CPRC: enfoque terapéutico de la enfermedad ósea · 2014. 6. 19. · targets the lumbar spine,...

CPRC: enfoque terapéutico

de la enfermedad ósea Javier Cassinello, Hospital Universitario de Guadalajara

AGENDA

I Importancia del problema

II Prevención o retraso de EREs en CPRC con metástasis

óseas

III Fármacos aprobados en CPRC con actividad sobre las

metástasis óseas: ¿son suficientes o es conveniente su

combinarlos con los agente dirigidos al hueso?

IV Prevención o retraso de metástasis óseas en CPRC

Bone Metastases Very Common in Prostate Cancer

It is estimated that > 350,000 people die with bone metastases annually in the USA.2

Bone metastasis occurs in most prostate cancer patients during the natural course of their disease and typically targets the lumbar spine, vertebrae, and pelvis.3

Estimated incidence (%)1,a

Myeloma 70-95

Renal 20-25

Melanoma 14-45

Bladder 40

Thyroid 60

Lung 30-40

Breast 65-75

Prostate 65-75

aIncidence of bone metastases at autopsy.

1. Coleman R. Cancer Treatment Rev. 2001;27:165-176; 2. Mundy G. Nat Rev Cancer. 2002;2:584-593;

3. Bubendorf L, et al. Hum Pathol. 2000;31:578-583.

Incidencia de complicaciones óseas (ERES) en Ensayos clínicos (%)

48

49

51

68

0 20 40 60 80

Patients with SREs (%)*

*Placebo arm of pamidronate or zoledronic acid randomized trials; †24 months; ‡21 months. Coleman RE. The Oncologist. 2004;9(suppl 4):14-27.

Lung cancer/Others‡

Prostate cancer†

Multiple myeloma‡

Breast cancer†

5

Skeletal-Related Events: A Serious Threat

Vertebral collapse

Requirement for surgery to bone

Pathologic fracture

Osteolytic lesion requiring palliative radiotherapy

33%

25%

8% 4%

Development of bone metastases in castration-resistant prostate cancer may be associated with increased mortality

1. Nørgaard M et al. (2010) J Urol 184:162

n= 23,087 with median follow-up of 2.2 years (Danish National Patient Registry)

5 year survival rate in patients without bone metastasis was 56%

compared to 3% with bone metastasis

BMFS (Jan2012) Sathiakumar N, et al Prostatic Dis 2011; 14: 177–83.

56%

3%

No bone mets

Bone mets

Bone metastases in prostate cancer have a significant impact on healthcare costs

Healthcare costs (US) in patients with prostate cancer:

Increased costs due to treatment of metastatic disease

and occurrence of SREs*1

*Footnote: Retrospective cohort study of 215,702 PC patients using claims data from large, US health insurance plans between Oct 2002 and Dec

2007. Primary measure was total healthcare costs after bone metastases, secondary measures included components of total healthcare costs

1. Data on file, 2011; 2. Oglesby et al. 2009

Preventing development of bone metastases in prostate cancer patients

would result in substantial reduction of costs

• Development of bone metastasis is associated with increased health resource utilization which leads to greater costs in:

Hospital inpatient care

Outpatient care including physician visits

Outpatient pharmacy

• These costs are conservative, and do not include newer therapies

• A separate study demonstrated a 91% increase in the risk of hospitalization after development of bone mets2

BMFS (Jan2012)

Incremento > 100%

Costes en España de EREs (SRE) 2010

Radioterapia sobre hueso………….2.377€

Cirugía ósea…………………………4.262€

Fractura patológica……………….…4.712€

Compresión medular………………..7.902€

N=93; 31 cáncer de mama: ; 21 cáncer de próstata; 41 cáncer de

pulmón

Durán I, Garzón C, Sánchez A, et al. Cost analysis of skeletal-related

events in Spanish patients with bone metastases from solid tumours.

Clin Transl Oncol 2014; 16:322-329

I Tratamiento de las metástasis óseas

Bisfosfonatos (Ac Zoledrónico)

Denosumab

Radioemisor de partículas alfa

-----------------

Radioterapia, Analgésicos, Cirugía

ortopédica, etc.

