1. Università Campus Bio-Medico
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. 2002;94(19): ; Saad F, et al. Eur Urol Suppl. 2007;6(11): 2 2

3. Change/Standard Deviation
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 < .05.
Data from Weinfurt KP, et al. Ann Oncol. 2005;16(4): 3

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 90
180
270
360
Survival, days
Abbreviations: CI, confidence interval; SRE, skeletal-related event.
DePuy V, et al. Support Care Cancer. 2007;15: 4

5. FISIOPATOLOGIA DELLA METASTASI ADDENSANTE
Osteocalcina
ALP
TGF-b1
IGF1
TGFb-1
IGF1
TGFb-1
ET1
uPA
Wnt DDK-1
>RANKL/<OPG
PTHrP
IL-6
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)
Cabazitaxel (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. confronto primitivi-metastasi considerando tutti i campioni
RANK is expressed by cancer cells both at primary tumor and at bone metastases
PRIMITIVI
METASTASI
PRIMITIVI
METASTASI
(p= .194)
(p= .528)
In animal models with intracardiac injection of human MDA-231 breast cancer cells, the ability of OPG to inhibit tumor-induced osteoclastogenesis, and osteolysis was evaluated.1 The injection of MDA-231 breast cancer cells into the left ventricle of nude mice resulted in experimental bone metastases that were associated with osteolytic lesions. Mice were treated with OPG (at the indicated doses, 3 times per week for 4 weeks) starting immediately after tumor cell inoculation. RANK Ligand inhibition with OPG dose-dependently decreased the number and area of radiographically evident lytic bone lesions.1 OPG treatment at the highest doses completely prevented the radiographic appearance of osteolytic lesions (right radiograph). In the animals treated with OPG, note the increased radio-opacity of the tibial and femoral metaphyseal growth plate region associated with OPG treatment. This increase is a normal pharmacological response to OPG treatment by growing mice, whereby resorption of the secondary spongiosa is inhibited, and trabecular bone accumulates. RANK Ligand inhibition was also observed to significantly decrease the number of osteoclasts within the tumor, with a maximal reduction of 90% at 3 mg/kg (P < 0.01). In this model of experimental bone metastases, RANK Ligand inhibition was associated with significant reductions in both the frequency and the size of skeletal tumor nests and in preventing tumor-associated osteolysis.1
Morony S, et al. Osteoprotegerin Inhibits Osteolysis and Decreases Skeletal Tumor Burden in Syngeneic and Nude Mouse Models of Experimental Bone Metastasis. Cancer Res ;61:
confronto primitivi-metastasi considerando tutti i campioni
b. confronto primitivi-metastasi considerando solo le coppie metastasi-tumore d’origine
Santini D. J Cell Phys, 2010 9

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 T
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
Denosumab
120 mg SC every 4 weeks
Placebo
Event-driven study: time to bone metastasis or death
Smith MR, et al. Lancet 10 10 10

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
Placebo
25.2
370
Denosumab
29.5
335
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
695
605
521
456
400
368
324
279
228
185
153
111 59 35
Smith MR, et al. Lancet

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
23% Risk Reduction
Median
Months
Delay
(Months)
Events
Placebo
18.7
242
7.2
Denosumab
25.9
197
Smith MR, et al. ASCO GU, 2012. 12

13. Sopravvivenza libera da metastasi ossee in pazienti con PSADT ≤4 mesi
F. Saad, ASCO 2012

14. 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 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. 14

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. + daily oral vitamin D 400 IU and calcium 500 mg
Randomized Trial of Zoledronic Acid Versus Placebo in Patients With Prostate Cancer R A N DO 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
15 months Core analysis1
24 months
Final analysis2
1. Saad F, et al. J Natl Cancer Inst. 2002;94:
2. Saad F, et al. J Natl Cancer Inst. 2004;96:

17. Risk Ratio (ZOL 4 mg vs Placebo)
Zoledronic Acid Reduced the Risk of SREs Regardless of Prior SRE History
Risk Reduction
P Value
Before Study Entry
0.670
No Prior SRE
33%
.027
0.603
Prior SRE
40%
.028
0.640
Overall Trial Population
36%
.002
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
1.8 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. 2007;5(6): 17 17

