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Daniele Santini
Università Campus Bio-Medico
Roma
Baseline (n = 376)
P < .0001
0 3 6 9 12 15 18 21 24
Time since randomization, months
Pro
port
ion d
ied
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
< 3
> 3
> 3 Bone Lesions associated With Shorter Survival
Shirina N, et al. Presented at ASCO 2006. Poster 8529.
> 3 Bone Lesions Associated with Shorter > 3 Bone Lesions Associated with Shorter Time to SRETime to SRE
Baseline (n = 376)
P < .0001
< 3
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0 3 6 9 12 15 18 21 24
Time since randomization, months
Pro
port
ion w
ith S
RE
> 3
Shirina N, et al. Presented at ASCO 2006. Poster 8529.
24 months
Pat
ien
ts W
ith
SR
E, %
Pathologic fracture
Radiation therapy
Surgical intervention
Spinal cord compression
Any
Saad F, et al. JNCI. 2002;94(19):1458-1468; Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.
Patients With Bone Metastases Patients With Bone Metastases From Pca Are at High Risk for Developing SREsFrom Pca Are at High Risk for Developing SREs
Skeletal Complications Reduce Quality Skeletal Complications Reduce Quality of Life in Prostate Cancer Patientsof Life in Prostate Cancer Patients
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
Radiation to bonePathologic fractureOther SREs
a P < .05.
Data from Weinfurt KP, et al. Ann Oncol. 2005;16(4):579-584.
Change in FACT-G score for patients with an event vs patients without an event
aa aa
aaaa
aa
aa
Ch
an
ge/S
tan
dard
Devi
ati
on
Total Physical Functional Emotional
SREs Are Associated With Lower SREs Are Associated With Lower Survival in Prostate CancerSurvival in Prostate Cancer
Abbreviations: CI, confidence interval; SRE, skeletal-related event. DePuy V, et al. Support Care Cancer. 2007;15:869-876.
Pro
bab
ilit
y
0 90 180 270 360
Survival, days
00.10.20.30.40.5
0.70.80.9
1
0.6
No SRE (n = 355)≥ 1 SRE (n = 116)
360 Days Survival
No SRE: 49.7%
≥ 1 SRE: 28.2%
P = .02
Median Survival Times
No SRE: 338 days (95% CI = 189, 460)
≥ 1 SRE: 248 days (95% CI = 181, 296)
PTHrPIL-6
FISIOPATOLOGIA DELLA METASTASI ADDENSANTE
IGF1 TGF
IGF1 TGF
ET1uPA
Osteocalcina ALP
TGF-1
Bertoldo F, Santini D Textbook of Osteoncology 2010
Wnt DDK-1OPGOPG
>RANKL/<OPG>RANKL/<OPG
0
10
20
30
40
50
60
<=3 lesions 4 to 6 lesions >6 lesions
0
10
20
30
40
50
60
Lytic/Mixed Blastic
Skeletal complications according to types and Skeletal complications according to types and number of bone lesionsnumber of bone lesions
p=0.01
p=n.s.
% o
f p
atie
nts
un
der
goin
g S
RE
120100806040200
1,0
,8
,6
,4
,2
0,0
120100806040200
1,0
,8
,6
,4
,2
0,0
Cu
mu
lati
ve p
rop
orti
on S
RE
fre
e su
rviv
ing
Cu
mu
lati
ve p
rop
orti
on S
RE
fre
e su
rviv
ing
Months Months
Mixed bone lesions
Blastic bone lesions
< 3 bone lesions
4-6 bone lesions
> 6 bone lesions
Skeletal Related Event (SRE) free survival according Skeletal Related Event (SRE) free survival according to types and number of bone lesions to types and number of bone lesions
Target therapies and potential Target therapies and potential applications in prostate cancerapplications in prostate cancer
CTIBLCTIBL
Bone met prevention in Bone met prevention in castration resistant prostate castration resistant prostate cancer patients cancer patients
SREs in castration resistant SREs in castration resistant metastatic diseasemetastatic disease
Prevention of Bone Metastases in PC: Prevention of Bone Metastases in PC: Phase III Denosumab Trial (AMG 147)Phase III Denosumab Trial (AMG 147)
N = 1.435Prostate cancer (non metastatic)Hormone-refractory diseaseHigh risk of bone metastases (PSA at least 8 and/or PSA doubling time less than 10 months
Adequate organ function
RANDOMIZATION
Denosumab
120 mg SC every 4 weeks
Denosumab
120 mg SC every 4 weeks
Placebo
Event-driven study:time to bone metastasis or death
Event-driven study:time to bone metastasis or death
Primary endpoint: Time to development of bone metastasis or deathSecondary endpoint: Time to development of bone metastasis (excluding death)
Primary endpoint: Time to development of bone metastasis or deathSecondary endpoint: Time to development of bone metastasis (excluding death)
Smith MR, et al. Lancet. 2012.