Fornier MN et al. J Clin Oncol 2010;28:5127-31

BIFOSFONATOS DENOSUMAB

BIFOSFONATOS PREVENCIÓN DE ERE

Rosen LS et al. Cancer 2003;98:1735-44

Saad F et al. J Natl Cancer Inst 2004;96:879-82

Rosen LS et al. J Clin Oncol 2003:21:3150-7

ZOL reduce el riesgo de ERE y retrasa su aparición

Útiles en el control del dolor óseo

Eficacia en el tratamiento de la hipercalcemia

Sin diferencias en SG

Ác. Zoledrónico en pacientes con metástasis óseas y cáncer de próstata

sensible a castración

CALGB 90202

N=645

ADT

Zoledrónico

Placebo

Seguimiento 24 m NO diferencias en el tiempo al primer ERE ( 32.5 vs 29.8 m, HR 0.96) NO diferencias en SG ( HR 0.89, IC 95% 0.70-1.14)

Smith MR, HalabiS, Ryan CJ, et al. J Clin Oncol 2013; 31: ABSTRACT 27

PTHrP, IL-1 IL-6, PGE2,

TNFα, M-CSF

Osteoblastos

Osteoclasto activado

PDGF, BMP, TGF-β, IGF,

FGF

RANKL

RANK

OPG Célula tumoral

RANKL, ligando del receptor activador del factor nuclear κB; RANK, receptor activador

del factor nuclear κB; OPG, osteoprotegerina

Adaptado de Boyle WJ et al. Nature 2003; 423: 337–342

“CÍRCULO VICIOSO” EN CÁNCER METASTÁSICO

Precursores del osteoclasto

Ca+2

Fornier MN et al. J Clin Oncol 2010;28:5127-31

BIFOSFONATOS DENOSUMAB

ESTUDIO 103

The Lancet

Febrero 2011

Time to First On-Study SRE

Zoledronic Acid 951 733 544 407 299 207 140 93 64 47

Denosumab 950 758 582 472 361 259 168 115 70 39

Subjects at risk:

0

1.00

Pro

po

rtio

n o

f S

ub

jects

Wit

ho

ut

SR

E

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

KM Estimate of Median Months

Denosumab Zoledronic acid

20.7 17.1

HR 0.82 (95% CI: 0.71, 0.95)

P = 0.0002 (Non-inferiority)

P = 0.008 (Superiority)

Study Month

18% Risk

Reduction

SREs-met Prostate (20050103)

Fizazi K. et al. J Clin Oncol 28:7s, 2010 (suppl. ASCO 2010). Abstract LBA4507 and Oral Presentation

Time to First and Subsequent On-Study SRE* (Multiple Event Analysis)

*Events occurring at least 21 days apart

Rate Ratio = 0.82 (95% CI: 0.71, 0.94)

Study Month

0.0

2.0

0 3 6 9 12 15 18 21 24 27

Cu

mu

lati

ve

Mean

Nu

mb

er

of

SR

Es p

er

Pati

en

t

30 33 36

0.2

0.6

1.0

1.4

1.8

0.4

0.8

1.2

1.6

18% Risk

Reduction

Denosumab Zoledronic acid 584

494

Events

P = 0.008



2-year Extended Analysis: Safety Summary

• No new safety signals were observed during open-label

denosumb treatment

• Among patients who switched from zoledronic acid to

denosumab a similar pattern and frequency of AEs was

observed as in those who continued with denosumab

• The cumulative incidence of ONJ was

• 3.8% among denosumab/ denosumab patients when

administered for up to 5.6 years

• 2.2% among patients who switched to denosumab with prior

exposure to zoledronic acid for up to 3.4 years

• No neutralizing anti-denosumab antibodies were detected

in either group

Fizazi K, Brown JE, Carducci M. et al. ESMO 2012: abstract 937P and poster presentation.

Phase 3

20050103 1

20050103 - ESMO 2012 - Poster 937P - Fizazi.pdf



20050136 - SABCS 2011 - Poster P3-16-07 - Stopeck.pdf

Pain Interference: Summary

• Denosumab demonstrated consistent improvement in pain

interference compared with zoledronic acid

• In the responder analysis of patients with no or mild pain at

baseline, relative improvements were approximately twofold

that reported for the full study group

• Fewer patients in the denosumab group shifted to strong

opioid use during the course of the study

• The impact of treatment was greater on pain interference

with activity than on pain interference with affect

Patrick D, Cleeland C, Fallowfield L, et al. AUA 2011: abstract 1101073 MP23 and poster presentation.

Phase 3

20050103 2

20050103 - AUA 2011 - Poster MP23 - Patrick.pdf



NNT: Summary

• Denosumab has a favorable NNT profile compared with

zoledronic acid or placebo

• For first SRE vs. zoledronic acid, NNT=10

• For multiple SREs vs. zoledronic acid, NNT=5

• For first SRE vs. placebo, NNT=3

• These low NNT values demonstrate the high therapeutic

efficacy of denosumab

Miller K, Fizazi K, Smith M, et al. AUA 2011: abstract 648 and oral presentation.