18. Study Design: International, Randomised, Double-Blind, Active-Controlled Study
XGEVA™ PI 2010: 9,14
Fizazi K, et al. Lancet 2011;377: 815,Table 1
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
XGEVA™ PI 2010: 2,2.1
Fizazi K, et al. Lancet 2011;377: 815,A,1
Fizazi K, et al. Lancet 2011;377: 814,B,1-2
Supplemental calcium and vitamin D strongly recommended
Fizazi K, et al. Lancet 2011;377: 815,A,2
N = 951 zoledronic acid 4 mg IV* and placebo SC Q4W
XGEVA™ PI 2010: 9,14
Fizazi K, et al. Lancet 2011;377: 813,Methods
Key Points
This was an international, randomized, double-blind, active-controlled trial comparing denosumab with zoledronic acid for the treatment of bone metastases in patients with castration-resistant prostate cancer
The primary endpoint was time to first on-study SRE comparing denosumab with zoledronic acid for noninferiority
Secondary efficacy endpoints, evaluated only if noninferiority was demonstrated, were superiority tests comparing denosumab and zoledronic acid for time to first on-study SRE and time to first and subsequent SRE(s) (multiple-event analysis)
Background
Eligible patients were men  18 years old with histologically confirmed prostate cancer and current or prior radiographic evidence of at least one bone metastasis and documented failure of at least 1 hormonal therapy
Patients were randomized 1:1 to receive either SC injections of denosumab 120 mg and an IV placebo Q4W, or an IV infusion (lasting no less than 15 minutes) of zoledronic acid 4 mg and an SC injection of placebo Q4W
Daily supplementation with calcium and vitamin D was strongly recommended
Key exclusion criteria included current or prior IV bisphosphonate or oral bisphosphonate administration to treat bone metastasis
References
XGEVA™ (denosumab) prescribing information, Amgen.
Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:
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 2011;377: 815,A,2
XGEVA™ PI 2010: 9,14
Fizazi K, et al. Lancet 2011;377: 814,A,2;B,1
Fizazi K, et al. Lancet 2011;377: 814,B,5; 815,A,1
Fizazi K, et al. Lancet. 2011;377:813–822.
XGEVA™ PI 2010: 2,2.1
Fizazi K, et al. Lancet 2011;377: 815,A,1
XGEVA™ PI 2010: 3,6.1
Fizazi K, et al. Lancet 2011;377: 814,B,1-2 18

19. Baseline Characteristics
Denosumab (N = 950)
Zoledronic Acid (N = 951)
Median age, years (IQR)
71 (64–77)
71 (66–77)
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)
Previous SRE, n (%)
232 (24)
231 (24)
Median time from diagnosis of bone metastasis to randomisation, months (IQR)
3.94 (1.22–15.67)
5.19 (1.31–16.10)
Fizazi K, et al. Lancet 2011;377: 815,Table 1
Key Points
A total of 1901 patients were randomized to receive denosumab (n = 950) or zoledronic acid (n = 951)
Baseline age, race, and ECOG performance status variables were balanced between groups
Background
Randomization was stratified by previous SRE, PSA level ( 10 g/L vs  10 g/L), and chemotherapy for prostate cancer within 6 weeks before randomization
Patients in the zoledronic acid arm had a slightly longer median time from bone metastases diagnosis to study randomization (denosumab, 3.94 months; zoledronic acid, 5.19 months) although the quartiles were similar
Reference
Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:
Fizazi K, et al. Lancet 2011;377: 815,Table 1
Fizazi K, et al. Lancet. 2011;377:813–822. 19

20. Primary Endpoint: Time to First On-Study SRE
XGEVA™ PI, 2010: 11,Table 2
Fizazi K, et al. Lancet 2011;377: 816,Figure 2
HR = 0.82 (95% CI, 0.71–0.95) P  (noninferiority)
P = (superiority)
1.00
0.75
Proportion of Subjects Without SRE
0.50
Kaplan-Meier Estimate of Median Months
0.25
Key Points
Denosumab significantly delayed the time to first on-study SRE by 18% compared with zoledronic acid (HR = 0.82; 95% CI, 0.71–0.95; P  .001 for noninferiority and P = .008 for superiority)1
The median (95% CI) time to first on-study SRE was 20.7 months in the denosumab group and 17.1 months in the zoledronic acid group, a difference of 3.6 months1
Between-group divergence is evident beginning at 3 months after initiation of treatment2
References
XGEVA™ (denosumab) prescribing information, Amgen.
Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:
Denosumab
Zoledronic acid
20.7
XGEVA™ PI, 2010: 11,Table 2
17.1
0.00
Fizazi K, et al. Lancet 2011;377: 816,Figure 2 3 6 9 12 15 18 21 24 27
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. 2011;377:813–822. 20

