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Denosumab en cáncer de próstata avanzado . Begoña Mellado Servicio de Oncología Médica Hospital Clinic. Barcelona. Indicaciones de Denosumab aprobadas en metástasis óseas . EMA, 19 May 2011

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denosumab en c ncer de pr stata avanzado
Denosumab en cáncer de próstata avanzado

Begoña Mellado

Servicio de Oncología Médica

Hospital Clinic. Barcelona

indicaciones de denosumab aprobadas en met stasis seas
Indicaciones de Denosumab aprobadas en metástasis óseas

EMA, 19 May 2011

The approved indication is: “Prevention of skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours”.

www.ema.europa.eu/docs/en_GB/document.../WC500106521.pdf

denosumab en c ncer de pr stata avanzado1
Denosumab en cáncer de próstata avanzado
  • Mecanismo de acción y características farmacológicas
  • de denosumab
  • Espectro del problema
  • Ensayos clave
  • Efecto anti-tumoral
  • Prevención de metástasis
denosumab
Denosumab

Bekker PJ, et al. J Bone Miner Res 2004;19:1059-66.

Elliott R, et al. Osteoporos Int 2007;18:S54. Abstract P149.

McClung MR, et al. New Engl J Med 2006;354:821-31.

Anticuerpo monoclonal totalment humanizado anti – RANK-L

Immunoglobulina tipo IgG2

Alta afinidad

Alta especificidad

No unión a TNFα, TNFβ, TRAIL o CD40L

No anticuerpos neutralizantes han sido detectados en los ensayos clínicos hasta el momento.

rankl madura y activa los osteoclastos
RANKL madura y activa los osteoclastos

RANK Ligand

RANK

Pre-fusionosteoclast

CFU-GM

M-CSF

Multinucleatedosteoclast

HormonesGrowth factors

Cytokines

Activated osteoclast

Osteoblasts

Bone formation

CFU-GM = colony forming unit granulocyte macrophage

M-CSF = macrophage colony stimulating factor.

Bone resorption

Adapted from Boyle WJ, et al. Nature 2003;423:337-42.

denosumab bloquea rankl y la activaci n de osteoclastos
Denosumab bloquea RANKL y la activación de osteoclastos

RANK Ligand

RANK

Pre-fusionosteoclast

CFU-GM

M-CSF

Multinucleatedosteoclast

HormonesGrowth factors

Cytokines

Activated osteoclast

Osteoblasts

Bone formation

CFU-GM = colony forming unit granulocyte macrophage

M-CSF = macrophage colony stimulating factor.

Bone resorption

Adapted from Boyle WJ, et al. Nature 2003;423:337-42.

c rculo vicioso de pogresi n de las met stasis seas
Círculo vicioso de pogresión de las metástasis óseas

RANK Ligand

RANK

OPG

Tumour cell

PTHrP, BMPs,TGF-β, IGF, FGF,VEGF, ET-1, WNT

PDGF, BMPs

TGF-β, IGFs

FGFs

Ca2+

Activated osteoclast

Osteoblasts

Adapted from Roodman D. NEJM 2004;350:1655.

denosumab romperia el c rculo vicioso de pogresi n de las met stasis seas
Denosumab romperia el círculo vicioso de pogresión de las metástasis óseas

RANK Ligand

RANK

OPG

Tumour cell

PTHrP, BMPs,TGF-β, IGF, FGF,VEGF, ET-1, WNT

PDGF, BMPs

TGF-β, IGFs

FGFs

Ca2+

Activated osteoclast

Osteoblasts

Adapted from Roodman D. NEJM 2004;350:1655.

denosumab caracter sticas farmacol gicas
Denosumab: características farmacológicas
  • Biodisponibilidad próxima al 100%
  • Vida media 25-46 días
  • No precisa ajustar dosis por la función renal
denosumab en c ncer de pr stata avanzado2
Denosumab en cáncer de próstata avanzado
  • Mecanismo de acción de denosumab
  • Espectro del problema
  • Ensayos clave
  • Efecto anti-tumoral
  • Prevención de metástasis
eventos esquel ticos se asocian a un riesgo aumentado de muerte en c ncer de pr stata
Eventos esqueléticos se asocian a un riesgo aumentado de muerte en cáncer de próstata