Phase 3

20050103

3

20050103 - AUA 2011 - Oral 648 - Miller.pdf






GUIAS ESMO 2014

GUIAS ESMO 2014

A: unánimemente recomendado B: generalmente recomendado

Agentes aprobados para hueso β-emitters Bisphosphonates Osteoclast

inhibitor

Strontium-89;1 Samarium-1532

Zoledronic acid3–6 Denosumab6,7

Proven impact on pain

Proven impact on SREs ×

Proven impact on overall survival

NO NO NO

Key safety issues Bone marrow suppression

Fatigue, anemia;

Rare but serious: osteonecrosis of

the jaw

Hypocalcemia;

Rare but serious:

osteonecrosis of the jaw

23

1. Lewington et al. Eur J Cancer 1991;27:954–8. 2. Sartor et al. Urology 2004;63:940–5. 3. Saad et al. J Natl Cancer Inst 2002;94:1458–68. 4. Saad et al. J Natl Cancer Inst 2004;96:879–82. 5. Smith et al. J Urol 2003;169:2008–12. 6. Fizazi et al. Lancet 2011;377:813–22. 7. Smith et al. N Engl J Med 2009;361:745–55.

223Ra ( Radium-223)

Emisor alfa

Afinidad ósea por su “parecido” al Calcio

6 injections at 4-wk intervals

ALSYMPCA: Fase III Diseño

Clinicaltrials.gov. NCT00699751. Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

Randomized 2:1 and stratified by total

ALP (< vs ≥ 220 U/L), bisphosphonate use (yes vs no),

and previous docetaxel (yes vs no)

Planned follow-up: 3 yrs

Patients with:

Confirmed symptomatic

CRPC

≥ 2 bone metastases

No known visceral

metastases

Post-docetaxel or unfit

for docetaxel

(N = 921)

Radium-223 50 kBq/kg + Best Standard of Care

Placebo (saline) + Best Standard of Care

Conclusiones

Radium-223: de la paliación al aumento de supervivencia

• Radium-223 es el primer radiofármaco alfa

aprobado para el CPRC con metástasis óseas

sintomáticas

• Radium-223 aumenta la supervivencia global y

retrasa la aparición de complicaciones óseas

• Está indicado tanto en pacientes que ya hayan

recibido docetaxel como en aquellos no aptos,

frágiles o que hayan rechazado su uso

Radium-223 has now been in november 15, 2013 approved by the European Commission

Nuevos datos con Radium-223

Oliver Sartor, et al Lancet Oncology 2014: 15:738-46

Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention.

Mayor eficacia en 2 EREs: Disminución de RT y de compresión medular NO reduce con significación estadística -el riesgo de fractura patológica -la necesidad de cirugía ortopédica

Seguridad de Rsdium-223 a largo plazo

ASCO 2014 Abs # 5070

Objetivo primario: respuestas por bone scan a 24 semanas de BSLA (bone scan lesion area, medición cuantitativa similar a RECIST Objetico secundario: testar la combinación de Radium-223, abiraterona y enzalutamida

Changing treatment paradigm for mCRPC

*Not approved in Europe. ADT=androgen-deprivation therapy; EMA=European Medicines Agency; FDA=Food and Drug Administration; mCRPC=metastatic castration-resistant prostate cancer. 1. Higgins C, et al. Arch Surg 1941;43:209. 2. Taxotere (docetaxel). Prescribing information. April 2010. 3. Taxotere (docetaxel). Summary of product characteristics. August 2013. 4. Provenge (sipuleucel-T). Prescribing information. June 2011. 5. EMA Press release 28 June 2013. http://www.ema.europa.eu.

Last accessed September 2013.

1940s 1996 2004 2010 2011 2012

ADT Suppression of gonadal androgens by medical or surgical castration1

Docetaxel FDA and EMA approved for treatment of hormone-refractory metastatic prostate cancer2,3

2013

Cabazitaxel EMA approved in 2011 for hormone-refractory metastatic prostate cancer previously treated with docetaxel6

Enzalutamide FDA and EMA approved in 2012 and 2013 for treatment of men with mCRPC previously treated with docetaxel9,10

Abiraterone EMA approved for treatment of men with mCRPC previously treated with docetaxel7

6. Jevtana (cabazitaxel). Summary of product characteristics. September 2013. 7. Zytiga (abiraterone). Summary of product characteristics. August 2013. 8. Xofigo (radium 223). Prescribing information. May 2013. 9. Xtandi (enzalutamide). Summary of product characteristics. July 2013. 10. Xtandi (enzalutamide). Prescribing information. August 2012.