21. Cumulative Mean Number of SREs per Patient
Secondary Endpoint: Time to First and Subsequent On-Study SRE(s) (Multiple-Event Analysis)
XGEVA™ PI, 2010: 11,Table 2
Fizazi K, et al. Lancet 2011;377: 816,Figure 3
2.0
Rate ratio = 0.82 (95% CI, 0.71–0.94)
P = (superiority)
1.8
1.6
1.4
1.2
Cumulative Mean Number of SREs per Patient
1.0
0.8
0.6
Key Points
Denosumab significantly delayed the time to first and subsequent on-study SREs (rate ratio = 0.82; 95% CI, 0.71–0.94; adjusted P = .009)1
A total of 1078 events occurred, 494 in the denosumab treatment group, and 584 in the zoledronic acid treatment group2
References
XGEVA™ (denosumab) prescribing information, Amgen.
Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:
XGEVA™ PI, 2010: 11,Table 2
Events
0.4
Denosumab
494
Fizazi K, et al. Lancet 2011;377: 816,Figure 3
0.2
Zoledronic acid
584
0.0 3 6 9 12 15 18 21 24 27 30 33 36
Study Month
Fizazi K, et al. Lancet. 2011;377:813–822. 21

22. Exploratory Endpoint: Overall Survival
Fizazi K, et al. Lancet 2011;377: 817,Figure 4,A
HR = 1.03 (95% CI, 0.91–1.17)
P = 0.65
1.00
0.75
Proportion of Patients
Survived
0.50
0.25
Fizazi K, et al. Lancet 2011;377: 817,Figure 4,A
Key Points
Overall survival (HR = 1.03; 95% CI, 0.91–1.17; P = .65) was similar between study groups1
Overall survival and progression-free survival were similar between arms in all three trials1
Mortality was higher with denosumab in a subgroup analysis of patients with multiple myeloma (HR = 2.26; 95% CI, 1.13–4.50; n = 180)2
References
Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:
XGEVA™ (denosumab) prescribing information, Amgen.
Denosumab
Zoledronic acid
XGEVA™ PI, 2010: 10-14
0.00 3 6 9 12 15 18 21 24 27 30
Study Month
Patients at Risk:
Zoledronic acid
951
864
745
635
519
401
297
207
143 98
Denosumab
950
872
746
645
552
427
310
233
156 99 55 54
Fizazi K, et al. Lancet. 2011;377:813–822. 22

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
8 (1)
Hypocalcaemia
121 (13)
55 (6)
New primary malignancy
18 (2)
Fizazi K, et al. Lancet 2011;377: 818,Table 4
Fizazi K, et al. Lancet 2011;377: 819,A,3
Fizazi K, et al. Lancet 2011;377: 818,Table 4
Key Point
The incidence of AEs of interest was similar between the two study treatment groups
Background
During the first 3 days of treatment, AEs potentially associated with acute phase reactions occurred in 8% of denosumab and 18% of zoledronic acid patients
AEs potentially associated with renal impairment occurred in 15% of the denosumab group and 16% of the zoledronic acid group
Positively adjudicated ONJ occurred in 22 (2%) patients in the denosumab group and 12 (1%) patients in the zoledronic acid group (P = .09)
AEs of hypocalcemia were reported in 121 (13%) patients in the denosumab group and 55 (6%) patients in the zoledronic acid group
New primary malignancies were identified in 18 (2%) patients in the denosumab group and 10 (1%) patients in the zoledronic acid group
Reference
Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:
Fizazi K, et al. Lancet 2011;377: 819,A,3
Fizazi K, et al. Lancet 2011;377: 818,Table 4
‡P = 0.09
Fizazi K, et al. Lancet. 2011;377:813–822. 23

