Document

Daniele Santini
Università Campus Bio-Medico
Roma
> 3 Bone Lesions associated With Shorter Survival
Proportion died
0.8
0.7
0.6
0.5
0.4
0.3
Baseline (n = 376)
>3
P < .0001
<3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
Time since randomization, months
Shirina N, et al. Presented at ASCO 2006. Poster 8529.
24
> 3 Bone Lesions Associated with Shorter Time to SRE
Baseline (n = 376)
0.8
0.7
0.6
>3
P < .0001
Proportion with SRE
0.5
0.4
<3
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
Time since randomization, months
Shirina N, et al. Presented at ASCO 2006. Poster 8529.
Patients With Bone Metastases
From Pca Are at High Risk for Developing SREs
Any
Pathologic fracture
Radiation therapy
Patients With SRE, %
Surgical intervention
Spinal cord compression
24 months
Saad F, et al. JNCI. 2002;94(19):1458-1468; Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.
Skeletal Complications Reduce Quality
of Life in Prostate Cancer Patients
Total
Change/Standard Deviation
0
Physical
P < .05.
Emotional
-0.1
-0.2
-0.3
a
-0.4
-0.5
a
a
a
a
a
Radiation to bone
Pathologic fracture
Other SREs
-0.6
-0.7
a
Functional
Change in FACT-G score for patients with an event
vs patients without an event
Data from Weinfurt KP, et al. Ann Oncol. 2005;16(4):579-584.
Probability
SREs Are Associated With Lower Survival in
Prostate Cancer
360 Days Survival
No SRE (n = 355)
≥ 1 SRE (n = 116)
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
 No SRE: 49.7%
 ≥ 1 SRE: 28.2%
 P = .02
Median Survival Times
 No SRE: 338 days
(95% CI = 189, 460)
0
90
180
270
Survival, days
360
Abbreviations: CI, confidence interval; SRE, skeletal-related event.
DePuy V, et al. Support Care Cancer. 2007;15:869-876.
 ≥ 1 SRE: 248 days
(95% CI = 181, 296)
FISIOPATOLOGIA DELLA METASTASI ADDENSANTE
IGF1
TGFb-1
IGF1
TGFb-1
Osteocalcina
ALP
TGF-b1
ET1
uPA
>RANKL/<OPG
PTHrP
IL-6
OPG
Bertoldo F, Santini D Textbook of Osteoncology 2010
Wnt
DDK-1
Skeletal complications according to types and
number of bone lesions
60
p=n.s.
% of patients undergoing SRE
50
40
30
20
10
0
Lytic/Mixed
60
Blastic
p=0.01
50
40
30
20
10
0
<=3 lesions
4 to 6 lesions
>6 lesions
Skeletal Related Event (SRE) free survival according
to types and number of bone lesions
1,0
Cumulative proportion SRE free surviving
Cumulative proportion SRE free surviving
1,0
,8
Mixed bone lesions
Blastic bone lesions
,6
,4
,2
Months
0,0
0
20
40
60
80
100
120
< 3 bone lesions
4-6 bone lesions
,8
> 6 bone lesions
,6
,4
,2
Months
0,0
0
20
40
60
80
100
120
Target therapies and potential
applications in prostate cancer
CTIBL
Bone met prevention in castration resistant
prostate cancer patients
SREs in castration resistant metastatic disease
Prevention of Bone Metastases in PC: Phase III
Denosumab Trial (AMG 147)
Primary endpoint: Time to development of bone metastasis or death
Secondary endpoint: Time to development of bone metastasis (excluding death)
N = 1.435
Prostate cancer (non metastatic)
Hormone-refractory disease
High risk of bone metastases
(PSA at least 8 and/or PSA
doubling time less than 10
months
Adequate organ function
R
A
N
D
O
M
I
Z
A
T
I
O
N
Denosumab
120 mg SC every 4 weeks
Placebo
Event-driven study:
time to bone metastasis or death
Smith MR, et al. Lancet. 2012.
Sopravvivenza libera da metastasi ossee in pazienti
con PSADT ≤4 mesi
F. Saad, ASCO 2012
Target therapies and potential
applications in prostate cancer
CTIBL
Bone met prevention in castration resistant
prostate cancer patients
SREs in castration resistant metastatic
disease
ZOL Reduced All Types of SREs vs Placebo at
2 Years in Patients With Bone Metastases From PC
P = .028
60
Patients With SRE, %
50
40
Zoledronic acid 4 mg (n = 214)
49
Placebo (n = 208)
38
33
30
26
25
17
20
8
10
4
6
7
2
4
0
Any SRE
Radiation
to Bone
Abbreviations: HCM, hypercalcemia of malignancy; SRE, skeletal-related event.
Adapted from Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.