Sipuleucel-T FDA and EMA approved for treatment of asymptomatic or minimally symptomatic mCRPC4,5

COU-AA-301 AFFIRM TROPIC ALSYMPCA

25 meses vs 20,3 meses

16,7 meses vs 13,3 meses No evaluado 15.6 meses vs 9,8meses

HR=0,615 HR=0,69 No evaluado

HR=0,66

P=0,0001 P<0,001

No evaluado

P = 0,00037

Tiempo hasta al aparición del 1er evento esquelético

Logothetis et al. Lancet Oncol 2012: 2012; 13: 1210–17; Bahl et al. Cancer Treat Rev. 2014 Feb;40(1):170-7; Scher et al. N Engl J Med 2012;367:1187-97.

Eventos óseos en el CaP: - Fractura patológica - Compresión medular - RT paliativa - Cirugía ósea

Abiraterona: Retraso en la aparición de eventos

esqueléticos y mejoría del dolor en 2ª línea

Tiempo para SRE

Una proporción menor de pacientes tiene SRE a los 6, 12 y 18 meses en el grupo de abiraterona + prednisona versus placebo + prednisona

La tasa global de SREs ajustada para la duración de la exposición al tratamiento fue menor en el grupo de abiraterona

Abiraterona + Prednisona Placebo + Prednisona

6 meses libres de eventos 82.2% 72.1%



Logothetis et al. Lancet Oncol 2012: 2012; 13: 1210–17

TDH Abiraterona/PDN

(n=546) PDN

(n=542) Total

(N=1088)

Ácido zoledrónico 172 (31.5%) 158 (29.2%) 330 (30.3%)

Otros bifosfonatos 7 (1.3%) 8 (1.5%) 15 (1.4%)

Denosumab 16 (2.9%) 6 (1.1%) 22 (2.0%)

Otros TDH 2 (0.4%) 3 (0.6%) 5 (0.5%)

Saad et al. Impact of concomitant bone-targeted therapies (BTT) on outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) without prior chemotherapy (ctx) treated with abiraterone acetate (AA) or prednisone (P).ASCO 2013

Uso concomitante de abiraterona con terapias dirigidas al hueso (TDH) en

población general: COU-AA-302

Cortesía Dr Joan Carles

Objetivo Sí TDH,

meses (95% IC) No TDH,

meses (95% IC) Hazard ratio

(95% IC) p

SLPr 13.60 (11.04-16.43) 10.97 (10.68-12.06) 0.855 (0.718-1.018) 0.079

SG NE (30.88-NE) 30.26 (28.58-33.18) 0.754 (0.604-0.940) 0.012

Tiempo para opiáceos

NE (27.63-NE) 27.86(23.62-30.88) 0.801(0.651-0.985) 0.036

Tiempo para quimioterapia

22.41(18.46-27.07) 21.06(19.22-23.36) 0.916(0.762-1.100) 0.348

Tiempo para ↓ ECOG PS

14.26 (11.17-15.84) 11.07(9.95-11.99) 0.750(0.643-0.874) < 0.001

Tiempo para progresión PSA

8.34 (8.31-11.07) 8.31 (8.21-8.34) 0.878(0.750-1.028) 0.105

Saad et al. Impact of concomitant bone-targeted therapies (BTT) on outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) without prior chemotherapy (ctx) treated with abiraterone acetate (AA) or prednisone (P).ASCO 2013

Impacto de uso concomitante de Abiraterona con terapias dirigidas al hueso (TDH) en población

general: COU-AA-302

Cortesía Dr Joan Carles

II Prevención del desarrollo de metástasis

óseas en el cáncer de próstata

MR Smith, F Saad, R Coleman et al

Lancet 2012; 379: 39-46

http://clinicaltrials.gov/ Accessed, 13/May/2010

Prostate cancer

Randomized, Double-Blind, Placebo-controlled, Phase 3 trial

Key Eligibility Criteria

Histologically-confirmed

prostate cancer

No prior or current

radiographic evidence of

bone metastasis

Hormone refractory with

PSA

> 8 or PSA doubling time

< 10 months

No prior IV bisphosphonate

use

Denosumab 120 mg SC

Q4W

Placebo

E

N

D

O

F

S

T

U

D

Y

E

N

R

O

L

L

M

E

N

T

EOS † * Treatment Period Screening/Enrollment

N = 1400

Prevention/delay bone

metas. Prostate (20050147)

Primary Objective

– Efficacy of denosumab compared to placebo to prolong bone metastasis-free survival

Secondary Objectives

– To compare the treatment effect of denosumab with placebo on: time to first bone metastasis excluding deaths

overall survival

† Event Driven. * End Of Study, Q4W: every 4 weeks.

