Daniele Santini

Università Campus Bio-Medico

Roma

Baseline (n = 376)

P < .0001

0 3 6 9 12 15 18 21 24

Time since randomization, months

Pro

port

ion d

ied

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

< 3

> 3

> 3 Bone Lesions associated With Shorter Survival

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

> 3 Bone Lesions Associated with Shorter > 3 Bone Lesions Associated with Shorter Time to SRETime 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

0 3 6 9 12 15 18 21 24

Time since randomization, months

Pro

port

ion w

ith S

RE

> 3

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

24 months

Pat

ien

ts W

ith

SR

E, %

Pathologic fracture

Radiation therapy

Surgical intervention

Spinal cord compression

Any

Saad F, et al. JNCI. 2002;94(19):1458-1468; Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.

Patients With Bone Metastases Patients With Bone Metastases From Pca Are at High Risk for Developing SREsFrom Pca Are at High Risk for Developing SREs

Skeletal Complications Reduce Quality Skeletal Complications Reduce Quality of Life in Prostate Cancer Patientsof Life in Prostate Cancer Patients

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Radiation to bonePathologic fractureOther SREs

a P < .05.

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

Change in FACT-G score for patients with an event vs patients without an event

aa aa

aaaa

aa

aa

Ch

an

ge/S

tan

dard

Devi

ati

on

Total Physical Functional Emotional

SREs Are Associated With Lower SREs Are Associated With Lower Survival in Prostate CancerSurvival in Prostate Cancer

Abbreviations: CI, confidence interval; SRE, skeletal-related event. DePuy V, et al. Support Care Cancer. 2007;15:869-876.

Pro

bab

ilit

y

0 90 180 270 360

Survival, days

00.10.20.30.40.5

0.70.80.9

1

0.6

No SRE (n = 355)≥ 1 SRE (n = 116)

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)

PTHrPIL-6

FISIOPATOLOGIA DELLA METASTASI ADDENSANTE

IGF1 TGF

IGF1 TGF

ET1uPA

Osteocalcina ALP

TGF-1

Bertoldo F, Santini D Textbook of Osteoncology 2010

Wnt DDK-1OPGOPG

>RANKL/<OPG>RANKL/<OPG

0

10

20

30

40

50

60

<=3 lesions 4 to 6 lesions >6 lesions

0

10

20

30

40

50

60

Lytic/Mixed Blastic

Skeletal complications according to types and Skeletal complications according to types and number of bone lesionsnumber of bone lesions

p=0.01

p=n.s.

% o

f p

atie

nts

un

der

goin

g S

RE

120100806040200

1,0

,8

,6

,4

,2

0,0

120100806040200

1,0

,8

,6

,4

,2

0,0

Cu

mu

lati

ve p

rop

orti

on S

RE

fre

e su

rviv

ing

Cu

mu

lati

ve p

rop

orti

on S

RE

fre

e su

rviv

ing

Months Months

Mixed bone lesions

Blastic bone lesions

< 3 bone lesions

4-6 bone lesions

> 6 bone lesions

Skeletal Related Event (SRE) free survival according Skeletal Related Event (SRE) free survival according to types and number of bone lesions to types and number of bone lesions

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

CTIBLCTIBL

Bone met prevention in Bone met prevention in castration resistant prostate castration resistant prostate cancer patients cancer patients

SREs in castration resistant SREs in castration resistant metastatic diseasemetastatic disease

Prevention of Bone Metastases in PC: Prevention of Bone Metastases in PC: Phase III Denosumab Trial (AMG 147)Phase III Denosumab Trial (AMG 147)

N = 1.435Prostate cancer (non metastatic)Hormone-refractory diseaseHigh risk of bone metastases (PSA at least 8 and/or PSA doubling time less than 10 months

Adequate organ function

RANDOMIZATION

Denosumab

120 mg SC every 4 weeks

Denosumab

120 mg SC every 4 weeks

Placebo

Event-driven study:time to bone metastasis or death

Event-driven study:time to bone metastasis or death

Primary endpoint: Time to development of bone metastasis or deathSecondary endpoint: Time to development of bone metastasis (excluding death)

Primary endpoint: Time to development of bone metastasis or deathSecondary endpoint: Time to development of bone metastasis (excluding death)

Smith MR, et al. Lancet. 2012.