Sopravvivenza libera da metastasi ossee in pazienti con PSADT ≤4 mesi
F. Saad, ASCO 2012F. Saad, ASCO 2012
Target therapies and potential Target therapies and potential applications in prostate cancerapplications in prostate cancer
CTIBLCTIBL
Bone met prevention in castration Bone met prevention in castration resistant prostate cancer patients resistant prostate cancer patients
SREs in castration resistant SREs in castration resistant metastatic diseasemetastatic disease
Abbreviations: HCM, hypercalcemia of malignancy; SRE, skeletal-related event.
Adapted from Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.
P = .028
38
26
17
46
20
49
33
25
8 74
10
10
20
30
40
50
60
Any SRE Radiationto Bone
Fractures Spinal CordCompression
Change inAntineoplastic
Therapy
Surgeryto Bone
HCM
Zoledronic acid 4 mg (n = 214) Placebo (n = 208)
Pat
ien
ts W
ith
SR
E,
%
ZOL Reduced All Types of SREs vs ZOL Reduced All Types of SREs vs Placebo at Placebo at
2 Years in Patients With Bone 2 Years in Patients With Bone Metastases From PCMetastases From PC
14
N = 951 zoledronic acid 4 mg IV* and placebo SC Q4W
N = 950 denosumab 120 mg SC and placebo IV Q4W
Study Design: International, Study Design: International, Randomised, Double-Blind, Active-Randomised, Double-Blind, Active-
Controlled StudyControlled Study
Fizazi K, et al. Lancet. 2011;377:813–822.
Primary Primary EndpointEndpoint
Time to first on-study skeletal-related event (SRE) (noninferiority)
Secondary Secondary EndpointsEndpoints
Time to first on-study SRE (superiority)Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE(s) Time to first and subsequent on-study SRE(s)
(superiority)(superiority)
Supplemental calcium and vitamin D strongly recommended
Key Inclusion Criteria
• Castration-resistant prostate cancer and 1 bone metastases
Key Exclusion Criteria
• Current or prior IV bisphosphonate treatment
Primary Endpoint: Time to First On-Primary Endpoint: Time to First On-Study SREStudy SRE
Fizazi K, et al. Lancet. 2011;377:813–822.
0.00
1.00
Pro
po
rtio
n o
f S
ub
ject
s W
ith
ou
t S
RE
0 3 9 12 15 18 21 24 27
0.25
0.50
0.75
Kaplan-Meier Estimate of Median Months
DenosumabZoledronic acid
20.7
17.1
HR = 0.82 (95% CI, 0.71–0.95)P 0.001 (noninferiority)P = 0.008 (superiority)
Study MonthPatients at Risk:Zoledronic acidZoledronic acid 951951 733733 544544 407407 299299 207207 140140 9393 6464 4747
DenosumabDenosumab 950950 758758 582582 472472 361361 259259 168168 115115 7070 3939
66
Secondary Endpoint: Time to First and Secondary Endpoint: Time to First and Subsequent On-Study SRE(s) Subsequent On-Study SRE(s)
(Multiple-Event Analysis)(Multiple-Event Analysis)
Fizazi K, et al. Lancet. 2011;377:813–822.