SC, subcutaneous; IV, intravenous

http://clinicaltrials.gov/

Key inclusion criteria

Men with castration-resistant prostate cancer

Total serum testosterone level 50 ng/dL

High risk for development of bone metastasis

– PSA value 8.0 µg/L within 3 months before randomisation,

And/or

– PSA doubling time 10.0 months

Key exclusion criteria

Radiographically detectable bone metastasis

Any metastatic involvement of distant organs (lymph node

metastases acceptable)

IV bisphosphonate administration

History or evidence of osteonecrosis or osteomyelitis of the jaw

PSA, prostate-specific antigen; IV, intravenous.

Smith MR, et al. Lancet 2012;379:3946.

Eligibility criteria

Denosumab (120 mg Q4W) is currently not approved for prevention of bone

metastases. Denosumab is investigational in that setting.

DMO-IHQ-AMG-514-2011


The primary endpoint was met: denosumab demonstrated

improved bone metastasis-free survival

Number at risk Denosumab Placebo

59 60

111 99

153 137

185 168

228 215

279 259

324 300

368 345

400 375

456 421

521 500

605 569

695 691

716 716

Month

Median survival (months) Events

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

29.5

25.2

335

370

Denosumab

Placebo

Pro

po

rtio

n o

f p

atie

nts

0.2

0.0

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 27 24 30 33 36 39 42 45

35 36



15% risk reduction


*Bone metastases that were symptomatic at the time of radiological detection.


Denosumab demonstrated improved time to

symptomatic bone metastasis*


47 51

96 94

143 130

160 142

200 189

260 242

308 293

360 347

385 368

441 411

503 474

603 565

683 667

716 716

Month

Events

HR 0.67 (95% Cl, 0.49–0.92) P = 0.01

69

96

Denosumab

Placebo

Pro

po

rtio

n o

f p

atie

nts

0.2

0.0

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 27 24 30 33 36 39 42 45



33% risk reduction



An overall survival benefit was not demonstrated


Month

HR 1.01 (95% Cl, 0.85–1.20) P = 0.91

Denosumab

Placebo

Pro

po

rtio

n o

f p

atie

nts

0.2

0.0

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 27 24 30 33 36 39 42 45

320 310

263 254

201 202

133 140

81 87

34 36

384 379

457 450

500 497

540 528

572 562

608 600

643 638

674 666

699 696

716 716




Shorter PSA Doubling Time is a Predictor of Increasing Risk for Bone Metastasis and Death

PSA Doubling Time in Months

Rela

tive R

isk f

or

Bo

ne M

eta

sta

sis

or

Death

Median

PSA DT at

study

entry

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

3.0

20 18 16 14 12 10 8 6 4 2

PSA DT

eligibility

criteria

Placebo arm, N = 716

• Placebo arm of the Denosumab study demonstrates shortening PSA doubling time as a

predictor of increasing risk for bone metastases development

• In a separate study, PSA was a key risk factor for bone metastasis and a PSADT ≤

6 months was significantly associated with shorter bone metastasis-free survival1

Smith et al (2005)

Post hoc analyses of sub-groups of Product A data

were conducted in patients with

shorter PSA doubling time

Denosumab is markedly effective at prolonging bone metastasis free survival in patients with shorter PSA doubling times

Population Median BMFS time:

Placebo (mo)

Median delay to

bone met: Product A

(mo)

Crude incidence reduction

(%)

Hazard Ratio P-value

Overall (N = 1,432)

25.2 4.2 4.9 0.85 0.028

≤10 month PSA DT (~80% of pop)

22.4 6.0 5.7 0.84 0.042


18.7 7.2 9.7 0.77 0.006


18.3 7.5 10.7 0.71 0.004

The median bone metastasis–free survival continues to improve with increasing

risk (as determined by reducing PSA doubling time)

The first large randomised study to demonstrate that

targeting the bone microenvironment can prevent bone

metastasis in men with prostate cancer

Denosumab significantly increased bone metastasis-

free survival and time to symptomatic bone

metastasis

Overall adverse events were similar between groups

– Denosumab was associated with increased incidence

of osteonecrosis of the jaw and hypocalcaemia vs placebo

This study provides clinical evidence for the important

role of the bone microenvironment and RANKL signaling

in the development of bone metastases in men with

prostate cancer RANK, receptor activator of nuclear factor κ B ligand.


