Curare l’osso per curare il Tumore - OverGroup...Nuova metastasi Bone Health nel pazienti...

Curare l’osso per curare il Tumore

Daniele Santini

University Campus Bio-Medico, Rome

Nuova metastasi

Bone Health nel pazienti neoplastico

ELEVATO TURNOVER OSSEO

CTIBLFRAGILITÀ

PROGRESSIONE OSSEA SRE

Perdita ossea Homing delle cellule tumorali

Crescita della metastasi ossea

CTXNTXP1NP

SDF-1TGF bPDGFIGF-1OP

CTXNTXP1NP

SDF-1TGF bPDGFOP

CTXNTXP1NP

SDF-1TGF bPDGFOP

Scheletro non metastatico Nicchia preneoplastica Metastasi osseaCourtesy of Francesco Bertoldo

Initial diagnosis

Death

SREPrevention of

SREs3

(Study 103)

PSA / tumour burden

The skeleton is affected throughout the natural history of prostate cancer

Time

Initial diagnosis

and therapyADT Bone mets

Castration-resistant

Prevention of bone mets2

(Study 147)Cancer treatment

induced bone loss1

(Study 138)

1. Smith, et al. N Engl J Med 2009;361:745–55; 2. NCT00286091; 3. NCT00321620.

Normal men

Late menop. women

Early menop women

Aromatase Inhibitor

1%

2 %

2.6%

0.5%

CANCER TREATMENT INDUCED BONE LOSS

Rate of BMD Loss

0 2 4 6 8

Bone Marrow transpl

Androgen deprivation

AI + GNrh agonist

Ovarian failure due

chemiother

3.3%

4.6%

7.0%

7.6%

Lumbar spine BMD (% /year Bone Loss)

FRACTUR-FREE SURVIVAL AMONG PATIENTS WITH PROSTATE CANCER ACCORDING TO ANDROGEN-DEPRIVATION THERAPY

Shahinian VB et al

Survival in Prostate Cancer Patients with and

without fracturesC

um

ula

tive

Pro

port

ion

of

Su

rviv

al

NO FX

Cu

mu

lati

ve

Pro

port

ion

of

Su

rviv

al

MesiOefelein MG, J Urol 2002

4

5

Risedronate 35mg

4.7%

Alendronate 70 mg)

Zoledronate 4 mg once y

Zoledronate 4mg/ 3 mo

DNB 60 mg/6 mo

. 4.2%

4%

4.6%

5.3%)

4.1%

4.8%

6

7

Bone target agents: effects on BMD in Men withADT Induced Bone Loss

7%

0

1

2

3

%

fro

m b

as

elin

e

2.4%

2%

Hip

2%

1.1% 1.1%

SpineIshizako K 2007 Smith NEJM 2009 Michaelson MD 2007; Satoh T 2009

Smith MR 2003; Campbell 2010Bhoopalam 2009

3.2%

Study Schema

Design: Randomised, double-blind, placebo-controlled, multicentreStudy protocol amended from 2 to 3 years to extend period for safety and fracture evaluation

RANDOM

Men with nonmetastatic prostate cancer

receiving continuous ADT (n=1468)

Stratified by

Denosumab60 mg SC Q6M (× 6 doses)

(n=734)

Placebo

Supplemental calcium and vitamin D

Baseline 36 months

MISE

Stratified by• Age (<70 y vs ≥70 y)• Prior ADT duration

(≤6 mo vs >6 mo)

PlaceboSC Q6M (× 6 doses)

(n=734)

End points

Primary � Percentage change from baseline at month 24 in lumbar spine BMD

Secondary � Incidence of new vertebral fractures over 36 months� Percentage change from baseline at month 36 in lumbar spine BMD� Percentage change from baseline at 24 and 36 months in total hip and femoral neck BMD� Fracture at any site (morphometric/clinical vertebral or nonvertebral)� Time to first clinical fracture� Safety events

Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361:745-755.

RR 0.15RR 0.31 RR 0.38

PREVENZIONE PRIMARIA IN DONNE IN MENOPAUSA

MASCHI > 50 ANNI

CON RISCHIO FRATTURA ELEVATO

Previsione di trattamento> 3 mesi PN > 5 mg (o equiv.)

