Denosumab en cáncer de próstata avanzado Begoña Mellado Servicio de Oncología Médica Hospital Clinic. Barcelona

Denosumab en cáncer de próstata avanzado

Begoña MelladoServicio de Oncología MédicaHospital Clinic. Barcelona

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

Mecanismo de acción y características farmacológicasde denosumab

Espectro del problema

Ensayos clave

Efecto anti-tumoral

Prevención de metástasis


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.

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.

RANKL madura y activa los osteoclastos

Osteoblasts

Activated osteoclast

CFU-GM Pre-fusionosteoclast

Multinucleatedosteoclast

HormonesGrowth factorsCytokines

RANK Ligand

RANK

Bone formation

Bone resorption

M-CSF

CFU-GM = colony forming unit granulocyte macrophageM-CSF = macrophage colony stimulating factor.Adapted from Boyle WJ, et al. Nature 2003;423:337-42.

Denosumab bloquea RANKL y la activación de osteoclastos

Osteoblasts


CFU-GM Pre-fusionosteoclast

Multinucleatedosteoclast

HormonesGrowth factorsCytokines

RANK Ligand

RANK

Bone formation

Bone resorption

M-CSF

CFU-GM = colony forming unit granulocyte macrophageM-CSF = macrophage colony stimulating factor.Adapted from Boyle WJ, et al. Nature 2003;423:337-42.

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

Osteoblasts


PDGF, BMPsTGF-β, IGFs

FGFs

RANK Ligand

RANK

OPGTumour cell

Círculo vicioso de pogresión de las metástasis óseas

Ca2+

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

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

Osteoblasts


PDGF, BMPsTGF-β, IGFs

FGFs

RANK Ligand

RANK

OPGTumour cell

Denosumab romperia el círculo vicioso de pogresión de las metástasis óseas

Ca2+

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

Denosumab se une RANK-L y no se acumula en hueso

Efecto reversible

Denosumab: características farmacológicas

– Biodisponibilidad próxima al 100%

– Vida media 25-46 días

– No precisa ajustar dosis por la función renal

Mecanismo de acción de denosumab


Ensayos clave

Efecto anti-tumoral



Eventos esqueléticos se asocian a un riesgo aumentado de muerte en cáncer de próstata

SRE, skeletal related eventdePuy, et al. Support Care Cancer 2007;15:869–76.

00

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

11

Pro

babi

lity

Pro

babi

lity

00 9090 180180 270270 360360

Survival (days)Survival (days)

No SREsOne or more SREsNo SREsOne or more SREs



Ensayos clave

Efecto anti-tumoral



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

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)

Denosumab reduce marcadores de actividad ósea en pacientes con metástasisóseas con tratamiento previo con bifosfonatos

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.

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

N = 950 denosumab 120 mg SC and placebo IV Q4W

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.

Primary Endpoint• Time to first on-study skeletal-related event (SRE)

(noninferiority)

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

Baseline Characteristics

IQR = interquartile range.ECOG = Eastern Cooperative Oncology Group.PSA = prostate-specific antigen.Fizazi K, et al. Lancet. 2011;377:813–822.

CharacteristicDenosumab

(N = 950)

Zoledronic Acid

(N = 951)

Median age, years (IQR) 71 (64–77) 71 (66–77)

ECOG performance status of 0 or 1, n (%) 882 (93) 886 (93)

Stratification Factors

PSA at randomisation 10 g/L, n (%) 805 (85) 806 (85)

Recent chemotherapy ( 6 weeks before randomisation), n (%)

132 (14) 132 (14)

Previous SRE, n (%) 232 (24) 231 (24)

Median time from diagnosis of bone metastasis to randomisation, months (IQR)

3.94 (1.22–15.67)

5.19 (1.31–16.10)


0.00

1.00

Pro

por

tion

of S

ubj

ects

With

out

SR

E

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

Kaplan-Meier Estimate of Median Months

DenosumabZoledronic acid

20.717.1

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

Study MonthPatients at Risk:

Zoledronic acid 951 733 544 407 299 207 140 93 64 47Denosumab 950 758 582 472 361 259 168 115 70 39

18%Risk reduction

Denosumab retrasa la aparición del primer evento óseo

*Events occurring at least 21 days apart.Fizazi K, et al. Lancet. 2011;377:813–822.

Rate ratio = 0.82 (95% CI, 0.71–0.94)

0.0

2.0

Cum

ula

tive

Mea

n N

umb

er o

f S

RE

s pe

r P

atie

nt

0.2

0.6

1.0

1.4

1.8

0.4

0.8

1.2

1.6

Denosumab

Zoledronic acid 584584494494

Events

P = 0.009 (superiority)

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

18%Risk reduction

Denosumab reduce la aparición del primero y subsecuentes eventos óseos

Patient IncidenceDenosumab

(N = 943)n (%)

Zoledronic Acid(N = 945)

n (%)

Any adverse event (AE) 916 (97) 918 (97)

Most Common AEs in Either Arm

Anaemia 337 (36) 341 (36)

Back pain 304 (32) 287 (30)

Decreased appetite 267 (28) 274 (29)

Nausea 272 (29) 245 (26)

Fatigue 257 (27) 222 (23)

