69
45
39
24
36
HR = 0.80 (95% CI, 0.65 to 0.97)
P
= .026
B
Proportion of Patients
Without Bone Metastasis
0
1.0
0.8
0.6
0.4
0.2
12
24
36
HR = 0.71 (95% CI, 0 to 0)
P
= .008
C
Proportion of Patients
Without Bone Metastasis
the placebo group (26.5
v
22.1months). Denosumab reduced the risk of
first bonemetastasisby20%(HR, 0.80; 95%CI, 0.65 to0.97;
P
!
.026; Fig
4B). Amongmenwith PSADT
!
4months, time to first bonemetastasis
was 8months longer in the denosumab group than in the placebo group
(26.4
v
18.5months).Denosumabreducedtheriskoffirstbonemetastasis
by 29%(HR, 0.71; 95%CI, 0.55 to 0.91;
P
!
.008; Fig 4C).
D
C
c
N
o
Placebo
Denosumab
Placebo
Denosumab
0
Study Month
0.6
0.4
0.2
12
6
No. at risk
Placebo
Denosumab
427
19
323
345
223
38
176
193
122
145
78
89
47
46
411
406
274
284
194
207
148
170
99
109
65
67
18
24
30
36
Bone Metastasis–Fre
Survival (proportion
0
Study Month
1.0
0.8
0.6
0.4
0.2
12
6
No. at risk
Placebo
Denosumab
289
263
209
217
138
143
105
117
71
89
46
56
279
254
176
176
117
123
86
102
58
67
35
38
18
24
30
36
HR = 0.71 (95% CI, 0.56 to 0.90)
P
= .004
C
Bone Metastasis–Free
Survival (proportion)
Fig 3.
Bone metastasis–free survival by prostate-specific antigen doubling time
(A)
!
10, (B)
!
6, and (C)
!
4 months. HR, hazard ratio.
Proportion of Patien
Proportion of Patients
(A
3804
© 2013 by American Society of Clinical Oncology
PREVENTION OF BONE METASTASES WITH DENOSUMAB
The improvement of BMFS with
denosumab
vs placebo is
greater as PSA-DT decreases
Smith MR, et al. J Clin Oncol. 2013;31(30):3800-6
ODAC – FDA voted “No” to recommend denosumab indication
to prevent bone mets development in high-risk M0 CRPC.
ODAC Chairman, Dr. Wilson: “There’s an assumption that
delaying bone metastases is beneficial. We are looking at a
radiographic benefit here; this is a completely artificial
endpoint”.