Sopravvivenza libera da metastasi ossee in pazienti con PSADT ≤4 mesi

F. Saad, ASCO 2012F. Saad, ASCO 2012

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

CTIBLCTIBL

Bone met prevention in castration Bone met prevention in castration resistant prostate cancer patients resistant prostate cancer patients

SREs in castration resistant SREs in castration resistant metastatic diseasemetastatic disease

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

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

P = .028

38

26

17

46

20

49

33

25

8 74

10

10

20

30

40

50

60

Any SRE Radiationto Bone

Fractures Spinal CordCompression

Change inAntineoplastic

Therapy

Surgeryto Bone

HCM

Zoledronic acid 4 mg (n = 214) Placebo (n = 208)

Pat

ien

ts W

ith

SR

E,

%

ZOL Reduced All Types of SREs vs ZOL Reduced All Types of SREs vs Placebo at Placebo at

2 Years in Patients With Bone 2 Years in Patients With Bone Metastases From PCMetastases From PC

14

N = 951 zoledronic acid 4 mg IV* and placebo SC Q4W

N = 950 denosumab 120 mg SC and placebo IV Q4W

Study Design: International, Study Design: International, Randomised, Double-Blind, Active-Randomised, Double-Blind, Active-

Controlled StudyControlled Study

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

Primary Primary EndpointEndpoint

Time to first on-study skeletal-related event (SRE) (noninferiority)

Secondary Secondary EndpointsEndpoints

Time to first on-study SRE (superiority)Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE(s) Time to first and subsequent on-study SRE(s)

(superiority)(superiority)

Supplemental calcium and vitamin D strongly recommended

Key Inclusion Criteria

• Castration-resistant prostate cancer and 1 bone metastases

Key Exclusion Criteria

• Current or prior IV bisphosphonate treatment

Primary Endpoint: Time to First On-Primary Endpoint: Time to First On-Study SREStudy SRE

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

0.00

1.00

Pro

po

rtio

n o

f S

ub

ject

s W

ith

ou

t S

RE

0 3 9 12 15 18 21 24 27

0.25

0.50

0.75

Kaplan-Meier Estimate of Median Months

DenosumabZoledronic acid

20.7

17.1

HR = 0.82 (95% CI, 0.71–0.95)P 0.001 (noninferiority)P = 0.008 (superiority)

Study MonthPatients at Risk:Zoledronic acidZoledronic acid 951951 733733 544544 407407 299299 207207 140140 9393 6464 4747

DenosumabDenosumab 950950 758758 582582 472472 361361 259259 168168 115115 7070 3939

66

Secondary Endpoint: Time to First and Secondary Endpoint: Time to First and Subsequent On-Study SRE(s) Subsequent On-Study SRE(s)

(Multiple-Event Analysis)(Multiple-Event Analysis)

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

Rate ratio = 0.82 (95% CI, 0.71–0.94)

0.0

2.0

Cu

mu

lati

ve M

ean

Nu

mb

er o

f S

RE

s p

er

Pat

ien

t

0.2

0.6

1.0

1.4

1.8

0.4

0.8

1.2

1.6

Denosumab

Zoledronic acid 584584

494494

Events

P = 0.009 (superiority)

0 3 6 9 12 15 18 21 24 27 30 33 36

Study Month

Exploratory Endpoint: Overall Exploratory Endpoint: Overall SurvivalSurvival

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

HR = 1.03 (95% CI, 0.91–1.17)P = 0.65

0.00

Pro

po

rtio

n o

f P

atie

nts

Su

rviv

ed

3 6 9 12 15 18 21 24 27Study Month

1.00

0.25

0.50

0.75

DenosumabZoledronic acid

Zoledronic acid

951 864 745 635 519 401 297 207 143 98

Denosumab 950 872 746 645 552 427 310 233 156 99

Patients at Risk:5554

3000

J Brown EAU, 2011J Brown EAU, 2011

Skeletal Complication Risk: Skeletal Complication Risk: Incremental Benefits in Prostate Incremental Benefits in Prostate

CancerCancer

No bisphosphonate 49% risk at 2 yrs

Zoledronic ~ 20% risk reduction Denosumab

Additional ~ 12% risk reduction

Denosumab Additional ~ 12%

risk reduction

Denosumab Additional 18%

time to first SRE increase

Saad F, JNCI, 2004, Fizazi K, Lancet, 2011

++

Why should we use CT/HT to delay skeletal related events?

To improve overal survivalTo improve overal survival

To improve quality of lifeTo improve quality of life

To delay SRETo delay SRE

To delay bone metastasesTo delay bone metastases

Abiraterone post-docetaxel does improve Overall Survival

Fizazi K et al. Lancet Oncology, 2012Fizazi K et al. Lancet Oncology, 2012

V3.0

COU-AA-302

Abiraterone pre-docetaxel does improve Overall Survival

546542

538534

482465

452437

2725

00

524509

503493

02

120106

258237

412387

100

80

60

40

20

0

0

Su

rviv

al (

%)

3 12 15 27

Time to Death (Months)

33

Abiraterone Prednisone

6 9 30242118

AbirateronePrednisone

Abiraterone (median, mos): NR

Prednisone (median, mos): 27.2

HR (95% CI): 0.75 (0.61-0.93)

P value: 0.0097

Ryan et al. NEJM, 2013

Enzalutamide post-docetaxel does improve Overall Survival

Scher HI et al, NEJM, 2012Scher HI et al, NEJM, 2012

S Nilsson et al, Clinical Genitourinary Cancer, 2013

Radium-223 does improve Overall Survival

Cabazitaxel does improve Overall Survival

De Bono JS et al. Lancet 2010De Bono JS et al. Lancet 2010

Why should we use CT/HT to delay skeletal related events?