CTCAE grade 3 or 4 AEs 678 (72) 628 (66)

Serious AEs 594 (63) 568 (60)

AEs leading to treatment discontinuation 164 (17) 138 (15)

Summary of Adverse Events

Summary of Adverse Events (continued)

Patient IncidenceDenosumab

(N = 943)n (%)

Zoledronic Acid (N = 945)

n (%)

Infectious AEs* 402 (43) 375 (40)

Acute phase reactions (first 3 days) 79 (8) 168 (18)

Renal AEs† 139 (15) 153 (16)

Cumulative rate of osteonecrosis of the jaw (ONJ)‡ 22 (2) 12 (1)

Year 1 10 (1) 5 (1)

Year 2 22 (2) 8 (1)

Hypocalcaemia 121 (13) 55 (6)

New primary malignancy 18 (2) 10 (1)

Patient Incidence Denosumabn (%)

Zoledronic Acidn (%)

Patients with positively adjudicated ONJ 22 (2) 12 (1)

Risk Factors

Tooth extraction, dental appliance, or poor oral hygiene

17 (77) 10 (83)

Chemotherapy 14 (64) 9 (75)

Treatment*

Limited surgery (eg, debridement) 10 (45) 3 (25)

Bone resection 2 (9) 1 (8)

Osteonecrosis mandibular

ONJ, osteonecrosis of the jaw

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


HR = 1.03 (95% CI, 0.91–1.17)P = 0.65

0.00

Pro

por

tion

of P

atie

nts

Sur

vive

d

0 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

30

No observaron diferencias en la evolución de PSA, supervivencia libre de progresión o supervivencia global

(análisis exploratorio)



Ensayos clave

Efecto anti-tumoral



RANK SE EXPRESA EN CELULAS TUMORALESRANK se expresa en células tumorales

Jones, Nature 2006

RANK/RANKL en cáncer de mama

Gonzalez Suarez, Clin Trasl Oncol 2011

RANK-L induce la expresión de genes implicados en el desarrollo de metástasis

Amstrong, 2005



Ensayos clave

Efecto anti-tumoral



Phase III Study 147

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.

• 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

Key eligibility criteria• CRPC with PSA >8ng/ml or

PSA doubling time <10 months• No bone metastases• No prior IV bisphosphonate use

R A N D O MIS A TI O N

N=1435

Denosumab120 mg SC Q4W

PlaceboSC Q4W

Denosumab vs placebo in non-metastatic CRPC

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

http://www.amgennews.com/index.php/article/274/

Baseline characteristics

Characteristic, n (%) or medianPlacebo

(n = 716)Denosumab

(n = 716)

Age, years 74.0 74.0

Time from diagnosis to study entry, years

6.10 6.10

PSA, ng/mL 12.5 12.2

PSA ≥8 ng/mL and PSADT ≤10 months 346 (48.3) 346 (48.3)

Prior chemotherapy 55 (7.7) 55 (7.7)

Duration of prior ADT, years 3.9 3.9

Local therapy 331 (46.2) 313 (43.7)

Gleason score at diagnosis

≤7 432 (60.3) 404 (56.4)

8–10 214 (29.9) 237 (33.1)

ECOG performance status ≤1 713 (99.6) 715 (99.9)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.

Denosumab716

Placebo716

Randomised patients1432*

*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

On study164 (23%)

On study174 (24%)

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)

Patient disposition at time of analysis



Bone metastasis-free survival

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

Study month

PlaceboDenosumab

0.0

0.2

0.4

0.6

0.8

1.0

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

Median months

25.229.5

Events

370335

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

Pro

port

ion

of p

atie

nts



Time to symptomatic bone metastasis*

*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 47

Study month

PlaceboDenosumab

0.0

0.2

0.4

0.6

0.8

1.0

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

Events

9669

HR = 0.67 (95% CI 0.49, 0.92)P = 0.01

Pro

port

ion

of p

atie

nts

96



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

Study Patients Treatment arms Selected endpointsResults/ Status

MRC PR041,2 M0; T24; WHO PS 02 Clodronate vs placeboTime to symptomatic bone mets or PCa death, OS

Primary not met

Smith et al 20053

M0 CRPC; rising PSA despite ADT

ZOL vs placeboTime to first bone mets, OS, bone mets-free survival

Terminated early

Nelson et al 20084

M0 CRPC; rising PSA despite ADT (20, 50% in 6 mo, or rising in 12 mo)

Atrasentan vs placeboTime to first mets, PSA progression, OS, bone mets-free survival, PSA doubling time

Primary not met

Enthuse M05 M0 CRPC; rising PSA despite ADT

Zibotentan 10 mg vs placebo

Progression-free survival, OSTerminated early

Smith et al 2011. Study 1476

M0 CRPC with PSA>8ng/ml or PSA doubling time <10 mo

Denosumab 120 mg SC Q4W vs placebo

Time to first bone mets or death from any cause; time to first bone mets, OS

Positive data reported

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.

Conclusiones

1. Denosumab reduce el riesgo de eventos esqueléticos frente ácido zoledrónico en cáncer de próstata mestastásico

2. 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

Documents

Denosumab en cáncer de próstata avanzado Begoña Mellado Servicio de Oncología Médica Hospital Clinic. Barcelona