Bocco ormonale adiuvante( per la durata del trattamento)

BMD T-score < -3BMD T-score < -4

Familiarità fx vertebree/o femore

+

G.U. 20/5/15 n 115

Sclerosi mult.ParkinsonGrave disabilità motoriaDiabete mellitoM. infiamm cron. Intest.AR+ connettivitiBPCOAIDS

1 Scelta:DenosumabAlendronatoRisedronatoAc zoledronico

1 scelta:.Alendronato

RisedronatoAc zoledronico

2 scelta:denosumab

1. alendronato/risedronato2. Denosumab,ac zoledronico,ibandronato3. raloxifeneCourtesy of Francesco Bertoldo

Low vit D Cancer

+

+

THE ROLE OF VITAMIN D IN BONE HEALTHIn CANCER PATIENT

Vit DSupplementation Mandatory:>50 yrHigh BMIBPs

Fabbisogno 1000 UI/die

PTH BonePrognosis/Survival High bone turnover

Bone MetastasesSRE

+

Bisphosphonates

Calcium

_

Fabbisogno 1000 UI/dieUtilizzare solo Colecalciferolo(DIBASE)

15 gg PRIMA DI INZIARE BPs300.000 UI per 2 giorni consecutivi

DOPO 100.000 UI 1fl/1-2 mesiCourtesy of Francesco Bertoldo

Initial diagnosis

Death

SREPrevention of

SREs3

(Study 103)

PSA / tumour burden


Time

Initial diagnosis





induced bone loss1

(Study 138)


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

N = 1.435Prostate cancer (non metastatic)

RANDOM

Denosumab

120 mg SC every 4 weeks

Primary endpoint: Time to development of bone metastasis or death

Secondary endpoint: Time to development of bone metastasis (excluding death)

Prostate 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

MIZATION

Placebo

Event-driven study:time to bone metastasis or death

Smith MR, et al. Lancet. 2012.

Bone metastasisBone metastasis--free survivalfree survival

0.6

0.8

1.0HR = 0.85 (95% CI 0.73, 0.98)P = 0.028

Pro

po

rtio

n o

f p

ati

en

ts

Study month

PlaceboDenosumab

0.0

0.2

0.4

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Median months

25.229.5

Events

370335

Pro

po

rtio

n o

f p

ati

en

ts

Placebo 716 691 569 500 421 375 345 300 259 215 168 137 99 60 36

Denosumab 716 695 605 521 456 400 368 324 279 228 185 153 111 59 35

Smith MR, et al. Lancet. 2012.

Bone MetastasisBone Metastasis--Free Survival in Patients with Free Survival in Patients with

PSADT ≤ 6 MonthsPSADT ≤ 6 MonthsDenosumab 147 Trial

HR = 0.77 (95% CI 0.64, 0.93)P = 0.006

Pat

ient

sW

ithis

-Fre

eS

urvi

val

1.0

0.6

0.8 23% Risk Reduction

PlaceboDenosumab

MedianMonths

Delay(Months) Events

18.725.9

7.2242197

Pro

port

ion

ofP

atie

nts

Bon

eM

etas

tasi

s-

0.4

0.2

0.0

120 24 36

Study Month

6 18 30

Placebo

Denosumab

427

419

411

406

323

345

274

284

223

238

194

207

176

193

148

170

122

145

99

109

78

89

65

67

47

46

Smith MR, et al. ASCO GU, 2012.

Phase II/III trials in M0 CRPC

Study PROSPERNCT02003924

STRIVENCT01664923

SPARTANNCT01946204

IMAAGENNCT01314118

ARAMISNCT02200614

Phase 3 (N=1500-1560)

2 US (N=400 mix pop)

3 (N=1200) 2 (N=134) 3 (N=1500)

Start/ Completion

08 2013/08 2017 08 2012/06 2015 10 2013/08 2019 05 2011/07 2015 09 2014/12 2020

Patient M0 CRPC high M0 CRPC and M1 M0 CRPC high risk M0 CRPC M0 CRPC high riskPatient population

M0 CRPC high risk

M0 CRPC and M1 CRPC

M0 CRPC high risk M0 CRPC currently receiving GNRH

M0 CRPC high risk

Treatment Enzalutamide vs placebo

Enzalutamide vs bicalutamide

ARN 509 vs placebo Abiraterone/pred + GNRH (single arm)

ODM-201 vs placebo

1o Endpoint MFS PFS MFS Proportion of pts with ≥50% reduction in PSA

MFS

Sponsor Astellas/ Medivation

Medivation/ Astellas Janssen Janssen Bayer/Orion

MFS, metastasis-free survival; PFS, progression-free survival; RT, radiotherapy

Initial diagnosis

Death

SREPrevention of

SREs3

(Study 103)

PSA / tumour burden


Time

Initial diagnosis





induced bone loss1

(Study 138)


Malattia ormonosensibile

18

Zoledronic acid: does not work in hormonosensitive PC

Docetaxel: bone target therapy?