Fractures
Spinal Cord
Change in
Compression Antineoplastic
Therapy
Surgery
to Bone
0
1
HCM
14
Study Design: International, Randomised, DoubleBlind, Active-Controlled Study
N = 950 denosumab 120 mg SC
and placebo IV Q4W
Key Inclusion Criteria
• Castration-resistant prostate
cancer and 1 bone metastases
Key Exclusion Criteria
• Current or prior IV
bisphosphonate treatment
Primary Endpoint
Secondary Endpoints
Supplemental calcium and
vitamin D strongly recommended
N = 951 zoledronic acid 4 mg IV*
and placebo SC Q4W
 Time
to first on-study skeletal-related event (SRE)
(noninferiority)
Time to first on-study SRE (superiority)
 Time to first and subsequent on-study SRE(s) (superiority)

Fizazi K, et al. Lancet. 2011;377:813–822.
Primary Endpoint: Time to First On-Study SRE
HR = 0.82 (95% CI, 0.71–0.95)
P  0.001 (noninferiority)
P = 0.008 (superiority)
Proportion of Subjects Without SRE
1.00
0.75
0.50
Kaplan-Meier Estimate
of Median Months
0.25
20.7
17.1
Denosumab
Zoledronic acid
0.00
0
Patients at Risk:
Zoledronic acid 951
Denosumab 950
3
6
9
733
758
544
582
407
472
Fizazi K, et al. Lancet. 2011;377:813–822.
15
12
Study Month
299
361
207
259
18
21
24
27
140
168
93
115
64
70
47
39
Cumulative Mean Number of SREs per Patient
Secondary Endpoint: Time to First and Subsequent
On-Study SRE(s) (Multiple-Event Analysis)
2.0
Rate ratio = 0.82 (95% CI, 0.71–0.94)
1.8
P = 0.009 (superiority)
1.6
1.4
1.2
1.0
0.8
0.6
Events
0.4
494
Denosumab
0.2
584
Zoledronic acid
0.0
0
3
6
9
12
15
18
21
Study Month
Fizazi K, et al. Lancet. 2011;377:813–822.
24
27
30
33
36
Exploratory Endpoint: Overall Survival
HR = 1.03 (95% CI, 0.91–1.17)
P = 0.65
Proportion of Patients
Survived
1.00
0.75
0.50
0.25
Denosumab
Zoledronic acid
0.00
0
Patients at Risk:
Zoledronic acid 951
Denosumab 950
3
864
872
Fizazi K, et al. Lancet. 2011;377:813–822.
6
9
745
746
635
645
12
15
18
Study Month
519
552
401
427
297
310
21
24
27
30
207
233
143
156
98
99
55
54
J Brown EAU, 2011
Skeletal Complication Risk:
Incremental Benefits in Prostate Cancer
No bisphosphonate
49% risk at 2 yrs
Zoledronic
~ 20% risk
reduction
Saad F, JNCI, 2004, Fizazi K, Lancet, 2011
Denosumab
Additional ~ 12%
risk reduction
+
Denosumab
Additional 18%
time to first SRE
increase
Why should we use CT/HT to delay
skeletal related events?
To improve overal survival
To improve quality of life
To delay SRE
To delay bone metastases
Abiraterone post-docetaxel does improve Overall Survival
Fizazi K et al. Lancet Oncology, 2012
COU-AA-302
Abiraterone pre-docetaxel does improve Overall Survival
100
Survival (%)
80
60
40
Abiraterone (median, mos):
NR
Prednisone (median, mos):
27.2
HR (95% CI):
20
Abiraterone
Prednisone
P value:
0.75 (0.61-0.93)
0.0097
0
0
3
6
9
12
15
18
21
24
27
30
33
0
2
0
0
Time to Death (Months)
Abiraterone 546
Prednisone 542
V3.0
538
534
524
509
503
493
482
465
452
437
412
387
258
237
120
106
27
25
Ryan et al. NEJM, 2013
Enzalutamide post-docetaxel does improve Overall Survival
Scher HI et al, NEJM, 2012
Radium-223 does improve Overall Survival
S Nilsson et al, Clinical Genitourinary Cancer, 2013
Cabazitaxel does improve Overall Survival
De Bono JS et al. Lancet 2010
Why should we use CT/HT to delay
skeletal related events?
To improve overal survival
To improve quality of life
To delay SRE
To delay bone progression
Abiraterone post-docetaxel improve quality of life
Palliation, n (%)
Median Time to palliation
(months)
(95% CI)
P Value
Abiraterone
+
Prednisone
(n = 797)
Placebo +
Prednisone
(n = 398)
132/223
(59.2)
38/100
(38.0)
0.0004
1.02
(0.92-1.91)
3.71
(2.69-4.44)
0.0009
Logothetis et al. Lancet Oncology, 2012
Abiraterone pre-docetaxel improve quality of
life
AA + P
(months)
Placebo + P
(months)
P Value
Hazard Ratio
(95% CI)
FACT-G
16.6
11.1
0.002
0.76
(0.63-0.91)
PCS
11.1
5.8
< 0.001
0.70
(0.60-0.83)
Physical wellbeing
14.8
11.1
0.002
0.76
(0.64-0.90)
Functional
well-being
13.3
8.4
0.001
0.76
(0.64-0.90)
Emotional
well-being
22.1
14.2
0.001
0.71
(0.59-0.87)
Social/Family
well-being
18.4
16.6
0.528
0.94
(0.78-1.14)
Ryan et al. NEJM, 2013
Enzalutamide post-docetaxel improve quality of life
JS De Bono, ASCO, 2012
Radium-223 improve quality of life
Parker CC et al. Eur Urology, 2012
Cabazitaxel improve quality of life
Tombal B, EAU, 2011
Why should we use CT/HT to delay
skeletal related events?