1

No SREs

One or more SREs

0.9

0.8

0.7

0.6

Probability

0.5

0.4

0.3

0.2

0.1

0

0

90

180

270

360

Survival (days)

SRE, skeletal related event

dePuy, et al. Support Care Cancer 2007;15:869–76.

denosumab en c ncer de pr stata avanzado3
Denosumab en cáncer de próstata avanzado
  • Mecanismo de acción de denosumab
  • Espectro del problema
  • Ensayos clave
  • Efecto anti-tumoral
  • Prevención de metástasis
slide14

Denosumab reduce marcadores de actividad ósea en pacientes con metástasis

óseas con tratamiento previo con bifosfonatos

Fase II aleatorizado

Pacientes con cáncer con > 1 M1 ósea y niveles de uNTx > 50 nmol/L a pesar de tratamiento previo con bifosfonatos

N= 111 pts (50% c de próstata)

Reducción uNTx < 50nmol/L

71% (D) vs 29%(Z), p<0.01

SREx 7% (D) vs 10% (Z)

Fizazi K et al. JCO 2009;27:1564-1571

slide15
Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study

Fizazi k et al.

Lancet. 2011 March 5; 377(9768): 813–822. doi:10.1016/S0140-6736(10)62344-6.

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

*Per protocol and Zometa® label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine.

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

baseline characteristics
Baseline Characteristics

IQR = interquartile range.

ECOG = Eastern Cooperative Oncology Group.

PSA = prostate-specific antigen.

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

slide18
Fizazi K, et al. Lancet. 2011;377:813–822.

Denosumab retrasa la aparición del primer evento óseo

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

P = 0.008 (superiority)

1.00

Risk reduction

18%

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

0

3

6

9

12

15

18

21

24

27

Study Month

Patients at Risk:

slide19
*Events occurring at least 21 days apart.

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

Denosumab reduce la aparición del primero y subsecuentes eventos óseos

2.0

Rate ratio = 0.82 (95% CI, 0.71–0.94)

P = 0.009 (superiority)

1.8

Risk reduction

18%

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

Zoledronic acid

584

0.0

0

3

6

9

12

15

18

21

24

27

30

33

36

Study Month

osteonecrosis mandibular
Osteonecrosis mandibular

ONJ, osteonecrosis of the jaw

*As of April 2010.Fizazi K, et al. Lancet. 2011;377:813–822.

slide23
Fizazi K, et al. Lancet. 2011;377:813–822.

No observaron diferencias en la evolución de PSA, supervivencia libre de progresión o supervivencia global (análisis exploratorio)

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

0

3

6

9

12

15

18

21

24

27

30

Study Month

Patients at Risk:

denosumab en c ncer de pr stata avanzado4
Denosumab en cáncer de próstata avanzado
    • Mecanismo de acción de denosumab
    • Espectro del problema
    • Ensayos clave
    • Efecto anti-tumoral
  • Prevención de metástasis
slide25

RANK se expresa en células tumorales

RANK SE EXPRESA EN CELULAS TUMORALES

Jones, Nature 2006

rank rankl en c ncer de mama
RANK/RANKL en cáncer de mama

Gonzalez Suarez, Clin Trasl Oncol 2011

rank l induce la expresi n de genes implicados en el desarrollo de met stasis
RANK-L induce la expresión de genes implicados en el desarrollo de metástasis

Amstrong, 2005

denosumab en c ncer de pr stata avanzado5
Denosumab en cáncer de próstata avanzado
    • Mecanismo de acción de denosumab
    • Espectro del problema
    • Ensayos clave
    • Efecto anti-tumoral
  • Prevención de metástasis
slide31

Denosumab vs placebo in non-metastatic CRPC

R A N D O M

I

S A T

I O N

Phase III Study 147

Denosumab

120 mg SC Q4W

  • Key eligibility criteria
  • CRPC with PSA >8ng/ml or PSA doubling time <10 months
  • No bone metastases
  • No prior IV bisphosphonate use

PlaceboSC Q4W

N=1435

  • Primary endpoint: Time to first occurrence of bone metastases or death from any cause
  • Secondary endpoints: Time to first occurrence of bone metastasis (excluding death), overall survival

Smith MR, Saad F, Coleman R, et al. Presented at: American Urological Association Annual Meeting; May 14 –19, 2011; Washington, DC.

