Quimioterapia en Cáncer deQuimioterapia en Cáncer de ... · INTRODUCCION (II) • Denominamos cáncer de próstata resistente a la castración (CPRC) al cáncer de próstata que

Quimioterapia en Cáncer deQuimioterapia en Cáncer de Próstata Avanzado: Docetaxel y yMás Allá.

Dra. Aránzazu González del AlbaHospital Universitario Son EspasesHospital Universitario Son EspasesXIII Congreso SEOM19 de octubre de 201119 de octubre de 2011

INTRODUCCION

• 15% de pacientes diagnosticados de CaP15% de pacientes diagnosticados de CaPfallecerán a causa de enfermedad avanzada

• La terapia de deprivación androgénica (ADT) es• La terapia de deprivación androgénica (ADT) es eficaz en la mayoría de casos, aunque la progresión es la norma al cabo de 1‐2 años de laprogresión es la norma al cabo de 1‐2 años de la respuesta inicial.

• Segundas maniobras hormonales pueden ser una• Segundas maniobras hormonales pueden ser una opción en algunos pacientes, aunque las respuestas son transitorias con agentesrespuestas son transitorias con agentes disponibles hasta la fecha y sin impacto en supervivenciasupervivencia.

INTRODUCCION (II)INTRODUCCION (II)

• Denominamos cáncer de próstata resistente a laDenominamos cáncer de próstata resistente a la castración (CPRC) al cáncer de próstata que progresa a pesar de niveles séricos de castraciónprogresa a pesar de niveles séricos de castración (<50 ng/ml)

• Manifestaciones clínicas:• Manifestaciones clínicas:

• Ascenso en niveles de PSA (90%)

• Metástasis óseas (90%)

• Dolor intenso (35%)

• Metástasis partes blandas/ganglios linfáticos (20%)( )

Nuevos conceptos: cáncer de próstata resistente a castración (CPRC)

• “Enfermedad resistente a castración,” “hormono‐refractaria ” y “andrógeno independiente” sonrefractaria, y andrógeno‐independiente son hoy distintos conceptos

E id i l d d i bEvidencia clara de que segundas maniobras hormonales (antiandrógenos, ketoconazol,

ó ) iestrógenos y nuevos agentes) consiguen respuesta clínica incluso en pacientes refractarios ADTa ADT

CPRC no es andrógeno independienteg p

• A pesar de niveles de testosterona en rango de ió l í d ñ l d di d ARcastración son las vías de señal dependientes de AR

las que promueven el crecimiento de la célula l á itumoral prostática.

• Mecanismos biológicos:

– Sobrexpresión/amplificación del AR

– Mutaciones de ARMutaciones de AR

– Incremento en la síntesis de ligandos de AR

C ti d d AR h– Coactivadores de AR y chaperonas

– Activación de AR por vía independiente de ligando Sharifi N, et al. J Investig Med. 2010;58:938-944.

Dutt SS, et al. Future Oncol. 2009;5:1403-1413.

Q imioterapia de primeraQuimioterapia de primera línea en CPRClínea en CPRC

Mejoría en control de dolor a favor de quimioterapia sin diferencia en supervivencia

La FDA aprobó Mitoxantrone‐Prednisona comoLa FDA aprobó Mitoxantrone Prednisona comotratamiento paliativo para pacientes con CPHR sintomáticosintomático

11/2/2011 SOGUG, Madrid

Docetaxel es el primer agente quimioterápico que mejora supervivencia en CPRC en dossupervivencia en CPRC en dos ensayos fase III independientes y ppublicados en NEJM en 2004.

Docetaxel 75 mg/m2

3 k 10 l

The TAX‐327 study

D t l 30 / 2 kl f 5

q3wks x 10 cycles

1006 Docetaxel 30 mg/m2 weekly for 5 of 6 weeks x 5 cycles

patients with CRPC

Mitoxantrone 12 mg/m2 q3 wks x 10 cycleswks x 10 cycles

All patients received prednisone 10mg/day

Survival in TAX‐327 Studyy1.0

D 3 wklyDocetaxel 3wklyD 3 wkly

Docetaxel wklyMitoxantrone

Mitox 3 wkly

Surviving

0 5

y

Median = 16 5 Median = 18.9

bility of S 0.5 Median = 16.5

months

Median 18.9 months (p=0.009)

Prob

a

0 6 12 18 24 300.0

Months

0 6 12 18 24 30

• Docetaxel trisemanal frente a MP:– Es seguro– Aumenta significativamente la supervivenciag p(18.9 vs 16.5 m)– Reduce un 24% el riesgo de muerte (95 % CI 0.62-

0.94, p= 0.009), p )– Aumenta significativamente respuesta PSA (45 vs

32%, p=0.0005)– Aumenta significativamente respuesta dolor (35 vs g p (

22%, p=0.01)– Mejora significativamente QoL (22 vs 13%, p=0.009)

N Engl J Med 2004; 351:1502-1512

Mayor toxicidad conMayor toxicidad con docetaxel/estramustina

comparado concomparado con mitoxantrone (y con

docetaxel/prednisona en TAX‐327)

