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
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 cáncer de próstata avanzado
Mecanismo de acción y características farmacológicas
de denosumab
Espectro del problema
Ensayos clave
Efecto anti-tumoral
Prevención de metástasis
Denosumab
 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.
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
Pre-fusion
osteoclast
CFU-GM
RANK Ligand
RANK
M-CSF
Multinucleated
osteoclast
Hormones
Growth factors
Cytokines
Osteoblasts
Activated
osteoclast
Bone formation
CFU-GM = colony forming unit granulocyte macrophage
M-CSF = macrophage colony stimulating factor.
Adapted from Boyle WJ, et al. Nature 2003;423:337-42.
Bone resorption
Denosumab bloquea RANKL y la activación de
osteoclastos
Pre-fusion
osteoclast
CFU-GM
RANK Ligand
RANK
M-CSF
Multinucleated
osteoclast
Hormones
Growth factors
Cytokines
Osteoblasts
Activated
osteoclast
Bone formation
CFU-GM = colony forming unit granulocyte macrophage
M-CSF = macrophage colony stimulating factor.
Adapted from Boyle WJ, et al. Nature 2003;423:337-42.
Bone resorption
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 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 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
Denosumab en cáncer de próstata avanzado
Mecanismo de acción de denosumab
Espectro del problema
Ensayos clave
Efecto anti-tumoral
Prevención de metástasis
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
Probability
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
90
180
Survival (days)
SRE, skeletal related event
dePuy, et al. Support Care Cancer 2007;15:869–76.
270
360
Denosumab en cáncer de próstata avanzado
Mecanismo de acción de denosumab
Espectro del problema
Ensayos clave
Efecto anti-tumoral
Prevención de metástasis
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
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
N = 950 denosumab 120 mg SC
and placebo IV Q4W
Key Inclusion Criteria
•Castration-resistant prostate cancer
and 1 bone metastases
Key Exclusion Criteria
•Current or prior IV bisphosphonate
treatment
Supplemental calcium and
vitamin D strongly recommended
N = 951 zoledronic acid 4 mg IV*
and placebo SC Q4W
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)
*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.
Baseline Characteristics
Denosumab
(N = 950)
Zoledronic
Acid
(N = 951)
71 (64–77)
71 (66–77)
882 (93)
886 (93)
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)
3.94 (1.22–
15.67)
5.19 (1.31–
16.10)
Characteristic
Median age, years (IQR)
ECOG performance status of 0 or 1, n (%)
Stratification Factors
Median time from diagnosis of bone metastasis
to randomisation, months (IQR)
IQR = interquartile range.
ECOG = Eastern Cooperative Oncology Group.
PSA = prostate-specific antigen.
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)
Proportion of Subjects Without SRE
1.00
18%
0.75
Risk
reduction
0.50
Kaplan-Meier Estimate
of Median Months
0.25
20.7
17.1
Denosumab
Zoledronic acid
0.00
0
3
6
9
733
758
544
582
407
472
Patients at Risk:
Zoledronic acid 951
Denosumab 950
Fizazi K, et al. Lancet. 2011;377:813–822.
12
15
Study Month
299
361
207
259
18
21
24
27
140
168
93
115
64
70
47
39
Cumulative Mean Number of SREs per Patient
Denosumab reduce la aparición del primero y
subsecuentes eventos óseos
2.0
Rate ratio = 0.82 (95% CI, 0.71–0.94)
1.8
P = 0.009 (superiority)
1.6
18%
1.4
Risk
reduction
1.2
1.0
0.8
0.6
Events
0.4
Denosumab
Zoledronic acid
0.2
494
584
0.0
0
3
6
*Events occurring at least 21 days apart.
Fizazi K, et al. Lancet. 2011;377:813–822.
9
12
15
18
21
Study Month
24
27
30
33
36
Summary of Adverse Events
Denosumab
(N = 943)
n (%)
Zoledronic Acid
(N = 945)
n (%)
916 (97)
918 (97)
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)
Patient Incidence
Any adverse event (AE)
Most Common AEs in Either Arm
Summary of Adverse Events
(continued)
Denosumab
(N = 943)
n (%)
Zoledronic Acid
(N = 945)
n (%)
402 (43)
375 (40)
79 (8)
168 (18)
139 (15)
153 (16)
22 (2)
12 (1)
Year 1
10 (1)
5 (1)
Year 2
22 (2)
8 (1)
121 (13)
55 (6)
18 (2)
10 (1)
Patient Incidence
Infectious AEs*
Acute phase reactions (first 3 days)
Renal AEs†
Cumulative rate of osteonecrosis of the jaw
(ONJ)‡
Hypocalcaemia
New primary malignancy
Osteonecrosis mandibular
Denosumab
n (%)
Zoledronic Acid
n (%)
22 (2)
12 (1)
Tooth extraction, dental appliance, or
poor oral hygiene
17 (77)
10 (83)
Chemotherapy
14 (64)
9 (75)
10 (45)
3 (25)
2 (9)
1 (8)
Patient Incidence
Patients with positively adjudicated ONJ
Risk Factors
Treatment*
Limited surgery (eg, debridement)
Bone resection
ONJ, osteonecrosis of the jaw
*As of April 2010.
