Zoledronic Acid

Daniele Santini
Università Campus Bio-Medico
Roma
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
Molecular states and bone targeted therapies
Armamentarium
Androgen deprivation therapy
Bisphosphonates (CITBL, only for BMD)
Denosumab (CITBL, also for fracture rate)
Nelson PS, J Clin Oncol, feb 2012
Molecular states and bone targeted therapies
Armamentarium
Castration-resistant patients
Docetaxel (only in metastating setting)
Cabazitaxel (in docetaxel-progressing
patients)
AR inhibitors (MDV3100) (in docetaxelprogressing patients, ASCO 2012)
Bisphosphonates (zoledronic acid only
in bone metastatic setting)
Denosumab (both in bone metastasis
prevention and in metastatig setting)
Abiraterone (only in metastating setting,
after docetaxel)
Nelson PS, J Clin Oncol, feb 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
RANK is expressed by cancer cells both at primary
tumor and at bone metastases
PRIMITIVI
METASTASI
(p= .194)
a. confronto primitivi-metastasi
considerando tutti i campioni
Santini D. J Cell Phys, 2010
PRIMITIVI
METASTASI
(p= .528)
b. confronto primitivi-metastasi
considerando solo le coppie
metastasi-tumore d’origine
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.
Bone metastasis-free survival
1.0
Proportion of patients
HR = 0.85 (95% CI 0.73, 0.98)
P = 0.028
0.8
0.6
0.4
0.2
Median months
Placebo
Denosumab
25.2
29.5
Events
370
335
0.0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42
Study month
Placebo
716 691 569 500 421 375 345 300 259 215 168 137
99
60
36
Denosumab
716 695 605 521 456 400 368 324 279 228 185 153 111
59
35
Smith MR, et al. Lancet. 2012.
Bone Metastasis-Free Survival in Patients with
PSADT ≤ 6 Months
Denosumab 147 Trial
Proportion of Patients With
Bone Metastasis-Free Survival
1.0
HR = 0.77 (95% CI 0.64, 0.93)
P = 0.006
0.8
23% Risk Reduction
0.6
0.4
Median
Months
0.2
Placebo
Denosumab
0.0
0
6
12
Delay
(Months) Events
18.7
25.9
242
197
7.2
18
24
Study Month
30
36
Placebo
427
411
323
274
223
194
176
148
122
99
78
65
47
Denosumab
419
406
345
284
238
207
193
170
145
109
89
67
46
Smith MR, et al. ASCO GU, 2012.
Sopravvivenza libera da metastasi ossee in pazienti
con PSADT ≤4 mesi
F. Saad, ASCO 2012
ZEUS: Zoledronic Acid for Prevention
of Bone Metastases in Prostate Cancer
Primary endpoint: Time to bone metastases
Secondary endpoints: Overall survival, PSA doubling time, substudies on bone
markers, adverse events
N = 1,433
Prostate cancer, M0
± previous local curative
treatment, ± ADT
High-risk PC with ≥ 1 of the
following criteria:
• Gleason Score 8-10
• pN+
• PSA  20 at diagnosis
Zoledronic acid 4 mg q 3 months
R
No zoledronic acid
Treatment duration: 4 years
Accrual complete
Abbreviations: ADT, androgen-deprivation therapy; PC, prostate cancer; PSA, prostate-specific antigen.
Target therapies and potential
applications in prostate cancer
CTIBL
Bone met prevention in castration resistant
prostate cancer patients
SREs in castration resistant metastatic
disease
Randomized Trial of Zoledronic Acid
Versus Placebo in Patients With Prostate Cancer
R
A
N
D
O
M
I
Z
E
D
n = 214
Zoledronic acid 4 mg q 3 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
n = 208
Placebo q 3 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
0
1. Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.
2. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.
15 months
Core analysis1
24 months
Final analysis2
Zoledronic Acid Reduced the Risk of SREs
Regardless of Prior SRE History
Risk
Reduction P Value
Before Study Entry
0.670
No Prior SRE
0.603
Prior SRE
33%
.027
40%
.028
36%
.002
0.640
Overall Trial
Population
0
0.2 0.4 0.6 0.8
1
1.2 1.4 1.6 1.8
Risk Ratio (ZOL 4 mg vs Placebo)
In favor of ZOL
Abbreviations: SRE, skeletal-related event; ZOL, zoledronic acid.
In favor of placebo
2
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.
