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Daniele Santini Università Campus Bio-Medico Roma. Baseline (n = 376). 0.8. 0.7. > 3. 0.6. P < .0001. 0.5. 0.4. 0.3. < 3. 0.2. 0.1. Proportion died. 0.0. 0. 3. 6. 9. 12. 15. 18. 21. 24. Time since randomization, months. > 3 Bone Lesions associated With Shorter Survival.

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Daniele Santini

Università Campus Bio-Medico

Roma


3 bone lesions associated with shorter survival

Baseline (n = 376)

0.8

0.7

> 3

0.6

P < .0001

0.5

0.4

0.3

< 3

0.2

0.1

Proportion died

0.0

0

3

6

9

12

15

18

21

24

Time since randomization, months

> 3 Bone Lesions associated With Shorter Survival

Shirina N, et al. Presented at ASCO 2006. Poster 8529.


3 bone lesions associated with shorter time to sre
> 3 Bone Lesions Associated with Shorter Time to SRE

Baseline (n = 376)

0.8

> 3

0.7

P < .0001

0.6

0.5

0.4

< 3

0.3

0.2

0.1

Proportion with SRE

0.0

0

3

6

9

12

15

18

21

24

Time since randomization, months

Shirina N, et al. Presented at ASCO 2006. Poster 8529.


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):1458-1468; Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.


Skeletal complications reduce quality of life in prostate cancer patients
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

aP < .05.

Data from Weinfurt KP, et al. Ann Oncol. 2005;16(4):579-584.


Sres are associated with lower survival in prostate cancer
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. 2007;15:869-876.


IGF1

TGFb-1

IGF1

TGFb-1

Osteocalcina

ALP

TGF-b1

ET1

uPA

PTHrP

IL-6

Wnt DDK-1

FISIOPATOLOGIADELLA METASTASI ADDENSANTE

>RANKL/<OPG

OPG

Bertoldo F, Santini D Textbook of Osteoncology 2010


Skeletal complications according to types and

number of bone lesions

p=n.s.

% of patients undergoing SRE

p=0.01


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


Target therapies and potential applications in prostate cancer
Target therapies and potential applications in prostate cancer

CTIBL

Bone met prevention in castration resistant prostate cancer patients

SREs in castration resistant metastatic disease


Prevention of bone metastases in pc phase iii denosumab trial amg 147
Prevention of Bone Metastases in PC: Phase III Denosumab Trial (AMG 147)

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

Event-driven study:time to bone metastasis or death

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.



Target therapies and potential applications in prostate cancer1
Target therapies and potential PSADT ≤4 mesi applications in prostate cancer

CTIBL

Bone met prevention in castration resistant prostate cancer patients

SREs in castration resistant metastatic disease


Zol reduced all types of sres vs placebo at 2 years in patients with bone metastases from pc
ZOL Reduced All Types of SREs vs Placebo at PSADT ≤4 mesi 2 Years in Patients With Bone Metastases From PC

P = .028

60

49

50

38

40

33

Patients With SRE, %

30

26

25

17

20

8

7

10

6

4

4

2

1

0

0

Any SRE

Radiationto Bone

Fractures

Spinal CordCompression

Change inAntineoplasticTherapy

Surgeryto Bone

HCM

Zoledronic acid 4 mg (n = 214)

Placebo (n = 208)

14

Abbreviations: HCM, hypercalcemia of malignancy; SRE, skeletal-related event.

Adapted from Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.


Study design international randomised double blind active controlled study
Study Design: International, Randomised, Double-Blind, Active-Controlled Study

Fizazi K, et al. Lancet. 2011;377:813–822.

  • 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 sre
Primary Endpoint: Time to First On-Study SRE Active-Controlled Study

Fizazi K, et al. Lancet. 2011;377:813–822.

HR = 0.82 (95% CI, 0.71–0.95)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

6

9

12

27

Study Month

Patients at Risk:


Secondary endpoint time to first and subsequent on study sre s multiple event analysis
Secondary Endpoint: Time to First and Subsequent On-Study SRE(s) (Multiple-Event Analysis)

Fizazi K, et al. Lancet. 2011;377:813–822.

2.0

Rate ratio = 0.82 (95% CI, 0.71–0.94)

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

15

27

30

6

9

12

18

21

24

33

36

Study Month


Exploratory endpoint overall survival
Exploratory Endpoint: Overall Survival SRE(s) (Multiple-Event Analysis)

Fizazi K, et al. Lancet. 2011;377:813–822.

