Daniele Santini

1
Daniele Santini Università Campus
Bio-Medico Roma
2
Patients With Bone Metastases From Pca Are at
High Risk for Developing SREs
Any
Pathologic fracture
Radiation therapy
Surgical intervention
Spinal cord compression
Patients With SRE,
24 months
Saad F, et al. JNCI. 200294(19)1458-1468 Saad
F, et al. Eur Urol Suppl. 20076(11)683-688.
3
Skeletal Complications Reduce Quality of Life in
Prostate Cancer Patients
Total Physical
Functional Emotional
a
Change/Standard Deviation
a
a
a
a
a
Change in FACT-G score for patients with an event
vs patients without an event
a P lt .05. Data from Weinfurt KP, et al. Ann
Oncol. 200516(4)579-584.
4
SREs Are Associated With Lower Survival in
Prostate Cancer

• 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)

No SRE (n 355) 1 SRE (n 116)
1
0.9
0.8
0.7
0.6
Probability
0.5
0.4
0.3
0.2
0.1
0
360
0
90
180
270
Survival, days
Abbreviations CI, confidence interval SRE,
skeletal-related event. DePuy V, et al. Support
Care Cancer. 200715869-876.
5
FISIOPATOLOGIA DELLA METASTASI ADDENSANTE
gtRANKL/ltOPG
OPG
Bertoldo F, Santini D Textbook of Osteoncology
2010
6
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
7
Molecular states and bone targeted therapies
Armamentarium Castration-resistant patients
Docetaxel (only in metastating setting) Cabazitax
el (in docetaxel-progressing patients) AR
inhibitors (MDV3100) (in docetaxel-progressing
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
8
Target therapies and potential applications in
prostate cancer

• CTIBL
• Bone met prevention in castration resistant
  prostate cancer patients
• SREs in castration resistant metastatic disease

9
RANK is expressed by cancer cells both at primary
tumor and at bone metastases
PRIMITIVI
PRIMITIVI
METASTASI
METASTASI
b. confronto primitivi-metastasi considerando
solo le coppie metastasi-tumore
dorigine

• confronto primitivi-metastasi considerando tutti
  i campioni

Santini D. J Cell Phys, 2010
10
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)
R A N D O M I Z A T I O N
Denosumab 120 mg SC every 4 weeks
Placebo
Smith MR, et al. Lancet. 2012.
11
Bone metastasis-free survival
1.0
HR 0.85 (95 CI 0.73, 0.98) P 0.028
0.8
0.6
Proportion of patients
0.4
0.2
Median months
Events
25.2
370
Placebo
29.5
Denosumab
335
0.0
0
6
9
15
18
27
30
33
39
42
3
12
21
24
36
Study month
Smith MR, et al. Lancet. 2012.
12
Bone Metastasis-Free Survival in Patients with
PSADT 6 Months
Denosumab 147 Trial
HR 0.77 (95 CI 0.64, 0.93) P 0.006
Median Months
Delay (Months)
Events
18.7
242
7.2
25.9
197
Smith MR, et al. ASCO GU, 2012.
13
Sopravvivenza libera da metastasi ossee in
pazienti con PSADT 4 mesi
F. Saad, ASCO 2012
14
ZEUS Zoledronic Acid for Preventionof Bone
Metastases in Prostate Cancer
Primary endpoint Time to bone metastases Secondar
y 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

R
Zoledronic acid 4 mg q 3 months
No zoledronic acid
Treatment duration 4 years
Accrual complete
Abbreviations ADT, androgen-deprivation therapy
PC, prostate cancer PSA, prostate-specific
antigen.
15
Target therapies and potential applications in
prostate cancer

• CTIBL
• Bone met prevention in castration resistant
  prostate cancer patients
• SREs in castration resistant metastatic disease

16
Randomized Trial of Zoledronic Acid Versus
Placebo in Patients With Prostate Cancer
R A N DO M I Z E D
Zoledronic acid 4 mg q 3 wk daily oral vitamin
D 400 IU and calcium 500 mg
n 214
n 208
Placebo q 3 wk daily oral vitamin D 400 IU and
calcium 500 mg
0
15 monthsCore analysis1
24 months Final analysis2
1. Saad F, et al. J Natl Cancer Inst.
2002941458-1468. 2. Saad F, et al. J Natl
Cancer Inst. 200496879-882.
17
Zoledronic Acid Reduced the Risk of SREs
Regardless of Prior SRE History
RiskReduction
P Value
Before Study Entry
0.670
.027
33
No Prior SRE
0.603
.028
40
Prior SRE
0.640
Overall TrialPopulation
.002
36
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0
0.2
Risk Ratio (ZOL 4 mg vs Placebo)
In favor of ZOL
In favor of placebo
Abbreviations SRE, skeletal-related event ZOL,
zoledronic acid. Adapted from Saad F, et al. Clin
Genitourin Cancer. 20075(6)390-396.
18
Study Design International, Randomised,
Double-Blind, Active-Controlled Study