Summary




GUIAS ESMO 2014

A: unánimemente recomendado B: generalmente recomendado

Cabozantinib es un nuevo inhibidor tirosin-quinasa que inhibe el c-Met,

el factor de crecimiento hepatocitario y VEGFR-2, receptor del factor de crecimiento

vásculo-endolelial 2.

Nuevos agentes en el CPRC con metastasis óseas

2 estudios fase III en marcha: el COMET-2 (CabOzantinib MET Inhibition CRPC Efficacy Trial) que enfrenta cabozantinib con mitoxantrone y prednisona y que ya ha demostrado cumplir un objetivo principal de reducción del dolor [ClinicalTrials.gov: NCT01522443]; y el COMET-1, [ClinicalTrials.gov identifier: NCT01605227],

Dasatinib es un inhibidor de tirosinquinasa que actúa sobre Src, mediador de

actividad osteoclástica, del crecimiento tumoral y del desarrollo de metástasis

DC Smith, et al J Clin Oncol 2013; 31(4): 412-419.

Araujo DC, et al Cancer 2012; 118:63-71

Conclusions:

Cabozantinib has clinical activity in men with CRPC,

including reduction of soft tissue lesions,

improvement in PFS, resolution of bone scans and

reductions in bone turnover markers, pain and narcotic use

Pendiente de los fases III

COMET-1 y COMET-2

Conclusiones enfermedad óseas en CPRC

1. Denosumab más eficaz que ácido zoledrónico en la

prevención de EREs

2. Radium-223 retrasa el desarrollo de EREs y aumenta la

supervivencia en pacientes con sólo metástasis óseas

sintomáticas.

3. Los agentes aprobados en CPRC también reducen o

retrasan los EREs, si bien datos iniciales favorecen su

combinación con las terapias dirigidas al hueso.

4. Denosumab retrasa el desarrollo de metástasis óseas en

pacientes con CPRC de alto riesgo ( PSADT < 10 ó menos

meses)

BACK UP

60


Secondary endpoint was met: denosumab

demonstrated improved time to first bone metastases


44 50

94 91

141 127

156 139

196 184

254 234

305 286

355 336

379 359

432 402

497 466

582 549

683 667

716 716

Month

Median time (months) Events

HR 0.84 (95% Cl, 0.71–0.98) P = 0.032

33.2

29.5

286

319

Denosumab

Placebo

Pro

po

rtio

n o

f p

atie

nts

0.2

0.0

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 27 24 30 33 36 39 42 45



16% risk reduction


Conclusiones

Radium-223: de la paliación al aumento de supervivencia

• Radium-223 presenta un excelente perfil de

seguridad, lo que permite estudiar su

combinación con otros agentes terapéuticos

en el CPRC

• Radium-223 ha sido aprobado el 15 de

noviembre de 2013 por la EMA para el

tratamiento del CPRC con metástasis óseas

sintomáticas

Conclusions from ALSYMPCA

In CRPC patients with bone metastases

• Radium Ra 223 dichloride significantly prolonged overall survival

– 14.9 months vs. 11.3 months placebo (P = 0.00007; HR 0.695, 95% CI 0.581–0.832)

• Radium Ra 223 dichloride significantly prolonged time to first SRE

– 12.2 months vs. 6.7 months placebo

(P < 0.0001; HR = 0.64 [95% CI: 0.52–0.78])

• Radium Ra 223 dichloride was very well tolerated

Radium Ra 223 dichloride may provide a new standard of care for the treatment of CRPC patients with bone metastases

Penetration of Ionizing Radiation Types

Paper Aluminum Lead or concrete

α

β

γ

α-Radiation consists of helium (4He) nuclei and is stopped by a sheet of paper or skin

β-Radiation, consisting of electrons, is halted by an aluminum plate or plastic

γ-Radiation, consisting of energetic photons, is only attenuated by dense material

Características Físicas

Rotura simple Reparables Baja letalidad

Rotura doble Apoptosis Alt. Mitótica Fase G0

Cortesía Dra. Méndez

Summary

• Denosumab was superior to zoledronic acid in delaying the time to

• First SRE

• First and subsequent SRE(s)

• Notable adverse events occurring in both treatment

groups included ONJ and hypocalcemia

• Hypocalcemia was more frequent in the denosumab arm

• Incidence of ONJ was similar between arms and not statistically

significantly different

• Denosumab had several select attributes

• Administered as a 120 mg SC injection once every 4 weeks

• No dose adjustment necessary for patients with renal impairment

• Fewer acute phase reactions in the denosumab arm

Fizazi K, Carducci M, Smith M, et al. Lancet 2011;377:813-22.