Linee Guida - aggiornamento AIOM 2014 –

come sono cambiate

Carcinoma prostatico con metastasi ossee

Malattia resistente alla castrazione

23

Denosumab* Phase III SRE prevention trialsThree trials of identical design in patients with bone metastases from solid tumours or multiple myeloma

Supplemental calcium and vitamin D

Denosumab 120 mg SC Q4W+

Placebo IV Q4W*

Study 1361

Breast cancer(N = 2049)

Study 1032

Prostate cancer(N = 1904)

RANDOMISA

Lipton et al ASCO, 2014

• Primary endpoint: time to first on-study SRE

• Secondary endpoints: time to first and subsequent SREs, time to disease progression, overall survival, incidence of adverse events

1. Stopeck AT, et al. J Clin Oncol 2010;28:5132–9;2. Fizazi K, et al. Lancet 2011;377:813–22;3. Henry DH, et al. J Clin Oncol 2011;29:1125−32.

†Excluding breast and prostate.MM, multiple myeloma; Q4W, every 4 weeks; SC, subcutaneously.

*IV product dose adjusted as per zoledronic acid product labelling.

Zoledronic acid 4 mg IV Q4W*

+ Placebo SC Q4W

(N = 1904)

Study 2443

Other solid tumours†/MM(N = 1779)

ATION

Patients baseline characteristics

Baseline characteristic, n (%) or medianZoledronic acid

(n = 2861)Denosumab(n = 2862)

Women 1349 (47.2) 1316 (46.0)

Age, years 63.0 63.0

ECOG status of 0 or 1 2546 (89.0) 2585 (90.3)

Tumour type*

Breast 1020 (35.7) 1026 (35.8)

Prostate 951 (33.2) 950 (33.2)

Non-small cell lung 352 (12.3) 350 (12.2)

Multiple myeloma 93 (3.3) 87 (3.0)

Renal 85 (3.0) 70 (2.4)

Small cell lung 48 (1.7) 61 (2.1)

Other 312 (10.9) 318 (11.1)

Time from first bone metastasis to randomisation, months 2.30 2.17

Previous SRE† 1157 (40.4) 1112 (38.9)

Lipton et al ASCO, 2014

Subgroup analyses by baseline characteristics.

Denosumab significantly delayed patients’ time to SREs compared to ZA regardless of patient’s baseline status.

Benefit of denosumab vs ZA on time to first on-study SRE

Baseline characteristic HR (95% CI) P-value

Axial bone mets only (n=1,422) 0.83 (0.70,1.00) 0.046

Appendicular bone mets only

(n=753) 0.78 (0.61,0.99) 0.042

Both axial & appendicular Both axial & appendicular

bone mets (n=1,695) 0.83 (0.71, 0.97) 0.022

≥2 bone mets (n=2,234) 0.81 (0.71,0.93) 0.003

<2 bone mets (n=3,489) 0.84 (0.74,0.94) 0.003

Visceral mets (n=2,341) 0.80 (0.69,0.93) 0.003

No visceral mets (n=3,382) 0.84 (0.75,0.94) 0.002

High uNTx (n=2,553) 0.86 (0.76,0.98) 0.028

Low uNTx (n=2,553) 0.75 (0.65, 0.86) <0.001

ECOG 0 (n=2,312) 0.82 (0.71,0.94) 0.006

ECOG ≥1 (n=3,398) 0.84 (0.75,0.94) 0.002Lipton et al ASCO, 2014

Adro-therapy with alpha emitters

223Ra: T1/2 11.43 gg

mean alfa energy:5.78 Mev (93.5% d)

< 4% Beta emission

U-235 -> Th-231 -> Pa-231 -> Ac-227 -> Th-227 -> Ra-223 -> Rn-219 ->

< 4% Beta emission

< 2% gamma emission269Kev (13.6%),154 Kev (6.04%),324 Kev (3.9%)

Rn-219 -> Po-215 -> Pb-211 -> Bi-211 -> Tl-207 -> Pb-207 (stable)

ALSYMPCA: Study Design

Radium-223 +

Best standard of care (BSoC)50 kBq/kg

Placebo + BSoC

2:1

Randomisationn=921

mCRPC patients

Parker C, et al. N Engl J Med. 2013;369:213-223.