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
Proportion of Patients
Survived
1.00
0.75
0.50
0.25
Denosumab
Zoledronic acid
0.00
0
3
6
9
12
635
519
401
645
552
427
Patients at Risk:
Zoledronic
951 864 745
acid
Denosumab 950 872 746
Fizazi K, et al. Lancet. 2011;377:813–822.
15
18
Study Month
21
24
27
30
297
207
143
98
55
54
310
233
156
99
Denosumab en cáncer de próstata avanzado
Mecanismo de acción de denosumab
Espectro del problema
Ensayos clave
Efecto anti-tumoral
Prevención de metástasis
RANK
se expresa
en células
tumorales
RANK
SE EXPRESA
EN CELULAS
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
Denosumab en cáncer de próstata avanzado
Mecanismo de acción de denosumab
Espectro del problema
Ensayos clave
Efecto anti-tumoral
Prevención de metástasis
Denosumab vs placebo in non-metastatic
CRPC
Phase III Study 147
Key eligibility criteria
• CRPC with PSA >8ng/ml or
PSA doubling time <10 months
• No bone metastases
• No prior IV bisphosphonate use
N=1435
•
•
R
A
N
D
O
M
I
S
A
T
I
O
N
Denosumab
120 mg SC Q4W
Placebo
SC Q4W
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.
Amgen Press Release December 13th, 2010 .
http://www.amgennews.com/index.php/article/274/ Fecha acceso 12 Abril 11
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.
Baseline characteristics
Placebo
(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
346 (48.3)
346 (48.3)
55 (7.7)
55 (7.7)
3.9
3.9
331 (46.2)
313 (43.7)
≤7
432 (60.3)
404 (56.4)
8–10
214 (29.9)
237 (33.1)
713 (99.6)
715 (99.9)
Characteristic, n (%) or median
PSA ≥8 ng/mL and PSADT ≤10 months
Prior chemotherapy
Duration of prior ADT, years
Local therapy
Gleason score at diagnosis
ECOG performance status ≤1
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
Randomised patients
1432*
Placebo
716
Denosumab
716
Discontinued, n (%)
Discontinued, n (%)
Bone metastasis
Consent withdrawn
Death
Disease progression**
Adverse event
Other±
On study
164 (23%)
*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
297 (41.5)
92 (13)
53 (7.4)
22 (3)
25 (3)
63 (9)
Bone metastasis
Consent withdrawn
Death
Disease progression**
Adverse event
Other±
247 (34.5)
100 (14)
56 (7.8)
36 (5)
36 (5)
67 (9)
On study
174 (24%)
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
1.0
HR = 0.85 (95% CI 0.73, 0.98)
P = 0.028
Proportion of patients
0.8
0.6
0.4
0.2
Median months Events
Placebo
Denosumab
25.2
29.5
370
335
0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Study month
Placebo
Denosumab
716 691 569 500 421 375 345 300 259 215 168 137 99 60
716 695 605 521 456 400 368 324 279 228 185 153 111 59
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.
36
35
Time to symptomatic bone
metastasis*
HR = 0.67 (95% CI 0.49, 0.92)
P = 0.01
1.0
Proportion of patients
0.8
0.6
0.4
0.2
Events
Placebo
Denosumab
96
69
0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Study month
Placebo
Denosumab
716 667 565 474 411 368 347 293 242 189 142 130 94
716 683 603 503 441 385 360 308 260 200 160 143 96
51
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.
*Confirmed bone metastasis reported
as symptomatic
Studies of bone-targeted agents for bone
metastases prevention in prostate cancer
Study
Patients
Treatment arms
Selected endpoints
Results/
Status
MRC PR041,2
M0; T24; WHO PS 02
Clodronate vs placebo
Time to symptomatic bone mets or
PCa death, OS
Primary not
met
Smith et al
20053
M0 CRPC; rising PSA
despite ADT
ZOL vs placebo
Time 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 placebo
Time 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, OS
Terminated
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
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.
ZOL, zoledronic acid;
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
PCa,
prostate cancer;
Clin Oncol 2005;23:2918–5; 4. Nelson et al. Cancer 2008; 113:2478–87 5. AstraZeneca Press Release February 7th, 2011;
OS,
overall
survival;
QoL,
quality of life
6. Smith MR et al. Presented at: American Urological Association Annual Meeting; May 14 –19, 2011; Washington, DC.
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