cprc: enfoque terapéutico de la enfermedad ósea · 2014. 6. 19. · targets the lumbar spine,...
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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
SREs-met Prostate (20050103)
Fizazi K. et al. J Clin Oncol 28:7s, 2010 (suppl. ASCO 2010). Abstract LBA4507 and Oral Presentation
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
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
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
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
3.6 m
7.8 m
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%
12 meses libres de eventos 71.1% 59.1%
18 meses libres de eventos 63.3% 57.2%
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
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
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
Smith MR, et al. Lancet 2012;379:3946.
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
Denosumab (120 mg Q4W) is currently not approved for prevention of bone
metastases. Denosumab is investigational in that setting.
15% risk reduction
DMO-IHQ-AMG-514-2011
*Bone metastases that were symptomatic at the time of radiological detection.
Smith MR, et al. Lancet 2012;379:3946.
Denosumab demonstrated improved time to
symptomatic bone metastasis*
Number at risk Denosumab Placebo
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
Denosumab (120 mg Q4W) is currently not approved for prevention of bone
metastases. Denosumab is investigational in that setting.
33% risk reduction
DMO-IHQ-AMG-514-2011
Smith MR, et al. Lancet 2012;379:3946.
An overall survival benefit was not demonstrated
Number at risk Denosumab Placebo
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
Denosumab (120 mg Q4W) is currently not approved for prevention of bone
metastases. Denosumab is investigational in that setting.
DMO-IHQ-AMG-514-2011
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
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
≤6 month PSA DT (~60% of pop)
18.7 7.2 9.7 0.77 0.006
≤4 month PSA DT (~40% of pop)
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.
Smith MR, et al. Lancet 2012;379:3946.
Summary
Denosumab (120 mg Q4W) is currently not approved for prevention of bone
metastases. Denosumab is investigational in that setting.
DMO-IHQ-AMG-514-2011
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
Smith MR, et al. Lancet 2012;379:3946.
Secondary endpoint was met: denosumab
demonstrated improved time to first bone metastases
Number at risk Denosumab Placebo
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
Denosumab (120 mg Q4W) is currently not approved for prevention of bone
metastases. Denosumab is investigational in that setting.
16% risk reduction
DMO-IHQ-AMG-514-2011
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
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
SREs-met Prostate (20050103)
SRE, Skeletal Related Event; Q4W, Every 4 weeks; IV, intravenous; SC, Subcutaneous
Fizazi K. et al. J Clin Oncol 28:7s, 2010 (suppl. ASCO 2010). Abstract LBA4507 and Oral Presentation
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
Radium-223, n = 262 Median: 16.1 months
Placebo, n = 133 Median: 11.5 months
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
Radium-223, n = 250 Median: 15.3 months
Placebo, n = 124 Median: 11.5 months
HR = 0.699 95% CI, 0.525, 0.931 P = 0.01378
Radium-223, n = 364 Median: 14.5 months
Placebo, n = 183 Median: 11.0 months
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
Radium-223, n = 348 Median: 17.0 months
Placebo, n = 169 Median: 15.8 months
HR = 0.825 95% CI, 0.635, 1.072 P = 0.14945
Radium-223, n = 266 Median: 11.4 months
Placebo, n = 138 Median: 8.1 months
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
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