Phase 3

20050103

Fizazi 2011 Lancet 377, 813-22.pdf





SREs

Abiraterona + Prednisona (n=797)

Placebo + Prednisona (n=398)

Total de pts con SREs Uno Dos Tres

22.6% 17.2% 4.4% 1.0%

24.6% 18.6% 5.0% 1.0%

Total número de SREs Radiación ósea Fractura patológica Cirugía en el hueso Compresión del núcleo espinal

235 61.7% 15.3% 4.3%

19.1%

130 70.8% 6.2% 1.5%

21.5%

Tasa SRE por 100 pacientes-año de exposición

Radiación ósea Fractura patológica Cirugía en el hueso Compresión del núcleo espinal

38.9% 24.0% 6.0% 1.7% 7.3%

65.1% 46.1% 4.0% 1.0%

14.0%

Investigación adicional necesaria para evaluar si el tratamiento con abiraterona podría estar asociado con

un mayor riesgo de fracturas patológicas (números pequeños en este estudio)

Logothetis et al. Lancet Oncol 2012: 2012; 13: 1210–17

Different Classes of Ionizing Radiation

Radiation Type Composition Range in Air

Alpha α Helium nuclei A few inches (several centimeters)

Beta β Electrons Several feet (many centimeters)

Gamma γ Electromagnetic waves (photons)

Many yards (many meters)

Radiation ranges (ie, distances over which energy is deposited):

γ >> β > α

223RaCl2 Datos generales

Vida media 11, 4 días

Detectable con equipos convencionales

No residuos radioactivos de larga vida

223RaCl2 Conclusiones

Agente emisor alfa con tropismo óseo

Baja irradiación de médula ósea y otros tejidos

Fácil manejo y administración

Pacientes ambulatorios

75

BC1-03 (n = 100)1 CRPC with painful bone metastases

Single doses: 5, 25, 50 or 100 kBq/kg

Overview of Phase II/III Clinical Development to Date

BC1-04 (n = 122)2 CRPC with bone metastases

Multiple doses: 3 x 25, 50 or 80 kBq/kg at 6-week intervals

BC1-02 (n = 64)3,4 CRPC with bone metastases

requiring EBRT Multiple doses: 4 x 50 kBq/kg or placebo

at 4-week intervals

ALSYMPCA5 Randomized Phase III Study

EBRT, external beam radiation therapy 1. Nilsson S, et al. Eur J Can Supp 2009;7:409 Abstract 7011. 2. Parker C, et al. Eur J Can Supp 2009;7:406 Abstract 7003. 3. Nilsson S, et al. Lancet Oncol. 2007;8(7):587-594. 4. Nilsson S, et al. Eur J Cancer Suppl. 2009;7:412 P-7018 5. www.clinicaltrials.gov. NCT00699751

Healthcare costs (US) in patients with prostate cancer:

Increased costs due to treatment of metastatic disease

and occurrence of SREs*1

Bone metastases in prostate cancer have a significant impact on healthcare costs

$16,998

*Footnote: Retrospective cohort study of 215,702 PC patients using claims data from large, US health insurance plans between Oct 2002 and Dec

2007. Primary measure was total healthcare costs after bone metastases, secondary measures included components of total healthcare costs

1. Data on file, 2011; 2. Oglesby et al. 2009

Preventing development of bone metastases in prostate cancer patients

would result in substantial reduction of costs

42%

• Development of bone metastasis is associated with increased health resource utilization which leads to greater costs in:

Hospital inpatient care

Outpatient care including physician visits

Outpatient pharmacy

• These costs are conservative, and do not include newer therapies

• A separate study demonstrated a 91% increase in the risk of hospitalization after development of bone mets2

BMFS (Jan2012)

Etapas en el desarrollo de las metástasis óseas

1Eastern Cooperative Oncology Group. † Event Driven. * End Of Study.

http://clinicaltrials.gov/ct2/show/NCT00321620?term=denosumab+prostate+zoledronate&rank=1 , Accessed 28/April/10

http://www.amgen.com/media/media_pr_detail.jsp?year=2010&releaseID=1385163, Accessed 28/April/10