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 24

25. 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
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

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 < 1ng/dl
Cholesterol
Desmolase
Deoxy-
corticosterone
Pregnenolone
Progesterone
Corticosterone
Aldosterone X
CYP17
17α-hydroxylase
17α-OH-
pregnenolone
17α –OH-
progesterone
11-Deoxy-
cortisol
Cortisol
ACTH
CYP17
C17,20-lyase
5α-reductase
DHEA
Androstenedione
Testosterone
DHT
Abiraterone
Yang, Drugs. 2011; Attard, JCO 2008

28. Baseline, Cycle 1 (Day 15), subsequent treatment cycles (Day 1)
Overall Study Design
R A N D O M I Z E D
Efficacy end points
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
This was a Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study conducted at 147 sites in the United States/Europe/Australia/Canada comparing the efficacy and safety of AA plus prednisone with placebo plus prednisone in men with metastatic CRPC who had failed 1 or 2 chemotherapy regimens, one of which contained docetaxel
Patients were randomized in a 2:1 ratio and were stratified according to ECOG performance status (0-1 vs. 2), worst pain over the past 24 hours on the Brief Pain Inventory (BPI)-Short Form (0-3 [absent] vs [present]), prior chemotherapy regimens (1 vs. 2), and type of progression (PSA only vs. radiographic progression with or without PSA progression).
Patients could receive treatment until documented disease progression (of all 3 types including 1) PSA progression, 2) radiographic progression and 3) symptomatic or clinical progression) or unacceptable toxicity
Efficacy analysis set: ITT (intent-to-treat)
Primary efficacy endpoint: Overall survival (OS)
Important secondary efficacy endpoints: prostate‑specific antigen (PSA) response rate, radiographic progression-free survival (rPFS).
Note: All analyses presented here are based on the interim data of this study! (Recently published in NEJM)
BPI questionnaire
Baseline, Cycle 1 (Day 15), subsequent treatment cycles (Day 1)
de Bono et al. NEJM 2011 28 28

29. Symptomatic Improvement - Pain Intensity Palliation
155/349
(44.4%)
44/163
(27.0%)
This figure compares improvement in patient reported pain intensity (based on the single item of the BPI questionnaire called "worst pain over the last 24 hours”) between AA and placebo
Shown is the proportion of patients in both study arms who experienced clinically meaningful palliation (for at least 2 cycles, as per prospective definitions) at any time during the study
Not shown: The cumulative proportion of patients with a change (vs baseline) in pain intensity was consistently in favor of AA. (See backup slide.)

30. Results AA (n = 797) Placebo (n = 398) P Value Overall survival
Median, months
14.8
10.9
<
PSA response rate
Total
38.0%
10.1%
Confirmed
29.1%
5.5%
Radiographic PFS
5.6
3.6
Time to first SRE (pathologic fracture/spinal cord compression/ palliative radiation/bone surgery)
25th percentile, days
301.0
150.0
SRE defined as: pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery
Convergence between additional outcomes and Pain/SRE data: AA not only delayed pain progression, but also provided pain palliation, associated with delayed time to SRE, increased overall survival, and greater progression free survival
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)
Overview delle nuove molecole target nel controllo dellabone health. E pertanto
Parlerò

37. Src knockout mice are osteopetrotic5
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): ; 2. Tanaka S, et al. FEBS Lett. 1992;313(1):85-89;
3. Boyce BF, et al. J Clin Invest. 1992;90(4): ; 4. Wong BR, et al. Mol Cell. 1999;4(6): ; 5. Lowe C, et al. Proc Natl Acad Sci U S A. 1993;90(10): ; 6. Zhang XH, et al. Cancer Cell. 2009;16(1):67-78. 37

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
The Src kinase pathway is important both in the cancer cell growth as well as in bone activity.
Activated osteoclast
Osteolysis
Src
Bone
Bone complications 38

39. Direct bone destruction
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
Dasatinib, a small-molecule Src tyrosine kinase inhibitor, should have some efficacy in both tumor cells and osteoclasts.
Osteolysis
Dasatinib
Bone 39

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 4513 Cabozantinib (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?
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

45. …. 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. 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