• Key Inclusion Criteria
• Castration-resistant prostate cancer and ?1 bone
  metastases
• Key Exclusion Criteria
• Current or prior IV bisphosphonate treatment

N 950 denosumab 120 mg SC and placebo IV Q4W
Supplemental calcium and vitamin D strongly
recommended
N 951 zoledronic acid 4 mg IV and placebo SC
Q4W
Primary Endpoint Time to first on-study skeletal-related event (SRE) (noninferiority)
Secondary Endpoints Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE(s) (superiority)

• Fizazi K, et al. Lancet. 2011377813822.

19
Baseline Characteristics
Characteristic Denosumab(N 950) Zoledronic Acid(N 951)
Median age, years (IQR) 71 (6477) 71 (6677)
ECOG performance status of 0 or 1, n () 882 (93) 886 (93)
Stratification Factors
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)
Median time from diagnosis of bone metastasis to randomisation, months (IQR) 3.94 (1.2215.67) 5.19 (1.3116.10)

• Fizazi K, et al. Lancet. 2011377813822.

20
Primary Endpoint Time to First On-Study SRE
HR 0.82 (95 CI, 0.710.95)P ? 0.001
(noninferiority) P 0.008 (superiority)
1.00
0.75
0.50
Proportion of Subjects Without SRE
Kaplan-Meier Estimate of Median Months
0.25
20.7
Denosumab Zoledronic acid
17.1
0.00
15
18
21
24
0
3
9
12
27
6
Study Month
Patients at Risk
Zoledronic acid 951 733 544 407 299 207 140 93 64 47
Denosumab 950 758 582 472 361 259 168 115 70 39

• Fizazi K, et al. Lancet. 2011377813822.

21
Secondary Endpoint Time to First and Subsequent
On-Study SRE(s) (Multiple-Event Analysis)
2.0
Rate ratio 0.82 (95 CI, 0.710.94)
P 0.009 (superiority)
1.8
1.6
1.4
1.2
1.0
Cumulative Mean Number of SREs per Patient
0.8
0.6
Events
0.4
Denosumab
494
0.2
584
Zoledronic acid
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
Study Month

• Fizazi K, et al. Lancet. 2011377813822.

22
Exploratory Endpoint Overall Survival
HR 1.03 (95 CI, 0.911.17) P 0.65
1.00
0.75
Proportion of Patients Survived
0.50
0.25
Denosumab
Zoledronic acid
0.00
21
24
3
6
9
12
15
18
27
30
0
Study Month
Patients at Risk
55
54
Zoledronic acid 951 864 745 635 519 401 297 207 143 98
Denosumab 950 872 746 645 552 427 310 233 156 99

• Fizazi K, et al. Lancet. 2011377813822.

23
Summary of Adverse Events
Patient Incidence Denosumab(N 943)n () Zoledronic Acid (N 945) n ()
Infectious AEs 402 (43) 375 (40)
Acute phase reactions (first 3 days) 79 (8) 168 (18)
Renal AEs 139 (15) 153 (16)
Cumulative rate of osteonecrosis of the jaw (ONJ) 22 (2) 12 (1)
Year 1 10 (1) 5 (1)
Year 2 22 (2) 8 (1)
Hypocalcaemia 121 (13) 55 (6)
New primary malignancy 18 (2) 10 (1)

• P 0.09
• Fizazi K, et al. Lancet. 2011377813822.

24
Skeletal Complication Risk Incremental Benefits
in Prostate Cancer
Zoledronic 20 risk reduction
No bisphosphonate 49 risk at 2 yrs
Denosumab Additional 18 time to first SRE
increase
Denosumab Additional 12 risk reduction

Saad F, JNCI, 2004, Fizazi K, Lancet, 2011
25
Bone targeted therapies nella neoplasia
prostatica metastatica - Aggiornamento 2012 -

• Lacido 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 allacido
  zoledronico in termini di tempo al primo SRE
• (Livello di evidenza 1 positiva forte)
• Il denosumab è superiore allacido zoledronico
  in termini di tempo al primo SRE e di tempo al
  primo e ai successivi SRE
• (Livello di evidenza 1- positiva debole)
• Safety
• Lincidenza 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)

26
Effect of Abiraterone Acetate on Pain Control and
Skeletal-Related Events in Patients With
Metastatic Castration-Resistant 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)
27
Meccanismo azione abiraterone