Baseline Characteristics
Denosumab
(N = 950)
Zoledronic
Acid
(N = 951)
71 (64–77)
71 (66–77)
882 (93)
886 (93)
PSA at randomisation  10 g/L, n (%)
805 (85)
806 (85)
Recent chemotherapy ( 6 weeks before
randomisation), n (%)
132 (14)
132 (14)
Previous SRE, n (%)
232 (24)
231 (24)
3.94 (1.22–15.67)
5.19 (1.31–16.10)
Characteristic
Median age, years (IQR)
ECOG performance status of 0 or 1, n (%)
Stratification Factors
Median time from diagnosis of bone metastasis
to randomisation, months (IQR)
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
Summary of Adverse Events
Denosumab
(N = 943)
n (%)
Zoledronic Acid
(N = 945)
n (%)
402 (43)
375 (40)
79 (8)
168 (18)
139 (15)
153 (16)
22 (2)
12 (1)
Year 1
10 (1)
5 (1)
Year 2
22 (2)
8 (1)
121 (13)
55 (6)
18 (2)
10 (1)
Patient Incidence
Infectious AEs
Acute phase reactions (first 3 days)
Renal AEs
Cumulative rate of osteonecrosis of the
jaw (ONJ)‡
Hypocalcaemia
New primary malignancy
‡P = 0.09
Fizazi K, et al. Lancet. 2011;377:813–822.
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
Bone targeted therapies nella neoplasia prostatica
metastatica
- Aggiornamento 2012 L’acido zoledronico si è dimostrato efficace nel ridurre le complicanze scheletriche di
pazienti con metastasi ossee da carcinoma prostatico
(Livello di evidenza 1++; positiva forte)
Il denosumab non è inferiore all’acido zoledronico in termini di tempo al primo SRE
(Livello di evidenza 1++; positiva forte)
Il denosumab è superiore all’acido zoledronico in termini di tempo al primo SRE e di
tempo al primo e ai successivi SRE
(Livello di evidenza 1-; positiva debole)
Safety:
L’incidenza di ONJ durante il trattamento con denosumab è almeno pari a quella
riscontratta durante il trattamento con acido zoledronico
(Livello di evidenza 1++; positiva forte)
Effect of Abiraterone Acetate on Pain
Control and Skeletal-Related Events in
Patients With Metastatic CastrationResistant Prostate Cancer Post
Docetaxel:
Results From The COU-AA-301 Phase
3 Study
C. Logothetis, J. S. de Bono, A. Molina, E. M. Basch, K. Fizazi,
S. North, K. N. Chi, R. J. Jones, O. B. Goodman, P. N. Mainwaring,
C. N. Sternberg, D. D. Gagnon, R. Dhawan, M. Rothman, Y. Hao,
C. S. Liu, T. S. Kheoh, H. I. Scher, and C. M. Haqq
Logothetis et al. JCO 2011; 29 (Suppl): Abst4520 (oral)
Meccanismo azione abiraterone
• Gli androgeni che stimolano la
proliferazione tumorale sono prodotti in tre
siti critici:
– Testicoli
– Ghiandola Deoxysurrenale
Corticosterone
Progesterone
corticosterone
– Cellule tumorali prostatiche
Cholesterol
Desmolase
Pregnenolone
Aldosterone
CYP17
X
17αhydroxylase
• Abiraterone inibisce la sintesi degli
androgeni in tutti e tre i siti
17α –OHprogesterone
17α-OHpregnenolone
X
11-Deoxycortisol
Cortisol
ACTH
Testosteronemia < 1ng/dl
CYP17
C17,20-lyase
5α-reductase
DHEA
Androstenedione
Testosterone
DHT
Abiraterone
Yang, Drugs. 2011; Attard, JCO 2008
Overall Study Design
Patients
(N = 1195)
R
A
N
D
O
M
I
Z
E
D
Efficacy end points
AA 1000 mg daily
Prednisone 5 mg BID
n = 797
Placebo daily
Prednisone 5 mg BID
n = 398
Primary end point:
• OS
Secondary end points:
• PSA response
• rPFS
Tertiary end points:
• Pain
• SREs
BPI questionnaire
Baseline, Cycle 1 (Day 15), subsequent treatment cycles (Day 1)
de Bono et al. NEJM 2011
Patients experiencing palliation
Symptomatic Improvement Pain Intensity Palliation
70%
60%
50%
155/349
P = 0.0002
(44.4%)
44/163
40%
(27.0%)
30%
20%
10%
0%
AA (n = 797)
Placebo (n = 398)
Results
AA
(n = 797)
Placebo
(n = 398)
P Value
14.8
10.9
< 0.0001
Total
38.0%
10.1%
< 0.0001
Confirmed
29.1%
5.5%
< 0.0001
5.6
3.6
< 0.0001
Overall survival
Median, months
PSA response rate
Radiographic PFS
Median, months
Time to first SRE (pathologic fracture/spinal cord compression/ palliative
radiation/bone surgery)
25th percentile, days
Logothetis et al. JCO 2011; 29 (Suppl): Abst4520 (oral)
301.0
150.0
< 0.0001
JS De Bono, ASCO, 2012
JS De Bono, ASCO, 2012
JS De Bono, ASCO, 2012
JS De Bono, ASCO, 2012
Molecular states and bone targeted therapies
Armamentarium
No standard drugs
Src inhibitors (dasatinib, saracatinib)?