To improve overal survivalTo improve overal survival

To improve quality of lifeTo improve quality of life

To delay SRETo delay SRE

To delay bone progressionTo delay bone progression

Abiraterone +

Prednisone

(n = 797)

Placebo + Predniso

ne(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 (0.92-1.91)

3.71 (2.69-4.44)

0.0009

Logothetis et al. Lancet Oncology, 2012

Abiraterone post-docetaxel improve quality of life

AA + P(months)

Placebo + P

(months)P Value

Hazard Ratio (95%

CI)

FACT-G 16.6 11.1 0.0020.76

(0.63-0.91)

PCS 11.1 5.8 < 0.0010.70

(0.60-0.83)Physical

well-being14.8 11.1 0.002

0.76(0.64-0.90)

Functional well-being

13.3 8.4 0.0010.76

(0.64-0.90)

Emotional well-being

22.1 14.2 0.0010.71

(0.59-0.87)

Social/Family

well-being18.4 16.6 0.528

0.94(0.78-1.14)

Abiraterone pre-docetaxel improve quality of life

Ryan et al. NEJM, 2013

JS De Bono, ASCO, 2012JS De Bono, ASCO, 2012

Enzalutamide post-docetaxel improve quality of life

Radium-223 improve quality of life

Parker CC et al. Eur Urology, 2012Parker CC et al. Eur Urology, 2012

Cabazitaxel improve quality of lifeCabazitaxel improve quality of life

Tombal B, EAU, 2011Tombal B, EAU, 2011

Why should we use CT/HT to delay skeletal related events?

To improve overal survivalTo improve overal survival

To improve quality of lifeTo improve quality of life

To delay SRETo delay SRE

To delay bone progressionTo delay bone progression

Abiraterone post-docetaxel does delay SREs

Logothetis et al. Lancet Oncology, 2012

4.7 months of difference4.7 months of difference

Abiraterone post-docetaxel does delay SREs

Logothetis et al. Lancet Oncology, 2012

JS De Bono, ASCO, 2012JS De Bono, ASCO, 2012

Enzalutamide post-docetaxel does delay SREs

3.4 months of difference3.4 months of difference

Pre-planned analysisPre-planned analysis

Enzalutamide post-docetaxel does reduce SREs

Radium-223 does delay SREs

C Parker et al, ASCO, 2012

5.5 months of difference5.5 months of difference

Pre-planned analysisPre-planned analysis

Cabazitaxel

No data on SREs

Why should we use CT/HT to delay skeletal related events?

To improve overal survivalTo improve overal survival

To improve quality of lifeTo improve quality of life

To delay SRETo delay SRE

To delay bone progressionTo delay bone progression

Abiraterone post-docetaxel does delay bone progression

Abiraterone +

Prednisone

(n = 797)

Placebo + Predniso

ne(n = 398)

P Value

Time to progression (months) 25th percentile (95% CI)

9.27 (7.39-12.88)

4.57 (2.79-6.47)

0.0019

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

V3.0

COU-AA-302

AbirateronePrednisone

100

80

60

40

20

0

0

Pro

gre

ssio

n-F

ree

(%)

3 6 9 15 1812

546542

489400

340204

16490

123

00

4630

Time to Progression or Death (Months)

AbirateronePrednisone

Abiraterone (median, mos): NR

Prednisone (median, mos): 8.3

HR (95% CI): 0.43 (0.35-0.52)

P value: < 0.0001

Abiraterone pre-docetaxel does delay bone progression

Ryan et al. NEJM, 2013

Enzalutamide post-docetaxel does delay bone progression

Scher HI et al, NEJM, 2012Scher HI et al, NEJM, 2012

Cabazitaxel does delay disease progression

De Bono JS et al., Lancet, 2010De 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 4513

Cabozantinib (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)

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

To improve overal survivalTo improve overal survival NONO

To improve quality of lifeTo improve quality of life YESYES

To delay SRETo delay SRE YESYES

To delay bone progressionTo delay bone progression NONO

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

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?

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:

1.Al momento della comparsa delle metastasi ossee

2.Al momento dell’introduzione della nuova terapia ormonale

3.Al momento dell’incremento dei marker di riassorbimento osseo

4.A tutti i pazienti con metastasi ossee?

• Esiste un effetto antitumorale sinergico?

Skeletal Complication Risk: Skeletal Complication Risk: Incremental Benefits in Prostate CancerIncremental Benefits in Prostate Cancer

No bisphosphonate 49% risk at 2 yrs

Zoledronic ~ 20% risk reduction Denosumab

Additional ~ 12% risk reduction

Denosumab Additional ~ 12%

risk reduction

Denosumab Additional 18%

time to first SRE increase

Saad F, JNCI, 2004, Fizazi K, Lancet, 2011

++

Questi dati sono pre-era nuovi

farmaci…. ora la storia deve

essere riscritta

Questi dati sono pre-era nuovi

farmaci…. ora la storia deve

essere riscritta

d.santini@unicampus.itd.santini@unicampus.it

Thank you very much for your

attention