HR = 1.03 (95% CI, 0.91–1.17)

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:


J brown eau 2011
J Brown EAU, 2011 SRE(s) (Multiple-Event Analysis)


Skeletal complication risk incremental benefits in prostate cancer
Skeletal Complication Risk: SRE(s) (Multiple-Event Analysis)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


Why should we use ct ht to delay skeletal related events
Why should we use CT/HT to delay skeletal related events? SRE(s) (Multiple-Event Analysis)

To improve overal survival

To improve quality of life

To delay SRE

To delay bone metastases


Abiraterone post-docetaxel does improve Overall Survival SRE(s) (Multiple-Event Analysis)

Fizazi K et al. Lancet Oncology, 2012


Abiraterone pre docetaxel does improve overall survival
Abiraterone pre-docetaxel does improve Overall Survival SRE(s) (Multiple-Event Analysis)

100

80

60

Survival (%)

40

20

Abiraterone

Prednisone

0

3

6

9

12

15

18

21

24

27

30

33

0

Time to Death (Months)

546

542

538

534

524

509

503

493

482

465

452

437

412

387

258

237

120

106

27

25

0

2

0

0

Abiraterone

Prednisone

Ryan et al. NEJM, 2013


Enzalutamide post-docetaxel does improve Overall Survival SRE(s) (Multiple-Event Analysis)

Scher HI et al, NEJM, 2012


Radium-223 does improve Overall Survival SRE(s) (Multiple-Event Analysis)

S Nilsson et al, Clinical Genitourinary Cancer, 2013


Cabazitaxel does improve Overall Survival SRE(s) (Multiple-Event Analysis)

De Bono JS et al. Lancet 2010


Why should we use ct ht to delay skeletal related events1
Why should we use CT/HT to delay skeletal related events? SRE(s) (Multiple-Event Analysis)

To improve overal survival

To improve quality of life

To delay SRE

To delay bone progression


Abiraterone post-docetaxel improve quality of life SRE(s) (Multiple-Event Analysis)

Logothetis et al. Lancet Oncology, 2012


Abiraterone pre-docetaxel improve quality of life SRE(s) (Multiple-Event Analysis)

Ryan et al. NEJM, 2013


Enzalutamide post-docetaxel improve quality of life SRE(s) (Multiple-Event Analysis)

JS De Bono, ASCO, 2012


Radium-223 improve quality of life SRE(s) (Multiple-Event Analysis)

Parker CC et al. Eur Urology, 2012


Cabazitaxel improve quality of life SRE(s) (Multiple-Event Analysis)

Tombal B, EAU, 2011


Why should we use ct ht to delay skeletal related events2
Why should we use CT/HT to delay skeletal related events? SRE(s) (Multiple-Event Analysis)

To improve overal survival

To improve quality of life

To delay SRE

To delay bone progression


Abiraterone post docetaxel does delay sres
Abiraterone post-docetaxel does delay SREs SRE(s) (Multiple-Event Analysis)

4.7 months of difference

Logothetis et al. Lancet Oncology, 2012


Abiraterone post docetaxel does delay sres1
Abiraterone post-docetaxel does delay SREs SRE(s) (Multiple-Event Analysis)

Logothetis et al. Lancet Oncology, 2012


Enzalutamide post-docetaxel does delay SREs SRE(s) (Multiple-Event Analysis)

3.4 months of difference

Pre-planned analysis

JS De Bono, ASCO, 2012


Enzalutamide post-docetaxel does reduce SREs SRE(s) (Multiple-Event Analysis)


Radium-223 does delay SREs SRE(s) (Multiple-Event Analysis)

5.5 months of difference

Pre-planned analysis

C Parker et al, ASCO, 2012


Cabazitaxel
Cabazitaxel SRE(s) (Multiple-Event Analysis)

No data on SREs


Why should we use ct ht to delay skeletal related events3
Why should we use CT/HT to delay skeletal related events? SRE(s) (Multiple-Event Analysis)

To improve overal survival

To improve quality of life

To delay SRE

To delay bone progression


Abiraterone post docetaxel does delay bone progression
Abiraterone post-docetaxel does delay bone progression SRE(s) (Multiple-Event Analysis)

Logothetis et al. J Clin Oncol 2011; 29 (Suppl): Abstract 4520 (oral presentation)


Abiraterone pre-docetaxel does delay bone progression SRE(s) (Multiple-Event Analysis)

100

80

60

Progression-Free (%)

40

20

Abiraterone

Prednisone

0

3

6

9

12

15

18

0

Time to Progression or Death (Months)

Abiraterone

Prednisone

546

542

489

400

340

204

164

90

46

30

12

3

0

0

Ryan et al. NEJM, 2013


Enzalutamide post-docetaxel does delay bone progression SRE(s) (Multiple-Event Analysis)

Scher HI et al, NEJM, 2012


Cabazitaxel does delay disease progression SRE(s) (Multiple-Event Analysis)

De 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 4513Cabozantinib (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
Risposta sulle lesioni ossee 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; (revisione indipendente)


What about bisphosphonate and denosumab
What about bisphosphonate and denosumab? 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;

To improve overal survival NO

To improve quality of life YES

To delay SRE YES

To delay bone progression NO


What about new ht ct agents in crpc
What about new HT/CT agents in CRPC? 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;

To improve overal survival YES

To improve quality of life YES

To delay SRE YES

To delay bone progression YES


Open issues 1

Open Issues 1 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;

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

Open Issues 2 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;

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?


Skeletal complication risk incremental benefits in prostate cancer1
Skeletal Complication Risk: 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; 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


Thank you very much for your attention 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;

[email protected]


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