Denosumab (120 mg Q4W) is not approved in the EU for use in patients with advanced cancer to treat or delay bone metastases. Denosumab is investigational in that setting.

Amgen Press Release December 13th, 2010 . http://www.amgennews.com/index.php/article/274/ Fecha acceso 12 Abril 11

baseline characteristics1
Baseline characteristics

PSA (prostate specific antigen); PSADT (PSA doubling time)

Smith MR, Saad F, Coleman R, et al. Oral Plenary Session, May 2011, AUA Annual Meeting 2011 Washington, D.C.

Denosumab (120 mg Q4W) is currently not approved outside the US. Denosumab is investigational in that setting.

patient disposition at time of analysis
Patient disposition at time of analysis

Randomised patients

1432*

Placebo

716

Denosumab

716

Discontinued, n (%)

Bone metastasis 297 (41.5)

Consent withdrawn 92 (13)

Death 53 (7.4)

Disease progression** 22 (3)

Adverse event 25 (3)

Other± 63 (9)

Discontinued, n (%)

Bone metastasis 247 (34.5)

Consent withdrawn 100 (14)

Death 56 (7.8)

Disease progression** 36 (5)

Adverse event 36 (5)

Other± 67 (9)

On study

164 (23%)

On study

174 (24%)

*Does not include three patients with insufficient IRB (international review board) oversight

**Not in bone

±Administrative decision, noncompliance, lost to follow-up, protocol deviation, ineligibility determined

Smith MR, Saad F, Coleman R, et al. Oral Plenary Session, May 2011, AUA Annual Meeting 2011 Washington, D.C.

Denosumab (120 mg Q4W) is currently not approved outside the US. Denosumab is investigational in that setting.

bone metastasis free survival
Bone metastasis-free survival

1.0

HR = 0.85 (95% CI 0.73, 0.98)

P = 0.028

0.8

0.6

Proportion of patients

0.4

0.2

Median months

Events

25.2

370

Placebo

Denosumab

29.5

335

0.0

0

3

6

9

12

15

18

21

24

27

30

33

36

39

42

Study month

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, Saad F, Coleman R, et al. Oral Plenary Session, May 2011, AUA Annual Meeting 2011 Washington, D.C.

Denosumab (120 mg Q4W) is currently not approved outside the US. Denosumab is investigational in that setting.

time to symptomatic bone metastasis
Time to symptomatic bone metastasis*

HR = 0.67 (95% CI 0.49, 0.92)

P = 0.01

1.0

0.8

0.6

Proportion of patients

0.4

0.2

Events

96

Placebo

Denosumab

69

0.0

0

3

6

9

12

15

18

21

24

27

30

33

36

39

Study month

*Confirmed bone metastasis reported as symptomatic

Placebo

716

667

565

474

411

368

347

293

242

189

142

130

94

51

Denosumab

716

683

603

503

441

385

360

308

260

200

160

143

96

47

Smith MR, Saad F, Coleman R, et al. Oral Plenary Session, May 2011, AUA Annual Meeting 2011 Washington, D.C.

Denosumab (120 mg Q4W) is currently not approved outside the US. Denosumab is investigational in that setting.

slide36

Studies of bone-targeted agents for bone metastases prevention in prostate cancer

Denosumab (120 mg Q4W) is not approved in the EU for use in patients with advanced cancer to delay SREs. Denosumab is investigational in that setting.

1. Mason, et al. J Natl Cancer Inst 2007;16;99:744–5; 2. Dearnaley, et al. Lancet Oncol 2009;10:872–6; 3. Smith, et al. J Clin Oncol 2005;23:2918–5; 4. Nelson et al. Cancer 2008; 113:2478–87 5. AstraZeneca Press Release February 7th, 2011; 6. Smith MR et al. Presented at: American Urological Association Annual Meeting; May 14 –19, 2011; Washington, DC.

ZOL, zoledronic acid;PCa, prostate cancer;OS, overall survival; QoL, quality of life

conclusiones
Conclusiones
  • Denosumab reduce el riesgo de eventos esqueléticos frente ácido zoledrónico en cáncer de próstata mestastásico
  • Denosumab está aprobado por la FDA y EMA en esta indicación, ofreciendo una opción novedosa para mejorar la calidad de vida de los pacientes.

3. Denosumab retrasa la aparición de metastásis óseas en pacientes con recidiva bioquímica resistente a la castración