Rate ratio = 0.82 (95% CI, 0.71–0.94)
0.0
2.0
Cu
mu
lati
ve M
ean
Nu
mb
er o
f S
RE
s p
er
Pat
ien
t
0.2
0.6
1.0
1.4
1.8
0.4
0.8
1.2
1.6
Denosumab
Zoledronic acid 584584
494494
Events
P = 0.009 (superiority)
0 3 6 9 12 15 18 21 24 27 30 33 36
Study Month
Exploratory Endpoint: Overall Exploratory Endpoint: Overall SurvivalSurvival
Fizazi K, et al. Lancet. 2011;377:813–822..
HR = 1.03 (95% CI, 0.91–1.17)P = 0.65
0.00
Pro
po
rtio
n o
f P
atie
nts
Su
rviv
ed
3 6 9 12 15 18 21 24 27Study Month
1.00
0.25
0.50
0.75
DenosumabZoledronic acid
Zoledronic acid
951 864 745 635 519 401 297 207 143 98
Denosumab 950 872 746 645 552 427 310 233 156 99
Patients at Risk:5554
3000
J Brown EAU, 2011J Brown EAU, 2011
Skeletal Complication Risk: Skeletal Complication Risk: Incremental Benefits in Prostate Incremental Benefits in Prostate
CancerCancer
No bisphosphonate 49% risk at 2 yrs
Zoledronic ~ 20% risk reduction Denosumab
Additional ~ 12% risk reduction
Denosumab Additional ~ 12%
risk reduction
Denosumab Additional 18%
time to first SRE increase
Saad F, JNCI, 2004, Fizazi K, Lancet, 2011
++
Why should we use CT/HT to delay skeletal related events?
To improve overal survivalTo improve overal survival
To improve quality of lifeTo improve quality of life
To delay SRETo delay SRE
To delay bone metastasesTo delay bone metastases
Abiraterone post-docetaxel does improve Overall Survival
Fizazi K et al. Lancet Oncology, 2012Fizazi K et al. Lancet Oncology, 2012
V3.0
COU-AA-302
Abiraterone pre-docetaxel does improve Overall Survival
546542
538534
482465
452437
2725
00
524509
503493
02
120106
258237
412387
100
80
60
40
20
0
0
Su
rviv
al (
%)
3 12 15 27
Time to Death (Months)
33
Abiraterone Prednisone
6 9 30242118
AbirateronePrednisone
Abiraterone (median, mos): NR
Prednisone (median, mos): 27.2
HR (95% CI): 0.75 (0.61-0.93)
P value: 0.0097
Ryan et al. NEJM, 2013
Enzalutamide post-docetaxel does improve Overall Survival
Scher HI et al, NEJM, 2012Scher HI et al, NEJM, 2012
S Nilsson et al, Clinical Genitourinary Cancer, 2013
Radium-223 does improve Overall Survival
Cabazitaxel does improve Overall Survival
De Bono JS et al. Lancet 2010De Bono JS et al. Lancet 2010
Why should we use CT/HT to delay skeletal related events?
To improve overal survivalTo improve overal survival
To improve quality of lifeTo improve quality of life
To delay SRETo delay SRE
To delay bone progressionTo delay bone progression
Abiraterone +
Prednisone
(n = 797)
Placebo + Predniso
ne(n = 398)
P Value
Palliation, n (%) 132/223 (59.2)
38/100 (38.0)
0.0004
Median Time to palliation (months)(95% CI)
1.02 (0.92-1.91)
3.71 (2.69-4.44)
0.0009
Logothetis et al. Lancet Oncology, 2012
Abiraterone post-docetaxel improve quality of life
AA + P(months)
Placebo + P
(months)P Value
Hazard Ratio (95%
CI)
FACT-G 16.6 11.1 0.0020.76
(0.63-0.91)
PCS 11.1 5.8 < 0.0010.70
(0.60-0.83)Physical
well-being14.8 11.1 0.002
0.76(0.64-0.90)
Functional well-being
13.3 8.4 0.0010.76
(0.64-0.90)
Emotional well-being
22.1 14.2 0.0010.71
(0.59-0.87)
Social/Family
well-being18.4 16.6 0.528
0.94(0.78-1.14)
Abiraterone pre-docetaxel improve quality of life
Ryan et al. NEJM, 2013
JS De Bono, ASCO, 2012JS De Bono, ASCO, 2012
Enzalutamide post-docetaxel improve quality of life
Radium-223 improve quality of life
Parker CC et al. Eur Urology, 2012Parker CC et al. Eur Urology, 2012
Cabazitaxel improve quality of lifeCabazitaxel improve quality of life
Tombal B, EAU, 2011Tombal B, EAU, 2011
Why should we use CT/HT to delay skeletal related events?