• Gli androgeni che stimolano la proliferazione
  tumorale sono prodotti in tre siti critici
• Testicoli
• Ghiandola surrenale
• Cellule tumorali prostatiche
• Abiraterone inibisce la sintesi degli androgeni
  in tutti e tre i siti
• Testosteronemia lt 1ng/dl

Cholesterol
Desmolase
Deoxy- corticosterone
Pregnenolone
Corticosterone
Progesterone
Aldosterone
CYP17 17a-hydroxylase
17a-OH- pregnenolone
17a OH- progesterone
11-Deoxy- cortisol
Cortisol
ACTH
CYP17 C17,20-lyase
5a-reductase
Androstenedione
DHT
DHEA
Testosterone
Abiraterone
Yang, Drugs. 2011 Attard, JCO 2008
28
Overall Study Design
Efficacy end points
RANDOMIZED
AA 1000 mg daily Prednisone 5 mg BID n 797

• Primary end point
• OS
• Secondary end points
• PSA response
• rPFS
• Tertiary end points
• Pain
• SREs

Patients
(N 1195)
Placebo daily Prednisone 5 mg BID n 398
BPI questionnaire
Baseline, Cycle 1 (Day 15), subsequent treatment
cycles (Day 1)
de Bono et al. NEJM 2011
29
Symptomatic Improvement -Pain Intensity
Palliation
P 0.0002
155/349 (44.4)
44/163 (27.0)
30
Results
AA (n 797) Placebo (n 398) P Value
Overall survival Overall survival Overall survival Overall survival
Median, months 14.8 10.9 lt 0.0001
PSA response rate PSA response rate PSA response rate PSA response rate
Total 38.0 10.1 lt 0.0001
Confirmed 29.1 5.5 lt 0.0001
Radiographic PFS Radiographic PFS Radiographic PFS Radiographic PFS
Median, months 5.6 3.6 lt 0.0001
Time to first SRE (pathologic fracture/spinal cord compression/ palliative radiation/bone surgery) Time to first SRE (pathologic fracture/spinal cord compression/ palliative radiation/bone surgery) Time to first SRE (pathologic fracture/spinal cord compression/ palliative radiation/bone surgery) Time to first SRE (pathologic fracture/spinal cord compression/ palliative radiation/bone surgery)
25th percentile, days 301.0 150.0 lt 0.0001
Logothetis et al. JCO 2011 29 (Suppl) Abst4520
(oral)
31
JS De Bono, ASCO, 2012
32
JS De Bono, ASCO, 2012
33
JS De Bono, ASCO, 2012
34
JS De Bono, ASCO, 2012
35
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
36
Overview bone health and target molecules

• Src inhibitors (Saracatinib, Dasatinib)

37
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.
1992119(4)1003-1013 2. Tanaka S, et al. FEBS
Lett. 1992313(1)85-89 3. Boyce BF, et al. J
Clin Invest. 199290(4)1622-1627 4. Wong BR, et
al. Mol Cell. 19994(6)1041-1049 5. Lowe C, et
al. Proc Natl Acad Sci U S A. 199390(10)4485-448
9 6. Zhang XH, et al. Cancer Cell.
200916(1)67-78.
38
Role of Src in Prostate Tumor Cell and Osteoclast
Activities
Tumor cells
Src
Systemic factors
Local factors
Direct bone destruction
Osteoclast activity
Growth factors
Src
Osteolysis
Activated osteoclast
Src
Bone
Bone complications
39
Dasatinib in PC Inhibition of Tumor Cells and
Osteoclast Activity Through Src
Tumor cells
Src
Dasatinib
Systemic factors
Local factors
Direct bone destruction
Osteoclast activity
Src
Growth factors
Osteolysis
Dasatinib
Bone
40
(No Transcript)
41
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)

42
Abstract 4513Cabozantinib (XL184) in
chemotherapy-pretreated 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

43
Risposta sulle lesioni ossee (revisione
indipendente)
44
Molecular states and bone targeted therapies
Armamentarium
No standard drugs Src inhibitors (dasatinib,
saracatinib)? Endothelin RA inhibitors
(atresartan, zibotentan)? Anti-HER2/neu? Octreotid
e? 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
45
Abstract LBA4512Updated 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).
. and how to place radium-223 ?

• 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. Garcia-Vargas,
  Minghua Shan, A. Oliver Sartor TLA

C Parker et al, ASCO, 2012
46
Disegno dello studio
A.O. Sartor et al, ASCO GU, 2012
47
Analisi aggiornata della sopravvivenza globale
C Parker et al, ASCO, 2012
48
Analisi aggiornata del tempo allo sviluppo del
primo evento scheletrico
C Parker et al, ASCO, 2012
49
Nuovi farmaci per nuovi e vecchi Target
Santini D et al. Cancer Treat Reviews, 2010
50
Thank you very much for your attention
d.santini_at_unicampus.it