Key inclusion criteria• Confirmed symptomatic CRPC• ≥2 bone metastases• No known visceral metastases• Post docetaxel or unfit/unwilling for

docetaxel

6 injections at 4 week intervals

Stratification factors• Total ALP: <220 U/L vs ≥220 U/L• Bisphosphonate use: Yes vs no• Prior docetaxel: Yes vs no

60

80

100Su

rviv

al (%

)

ALSYMPCA: Overall Survival3.6 month improvement vs placebo

Su

rviv

al

(%)

HR=0.70 (95% CI,0.58–0.83) p<0.00130% reduction in risk of death

0

20

40

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Surv

ival

(%)

Parker et al. N Engl J Med. 2013; 18;369(3):213–223.

Radium 223Placebo

Su

rviv

al

Months since Randomization

Placebo (median overall survival,

11.3 mo)

Radium-223 (median overall

survival, 14.9 mos)

No. at Risk

Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0

Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0

SubgroupNumber ofPatients

Median Overall Survival (months) Hazard Ratio (95% CI)

Radium-223 Placebo Radium-223 Placebo

All patients 614 307 14.9 11.3 0.70 0.58-0.83Total ALP

<220 U/L≥220 U/L

348266

169138

17.011.4

15.88.1

0.820.62

0.64-1.070.49-0.79

Current use of bisphosphonatesYesNo

250364

124183

15.314.5

11.511.0

0.700.74

0.52-0.930.59-0.92

Prior use of docetaxel 352 174 14.4 11.3 0.71 0.56-0.89

ALSYMPCA: Overall Survival Across Patient Subgroups

Prior use of docetaxelYesNo

352262

174133

14.416.1

11.311.5

0.710.74

0.56-0.890.56-0.99

Baseline ECOG PS0 or 1≥2

53677

26541

15.410.0

11.98.4

0.680.82

0.56-0.820.50-1.35

Extent of disease<6 metastases6-20 metastases>20 metastasesSuperscan

10026219554

381479130

27.013.712.511.3

NE11.69.17.1

0.950.710.640.71

0.46-1.950.54-0.920.47-0.880.40-1.27

Opioid useYesNo

345269

168139

13.916.4

10.412.8

0.680.70

0.54-0.860.52-0.93

0.5 1 2ALP, alkaline phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance status; NE, not evaluatedParker C, et al. N Engl J Med. 2013;369:213-223. Copyright ©Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Favours placebo

Favours Radium 223

Phase 3 ALSYMPCA Overall Survival by prior docetaxel

Vogelzang NJ, et al. J Clin Oncol. 31, 2013 (suppl; abstr 5068).

ALSYMPCA: Median Time to First SSE

50

60

70

80

90

100P

ati

en

ts W

ith

ou

tS

SE

s (

%)

HR=0.66; 95% CI: 0.52-0.83 P<0.001

Month 0 3 6 9 12 15 18 21 24 27 30

0

10

20

30

40

Pati

en

ts W

ith

ou

t

Radium-223 614 496 342 199 129 63 31 8 8 1 0

Placebo 307 211 117 56 36 20 9 7 4 1 0

Radium 223 + BSoC median time to SSE: 15.6 months (n=614)Placebo + BSoC median time to SEE: 9.8 months (n=307)

Parker C, et al. N Engl J Med. 2013;369:213-223.

Radium-223 in combination with denosumab/abiraterone may improve OS

Saad et al. J Clin Oncol 2015; 33(s): abstract 5034

Phase III Randomized Study of Abiraterone *- Radium 223 in Patients with Asymptomatic/Mildly Symptomatic CRPC

Why abiraterone and enzalutamide in bone metastatic disease?Why abiraterone and enzalutamide in bone metastatic disease?