To improve overal survivalTo improve overal survival
To improve quality of lifeTo improve quality of life
To delay SRETo delay SRE
To delay bone progressionTo delay bone progression
Abiraterone post-docetaxel does delay SREs
Logothetis et al. Lancet Oncology, 2012
4.7 months of difference4.7 months of difference
Abiraterone post-docetaxel does delay SREs
Logothetis et al. Lancet Oncology, 2012
JS De Bono, ASCO, 2012JS De Bono, ASCO, 2012
Enzalutamide post-docetaxel does delay SREs
3.4 months of difference3.4 months of difference
Pre-planned analysisPre-planned analysis
Enzalutamide post-docetaxel does reduce SREs
Radium-223 does delay SREs
C Parker et al, ASCO, 2012
5.5 months of difference5.5 months of difference
Pre-planned analysisPre-planned analysis
Cabazitaxel
No data on SREs
Why should we use CT/HT to delay skeletal related events?
To improve overal survivalTo improve overal survival
To improve quality of lifeTo improve quality of life
To delay SRETo delay SRE
To delay bone progressionTo delay bone progression
Abiraterone post-docetaxel does delay bone progression
Abiraterone +
Prednisone
(n = 797)
Placebo + Predniso
ne(n = 398)
P Value
Time to progression (months) 25th percentile (95% CI)
9.27 (7.39-12.88)
4.57 (2.79-6.47)
0.0019
Logothetis et al. J Clin Oncol 2011; 29 (Suppl): Abstract 4520 (oral presentation)
V3.0
COU-AA-302
AbirateronePrednisone
100
80
60
40
20
0
0
Pro
gre
ssio
n-F
ree
(%)
3 6 9 15 1812
546542
489400
340204
16490
123
00
4630
Time to Progression or Death (Months)
AbirateronePrednisone
Abiraterone (median, mos): NR
Prednisone (median, mos): 8.3
HR (95% CI): 0.43 (0.35-0.52)
P value: < 0.0001
Abiraterone pre-docetaxel does delay bone progression
Ryan et al. NEJM, 2013
Enzalutamide post-docetaxel does delay bone progression
Scher HI et al, NEJM, 2012Scher HI et al, NEJM, 2012
Cabazitaxel does delay disease progression
De Bono JS et al., Lancet, 2010De Bono JS et al., Lancet, 2010
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
Abstract 4513
Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration
resistant prostate cancer (mCRPC): Results from a phase II nonrandomized
expansion cohort (NRE).
Risposta sulle lesioni ossee (revisione indipendente)
What about bisphosphonate What about bisphosphonate and denosumab?and denosumab?
To improve overal survivalTo improve overal survival NONO
To improve quality of lifeTo improve quality of life YESYES
To delay SRETo delay SRE YESYES
To delay bone progressionTo delay bone progression NONO
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 MDV-3100 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: Skeletal Complication Risk: Incremental Benefits in Prostate CancerIncremental Benefits in Prostate Cancer
No bisphosphonate 49% risk at 2 yrs
Zoledronic ~ 20% risk reduction Denosumab
Additional ~ 12% risk reduction
Denosumab Additional ~ 12%
risk reduction
Denosumab Additional 18%
time to first SRE increase
Saad F, JNCI, 2004, Fizazi K, Lancet, 2011
++
Questi dati sono pre-era nuovi
farmaci…. ora la storia deve
essere riscritta
Questi dati sono pre-era nuovi
farmaci…. ora la storia deve
essere riscritta