Endothelin RA inhibitors (atresartan,
zibotentan)?
Anti-HER2/neu?
Inhibitor of MET and VEGFR2
(cabozantinib)?
AR inhibitors (MDV3100)?
Bisphosphonates (problably)
Denosumab (strong biological rational – src
in a down stream gene of rank- rank is
expressed also in prostate cancer cells)
Denosumab works also in patients without
NTX suppression during zoledronic acid
Nelson PS, J Clin Oncol, feb 2012
Overview:
bone health and target molecules
• Src inhibitors (Saracatinib, Dasatinib)
Evidence for a Role of Src in Bone Metabolism
and Metastatic Bone Disease
• Src kinase is a nonreceptor tyrosine kinase,
highly expressed in normal osteoclasts1,2
• Src plays an essential role in RANKL-mediated
osteoclast activation3 and perhaps survival4
• Src knockout mice are osteopetrotic5
• Src may be critical for tumor cell survival in bone
microenvironment6
1. Horne WC, et al. J Cell Biol. 1992;119(4):1003-1013; 2. Tanaka S, et al. FEBS Lett. 1992;313(1):85-89;
3. Boyce BF, et al. J Clin Invest. 1992;90(4):1622-1627; 4. Wong BR, et al. Mol Cell. 1999;4(6):1041-1049;
5. Lowe C, et al. Proc Natl Acad Sci U S A. 1993;90(10):4485-4489; 6. Zhang XH, et al. Cancer Cell. 2009;16(1):67-78.
Role of Src in Prostate Tumor Cell and
Osteoclast Activities
Tumor cells
Systemic factors
Src
Local factors
Osteoclast
activity
Growth
factors
Direct bone
destruction
Src
Activated
osteoclast
Osteolysis
Src
Bone
Bone complications
Dasatinib in PC: Inhibition of Tumor Cells
and Osteoclast Activity Through Src
Tumor cells
Src
Dasatinib
Systemic factors
Local factors
Osteoclast activity
Direct bone
destruction
Src
Growth
factors
Osteolysis
Dasatinib
Bone
Phase III study: READY (ongoing)
(metastatic hormonorefractory prostate cancer patients)
Doc + P vs Doc + P + DASATINIB
Preliminary results:
• 4.8 months OS improvement with the combination
• Longer PFS with the combination
• Median time to SRE longer (7.5 vs. 6.0 months)
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)
Molecular states and bone targeted therapies
Armamentarium
No standard drugs
Src inhibitors (dasatinib, saracatinib)?
Endothelin RA inhibitors (atresartan,
zibotentan)?
Anti-HER2/neu?
Octreotide?
Pasireotide?
TKIs?
Inhibitor of MET and VEGFR2
(cabozantinib)?
Bisphosphonates (problably)
Denosumab (strong biological rational – src
in a down stream gene of rank- rank is
expressed also in prostate cancer cells)
Denosumab works also in patients without
NTX suppression during zoledronic acid
Nelson PS, J Clin Oncol, feb 2012
…. and how to place radium-223 ?
Abstract LBA4512
Updated analysis of the phase III, double-blind,
randomized, multinational study of radium-223
chloride in castration-resistant prostate cancer
(CRPC) patients with bone metastases
(ALSYMPCA).
Autori, Chris Parker, Sten Nilsson, Daniel Heinrich, Joe M. O'Sullivan, Sophie D.
Fossa, Ales Chodacki, Pawel J. Wiechno, John P. Logue, Mihalj Seke, Anders
Widmark, Dag Clement Johannessen, Peter Hoskin, David Bottomley, Robert
Edward Coleman, Nicholas J. Vogelzang, C. Gillies O'Bryan-Tear, Jose E. GarciaVargas, Minghua Shan, A. Oliver Sartor; TLA
C Parker et al, ASCO, 2012
Disegno dello studio
A.O. Sartor et al, ASCO GU, 2012
Analisi aggiornata della sopravvivenza globale
C Parker et al, ASCO, 2012
Analisi aggiornata del tempo allo
sviluppo del primo evento scheletrico
C Parker et al, ASCO, 2012
Nuovi farmaci per nuovi e
vecchi Target
Santini D et al. Cancer Treat Reviews, 2010
Thank you very much for your attention
[email protected]