1. Università Campus Bio-Medico
Daniele Santini
Università Campus Bio-Medico
Roma

2. > 3 Bone Lesions associated With Shorter Survival
Curatio PowerPoint Template
Zoledronic Acid (ZOMETA®) in Breast Cancer
3/27/2017 5:32 AM
> 3 Bone Lesions associated With Shorter Survival
Baseline (n = 376)
P < .0001 3 6 9 12 15 18 21 24
Time since randomization, months
Proportion died
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
< 3
> 3
Shirina N, et al. Presented at ASCO Poster 8529.

3. > 3 Bone Lesions Associated with Shorter Time to SRE
Curatio PowerPoint Template
Zoledronic Acid (ZOMETA®) in Breast Cancer
3/27/2017 5:32 AM
> 3 Bone Lesions Associated with Shorter Time 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 3 6 9 12 15 18 21 24
Time since randomization, months
Proportion with SRE
> 3
Shirina N, et al. Presented at ASCO Poster 8529.

4. 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): 4 4

5. 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): 5

6. 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: 6

7. 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

8. Skeletal complications according to types and
number of bone lesions
p=n.s.
% of patients undergoing SRE
p=0.01

9. Skeletal Related Event (SRE) free survival according
to types and number of bone lesions
< 3 bone lesions
4-6 bone lesions
> 6 bone lesions
Mixed bone lesions
Blastic bone lesions
Cumulative proportion SRE free surviving
Cumulative proportion SRE free surviving
Months
Months

10. Target therapies and potential applications in prostate cancer
CTIBL
Bone met prevention in castration resistant prostate cancer patients
SREs in castration resistant metastatic disease

11. 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 11 11 11

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

13. Target therapies and potential applications in prostate cancer
CTIBL
Bone met prevention in castration resistant prostate cancer patients
SREs in castration resistant metastatic disease

14. ZOL Reduced All Types of SREs vs Placebo at 2 Years in Patients With Bone Metastases From PC38 26 17 4 6 2 49 33 25 8 7 1 10 20 30 40 50 60
Any SRE
Radiation to Bone
Fractures
Spinal Cord Compression
Change in Antineoplastic Therapy
Surgery to Bone
HCM
Zoledronic acid 4 mg (n = 214)
Placebo (n = 208)
Patients With SRE, %
Abbreviations: HCM, hypercalcemia of malignancy; SRE, skeletal-related event.
Adapted from Saad F, et al. Eur Urol Suppl. 2007;6(11): 14 14 14

15. 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 15

16. 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. 16

17. 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. 17

18. 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. 18

19. J Brown EAU, 2011

20. 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 20

21. 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

22. Abiraterone post-docetaxel does improve Overall Survival
Fizazi K et al. Lancet Oncology, 2012

23. Abiraterone pre-docetaxel does improve Overall Survival
546
542
538
534
482
465
452
437 27 25
524
509
503
493 2
120
106
258
237
412
387
100 80 60 40 20
Survival (%) 3 12 15
Time to Death (Months) 33
Abiraterone
Prednisone 6 9 30 24 21 18
Abiraterone (median, mos): NR
Prednisone (median, mos):
27.2
HR (95% CI):
0.75 ( )
P value:
0.0097
Ryan et al. NEJM, 2013 23

24. Enzalutamide post-docetaxel does improve Overall Survival
Scher HI et al, NEJM, 2012

25. Radium-223 does improve Overall Survival
S Nilsson et al, Clinical Genitourinary Cancer, 2013

26. Cabazitaxel does improve Overall Survival
De Bono JS et al. Lancet 2010

27. 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

28. Abiraterone post-docetaxel improve quality of life
Abiraterone + Prednisone
(n = 797)
Placebo + Prednisone
(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
( )
3.71
( )
0.0009
When comparing self-reported pain interference in AA-treated patients with placebo-treated patients, there is an increased proportion of palliation, greater duration of palliation and a longer time to symptom progression  all favored the AA arm
Curves of time to palliation and time to progression of pain interference are similar to those shown for pain intensity
Logothetis et al. Lancet Oncology, 2012

29. 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
( )
PCS
5.8
< 0.001
( )
Physical well- being
14.8
( )
Functional well-being
13.3
8.4
0.001
Emotional well-being
22.1
14.2
( )
Social/Family well-being
18.4
0.528
( )
Ryan et al. NEJM, 2013 29

30. Enzalutamide post-docetaxel improve quality of life
JS De Bono, ASCO, 2012

32. Radium-223 improve quality of life
Parker CC et al. Eur Urology, 2012

33. Cabazitaxel improve quality of life
Tombal B, EAU, 2011

34. 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

35. Abiraterone post-docetaxel does delay SREs
4.7 months of difference
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. Lancet Oncology, 2012

36. Abiraterone post-docetaxel does delay SREs
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. Lancet Oncology, 2012

37. Enzalutamide post-docetaxel does delay SREs
3.4 months of difference
Pre-planned analysis
JS De Bono, ASCO, 2012

38. Enzalutamide post-docetaxel does reduce SREs

39. Radium-223 does delay SREs
5.5 months of difference
Pre-planned analysis
C Parker et al, ASCO, 2012

40. Cabazitaxel
No data on SREs

41. 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

42. Abiraterone post-docetaxel does delay bone progression
Abiraterone + Prednisone
(n = 797)
Placebo + Prednisone
(n = 398)
P Value
Time to progression (months)
25th percentile (95% CI)
9.27
( )
4.57
( )
0.0019
When comparing self-reported pain interference in AA-treated patients with placebo-treated patients, there is an increased proportion of palliation, greater duration of palliation and a longer time to symptom progression  all favored the AA arm
Curves of time to palliation and time to progression of pain interference are similar to those shown for pain intensity
Logothetis et al. J Clin Oncol 2011; 29 (Suppl): Abstract 4520 (oral presentation)

43. Abiraterone pre-docetaxel does delay bone progression
100 80 60 40 20
Progression-Free (%) 3 6 9 15 18 12
546
542
489
400
340
204
164 90 46 30
Time to Progression or Death (Months)
Abiraterone
Prednisone
Abiraterone (median, mos): NR
Prednisone (median, mos):
8.3
HR (95% CI):
0.43 ( )
P value:
<
Abiraterone
Prednisone
Ryan et al. NEJM, 2013 43

44. Enzalutamide post-docetaxel does delay bone progression
Scher HI et al, NEJM, 2012

45. Cabazitaxel does delay disease progression
De Bono JS et al., Lancet, 2010

46. 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

47. Risposta sulle lesioni ossee (revisione indipendente)

48. 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

49. 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

50. 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?

51. 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:
Al momento della comparsa delle metastasi ossee
Al momento dell’introduzione della nuova terapia ormonale
Al momento dell’incremento dei marker di riassorbimento osseo
A tutti i pazienti con metastasi ossee?
Esiste un effetto antitumorale sinergico?

52. 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 +
Questi dati sono pre-era nuovi farmaci…. ora la storia deve essere riscritta
Saad F, JNCI, 2004, Fizazi K, Lancet, 2011 52

53. Thank you very much for your attention