To improve overal survival
To improve quality of life
To delay SRE
To delay bone progression
Abiraterone post-docetaxel does delay SREs
4.7 months of difference
Logothetis et al. Lancet Oncology, 2012
Abiraterone post-docetaxel does delay SREs
Logothetis et al. Lancet Oncology, 2012
Enzalutamide post-docetaxel does delay SREs
3.4 months of difference
Pre-planned analysis
JS De Bono, ASCO, 2012
Enzalutamide post-docetaxel does reduce SREs
Radium-223 does delay SREs
5.5 months of difference
Pre-planned analysis
C Parker et al, ASCO, 2012
Cabazitaxel

No data on SREs
Why should we use CT/HT to delay
skeletal related events?
To improve overal survival
To improve quality of life
To delay SRE
To delay bone progression
Abiraterone post-docetaxel does delay bone progression
Time to progression
(months)
25th percentile (95% CI)
Abiraterone
+
Prednisone
(n = 797)
Placebo +
Prednisone
(n = 398)
9.27
(7.39-12.88)
4.57
(2.79-6.47)
P Value
0.0019
Logothetis et al. J Clin Oncol 2011; 29 (Suppl): Abstract 4520 (oral presentation)
COU-AA-302
Abiraterone pre-docetaxel does delay bone progression
100
Abiraterone (median, mos):
NR
Prednisone (median, mos):
8.3
HR (95% CI):
Progression-Free (%)
80
P value:
0.43 (0.35-0.52)
< 0.0001
60
40
20
Abiraterone
Prednisone
0
0
3
6
9
12
15
18
Time to Progression or Death (Months)
Abiraterone
Prednisone
V3.0
546
542
489
400
340
204
164
90
46
30
12
3
0
0
Ryan et al. NEJM, 2013
Enzalutamide post-docetaxel does delay bone progression
Scher HI et al, NEJM, 2012
Cabazitaxel does delay disease progression
De Bono JS et al., Lancet, 2010
Abstract 4513
Cabozantinib (XL184) in chemotherapypretreated metastatic castration
resistant prostate cancer (mCRPC):
Results from a phase II nonrandomized
expansion cohort (NRE).
Autori, Matthew Raymond Smith, Christopher Sweeney, Dana E. Rathkopf, Howard I.
Scher, Christopher Logothetis, Daniel J. George, Celestia S. Higano, Evan Y. Yu,
Andrea Lynne Harzstark, Eric Jay Small, A. Oliver Sartor, Michael S. Gordon,
Nicholas J. Vogelzang, David C. Smith, Maha Hussain, Johann Sebastian De Bono,
Naomi B. Haas, Christian Scheffold, Yihua Lee, Paul G. Corn;
ASCO 2012
Risposta sulle lesioni ossee
(revisione indipendente)
What about bisphosphonate and
denosumab?
To improve overal survival
NO
To improve quality of life
YES
To delay SRE
YES
To delay bone progression
NO
What about new HT/CT agents in
CRPC?
To improve overal survival
YES
To improve quality of life
YES
To delay SRE
YES
To delay bone progression
YES
Open Issues 1
• Nello studio AA post-docetaxel il 42% circa dei pazienti
avevano ricevuto bisfosfonati in ciascun braccio di
trattamento: come sono andati i pazienti non trattati con BPs?
• Nello studio MDV-3100 post-docetaxel il 30% circa dei
pazienti avevano ricevuto bisfosfonati in ciascun braccio di
trattamento: come sono andati i pazienti non trattati con BPs?
• Necessità di studi mirati a valutare l’effetto di AA e MDV3100 sui marker di riassorbimento osseo (CTX, NTX, BALP):
cosa succederebbe se scoprissimo una modulazione degli
stessi?
Open Issues 2
• Necessità di studiare le modificazioni del metabolismo osseo in
corso di terapia combinata tra bone target therapies e nuovi
farmaci ormonali
• Necessità di comprendere meglio quando e per chi usare le
bone target therapies INSIEME ai nuovi farmaci:
1.Al momento della comparsa delle metastasi ossee
2.Al momento dell’introduzione della nuova terapia ormonale
3.Al momento dell’incremento dei marker di riassorbimento
osseo
4.A tutti i pazienti con metastasi ossee?
• Esiste un effetto antitumorale sinergico?
Skeletal Complication Risk:
Incremental Benefits in Prostate Cancer
No bisphosphonate
49% risk at 2 yrs
Zoledronic
~ 20% risk
reduction
Saad F, JNCI, 2004, Fizazi K, Lancet, 2011
Denosumab
Additional ~ 12%
risk reduction
+
Denosumab
Additional 18%
time to first SRE
increase
[email protected]