Abiraterone postAbiraterone post--docetaxel does delay SREsdocetaxel does delay SREs

4.7 months of difference

Logothetis et al. Lancet Oncology, 2012


Abiraterone preAbiraterone pre--docetaxeldocetaxel

Statistically Significant Improvement in All Secondary End Points Statistically Significant Improvement in All Secondary End Points

AA + P Placebo + P

Median (months)

Median (months) HR (95% CI) P Value

Time to opiate use

(cancer related pain)33.4 23.4

0.72

(0.61, 0.85)< 0.0001

Time to chemotherapy 0.58 Time to chemotherapy initiation

25.2 16.80.58

(0.49, 0.69)<0.0001

Time to ECOG PS deterioration

12.3 10.90.82

(0.71, 0.94)0.0053

Time to PSA progression

11.1 5.60.49

(0.42, 0.57)<0.0001

Note: All secondary end points remain significant after adjusting for multiplicity testing

Ryan C et al. ESMO 2014; Abstract 7530 (oral presentation)

Enzalutamide post-docetaxel does delay SREs


JS De Bono, ASCO, 2012

Pre-planned analysis

Enzalutamide Reduced Risk of First <br />Skeletal-Related Event*

Enzalutamide pre-docetaxel does delay SREs

Beer TM et al. N Engl J Med. 2014 Presented By Andrew Armstrong at 2014 ASCO Annual Meeting

Linee Guida - aggiornamento AIOM 2015

Carcinoma prostatico con metastasi ossee

Le nuove molecole: abiraterone e enzalutamide

L’abiraterone e l’enzalutamide sono capaci, nei pazientiaffetti da tumore della prostata metastatico allo scheletroin fase di resistenza alla castrazione, di ritardare lacomparsa degli SRE e la progressione scheletricaLivello di evidenza: 1+

Cosa abbiamo scoperto

circa l’effetto di abiraterone circa l’effetto di abiraterone

sul microambiente osseo?

Il microambiente osseo può fare brutti scherzi durante la terapia con abiraterone

Pre-trattamento FCH-PET/CT

Metastasi pubicaSUVmax = 6

+ 7 settimaneSUVmax = 13

+ 15 settimaneSUVmax = 4

Iperattivazione

microambiente osseo

Inibizione del circolo

vizioso della metastasi

ossea

Courtesy U De Giorgi

PSA = 4.5 PSA = 1.8 PSA = 1.1

I targets molecolari di abiraterone sono presenti sia negli osteoclasti che negli osteoblasti

β

HUMAN PRIMARY OSTEOCLAST HUMAN PRIMARY OSTEOBLAST

REAL TIME PCR

M. Iuliani, F. Pantano and D. Santini D, Oncotarget, 2015

mR

NA

LE

VE

LS v

s G

US

-β

mR

NA

LE

VE

LS v

s G

US

-βMONOCYTE PRE-OCL OCL

MESENCHYMAL

CELLS PRE-OBL OBL

Abiraterone inibisce la differenziazione e la funzione degli osteoclasti

TRAP ASSAYCTRL

CTRL ABIRATERONE


Abiraterone promuove la differenziazione e la funzione degli osteoblasti

CTRL WITH STEROID CTRL WITHOUT STEROID

CTRL ABIRATERONE


ABIRATERONE

Riepilogando….

Le potenzialità delle tumor target theraphiessulla salute dell’osso nel paziente oncologico

CTIBLFRAGILITÀ1

Modified from Francesco Bertoldo

CTXNTXP1NP


CTXNTXP1NP

SDF-1TGF bPDGF

OP

CTXNTXP1NP

SDF-1TGF bPDGFOP

Scheletro non metastatico Nicchia preneoplastica Metastasi ossea

Perdita ossea

Percent Incidence of AEs by Duration of Exposure and by Grade (cont)

Rathkopf D et al. Eur Urol 2014; [epub]

PROGRESSIONE OSSEA3

Homing delle Crescita della

Nuova metastasi2


Courtesy of Francesco Bertoldo

CTXNTXP1NP


CTXNTXP1NP

SDF-1TGF bPDGF

OP

CTXNTXP1NP

SDF-1TGF bPDGFOP


Homing delle cellule tumorali


SRE/PAIN4


Courtesy of Francesco Bertoldo

CTXNTXP1NP


CTXNTXP1NP

SDF-1TGF bPDGF

OP

CTXNTXP1NP

SDF-1TGF bPDGFOP



Posso associare le bone target therapiesall’abiraterone/enzalutamide?

The benefit of abiraterone on clinical outcomes

were increased with concomitant use of BTT

Saad F, Eur Urol, 2015, in press

Grazie per la Vostra Attenzione

Curare l’osso per curare il Tumore - OverGroup...Nuova metastasi Bone Health nel pazienti...

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