Prostate cancer Randomized, Double-Blind, Active-Controlled study, phase 3 trial

Key Eligibility Criteria

• Adult histologically

confirmed prostate cancer

• Prior or current

radiographic evidence of at

least 1 bone metastasis

• Documented failure of at

least one hormonal agent,

evidenced by rising PSA

• Serum testosterone < 50

ng/dL

• ECOG1 performance status

of 0, 1, or 2

• No prior or current IV

bisphosphonate use

Denosumab 120 mg SC

+

Placebo IV

infusion over 15 minutes

Q4W

Placebo SC

+

Zoledronic acid 4 mg IV

infusion over 15 minutes

Q4W

E

N

D

O

F

S

T

U

D

Y

E

N

R

O

L

L

M

E

N

T

EOS † * Study Week

Treatment Period Screening/Enrollment

N = 1901


SRE, Skeletal Related Event; Q4W, Every 4 weeks; IV, intravenous; SC, Subcutaneous


http://www.amgen.com/media/media_pr_detail.jsp?year=2010&releaseID=1385163

Denosumab is markedly effective at prolonging bone metastasis free survival in patients at higher risk of developing bone mets

Denosumab

[n=419]

PLACEBO

[n=427]

Median time:

25.9 months

Median time:

18.7 months

7.2 MONTHS

N = Number of subjects randomized with baseline PSA doubling time <6 months

23% RISK

REDUCTION

HR:0.77 (95% CI: 0.64, 0.93)

p=0.0064

• Patients with PSADT ≤ 6 months constitute 60% of the Product A trial population

• Median bone metastasis–free survival in the placebo group with PSADT ≤ 6 months (18.7

months) was 6.5 months shorter than for the placebo group in the full population (25.2

months), indicating that these men are at particularly high risk

Bone Metastasis-Free Survival in Patients with PSA Doubling Time (PSADT) ≤ 6

Months

Post Hoc Analysis

223RaCl2 Mecanismo de acción

Administración intravenosa

Forma complejos con la Hidroxiapatita

(Ca10(PO4)6(OH)2) en áreas de elevado turn-over óseo (metastasis óseas )

40-60% dosis administrada se

localiza en esqueleto

Escasa redistribución extraósea

Escasa exposición de médula ósea

Prior docetaxel use NO prior docetaxel use

ALSYMPCA OS : Prior Docetaxel Use

Radium-223 352 327 238 155 88 45 27 5 1 0 0

Placebo 174 152 104 61 35 15 5 4 1 1 0

Radium-223, n = 352 Median: 14.4 months

Placebo, n = 174 Median: 11.3 months

HR = 0.710 95% CI, 0.565, 0.891 P = 0.00307



HR = 0.745 95% CI, 0.562, 0.987 P = 0.03932

100

90

80

70

60

50

40

30

20

10

0 0 4 8 12 16 20 24 28 32 36 40 Month

%

Radium-223 262 236 168 119 70 31 14 7 1 0

Placebo 133 113 74 42 24 14 9 3 1 0

100

90

80

70

60

50

40

30

20

10

0 0 4 8 12 16 20 24 28 32 36

%

Month

Current bisphosphonate use NO current bisphosphonate use



HR = 0.699 95% CI, 0.525, 0.931 P = 0.01378



HR = 0.736 95% CI, 0.587, 0.923 P = 0.00775

ALSYMPCA Updated Analysis OS by Stratification Variables: Bisphosphonate Use

Radium-223 364 331 235 159 97 50 27 6 0 0 0

Placebo 183 155 102 58 33 16 10 6 2 1 0

100

90

80

70

60

50

40

30

20

10

0 0 4 8 12 16 20 24 28 32 36 40

Radium-223 250 232 171 115 61 26 14 6 2 0

Placebo 124 110 76 45 26 13 4 1 0 0

100

90

80

70

60

50

40

30

20

10

0 0 4 8 12 16 20 24 28 32 36

% %

Month Month

ALSYMPCA SG y Fosfatasa alcalina basal

Total ALP < 220 U/L Total ALP ≥ 220 U/L



HR = 0.825 95% CI, 0.635, 1.072 P = 0.14945



HR = 0.619 95% CI, 0.486, 0.788 P = 0.00009

Radium-223 266 238 160 95 51 24 10 3 0 0 0

Placebo 138 114 63 28 15 9 3 2 1 1 0

100

90

80

70

60

50

40

30

20

10

0 0 4 8 12 16 20 24 28 32 36 40

Radium-223 348 325 246 179 107 52 31 9 2 0

Placebo 169 151 115 75 44 20 11 5 1 0

100

90

80

70

60

50

40

30

20

10

0 0 4 8 12 16 20 24 28 32 36

% %

Month Month

Trial profile

CPRC: enfoque terapéutico de la enfermedad ósea · 2014. 6. 19. · targets the lumbar spine,...

Documents

Transcript of CPRC: enfoque terapéutico de la enfermedad ósea · 2014. 6. 19. · targets the lumbar spine,...