TAX 327. Updated survival

Berthold ,JCO 2008; 26: 242

TAX 327: Secondary Endpointsy p

Docetaxel q 3wk

Docetaxel weekly

Mitoxantrone q 3wk

Pain Response Rate

34.6%

p=0 01

31.2%

p=0 08

21.7%

p=0.01 p=0.08

PSA Response Rate

45.4% 47.9% 31.7%Rate p=0.0005 p<0.0001

QOL Response 21.9% 22.6% 13.1%rate p=0.009 p=0.005

Tannock SOGUG 2011

mCPRC tratamiento de primera lílínea

Docetaxel 75 mg/m2 cada 3 semanas3 semanas

es el estandar en primera línea de CRPC metastático

1H id i h A t l (2010 d t ) b1Heidenreich A, et al. (2010 update) www.uroweb.org 2Mohler J, et al. (2009 update) www.nccn.org 3Basch EM, et al. J Clin Oncol 2007;25:1–64Horwich A, et al. Ann Oncol 2009;20(Suppl 4):76–8

DISTINTAS SITUACIONES CLINICAS CPRC

ASINTOMATICO MINIMAMENTE SINTOMATICOASINTOMATICO MINIMAMENTEASINTOMATICO

SINTOMATICO

PROGRESION PSA PROGRESION GGO PROGRESION VISCERALVISCERAL

BAJA CARGA TUMORAL

ALTA CARGA TUMORAL

Criterios de progresión en CPHR

Scher et al. J Clin Oncol 2008;26:1148-59

•Metástasis hepáticas•Nº localizaciones m1 (<2 vs >2)( )•Dolor al inicio del tto.•PS (<80 vs >80)•Tipo de progresión

•Enfermedad medible•Empeoramiento GGO

•Grado Gleason (<8 vs >8)•PSA-DT (<55 vs >55 días)•PSA basal ↑•F alcalina ↑Hb ↓•Hb ↓

Limitaciones de QTQ

• Beneficio global modesto a pesar de aumento en supervivencia

• No hay evidencia acerca del momento óptimo para iniciar QTp

• La mayoría de pacientes progresan a los 6‐8 m

• Nuevas estrategias terapeúticas en desarrollo• Nuevas estrategias terapeúticas en desarrollo incluyen otros quimioterápicos, fármacos anti diana y diferentes esquemas deanti‐diana y diferentes esquemas de combinación.

Mecanismos de resistencia a docetaxel

SunitinibSunitinibSorafenibBevacizumabAfliberceptAfliberceptTalidomidaLenalidomida

AtrasentanZibotentan

OblimersenAT-101

Dasatinib

11/2/2011 SOGUG, Madrid

Custirsen

SsSerrsSeruga et al Nature Reviews Clinical Oncology, january 2011

ESTUDIOS FASE III DE COMBINACIÓN EN MARCHAESTUDIOS FASE III DE COMBINACIÓN EN MARCHA

ASCO 2010

Combinaciones de docetaxel

Hasta la fecha ningún estudio fase III de combinación en primera línea ha conseguido mejorar la supervivencia global del CPRC comparado con el tratamiento estándar de docetaxel‐Prednisona

O ll S i l B fi i R CRPC T i lOverall Survival Benefit in Recent CRPC Trials

Agent (trial, year) Disease State Comparator Hazard

Ratio P value

Radium 223/Alpharadin Bone Placebo + 0 695 0 00185Radium-223/Alpharadin(ALSYMPCA 2011) metastases

CRPCbest standard of care

0.695 0.00185

Docetaxel/Taxotere1 Chemo-naive MitoxantroneDocetaxel/Taxotere(TAX327 2004)

Chemo-naive CRPC

Mitoxantrone Prednisone 0.76 0.009

Cabazitaxel/Jevtana2

(TROPIC 2010)Post-docetaxel CRPC

Mitoxantrone Prednisone 0.70 <0.0001(TROPIC 2010) CRPC Prednisone

Sipuleucel-T/Provenge3

(IMPACT 2010)Chemo-naive CRPC Placebo 0.775 0.032

Abiraterone/Zytiga4

(COU-AA-301 2010)Post-docetaxel CRPC

Placebo Prednisone 0.65 <0.001

1. Tannock et al. N Engl J Med. 2004;351:1502-1512.2. de Bono. Lancet. 2010;376:1147-1154.3. Kantoff et al. N Engl J Med. 2010;363:411-422.4. de Bono. N Engl J Med. 2011;364:1995-2005.

Sipuleucel T

Sipuleucel‐TSipuleucel T

C $93 000Coste = $93,000

Quimioterapia de segundaQuimioterapia de segunda línea en mCPRClínea en mCPRC

Satraplatin and Prednisone Against Refractory Cancerp g y(SPARC)

MetastaticHRPC ft 1 i S t l ti 80 / 2 d il d 1 5 35RHRPC after 1 prior

chemotherapySatraplatin 80 mg/m2 po daily d 1-5 q35 + Prednisone 5 mg po BID continuously + anti-emetic daily d 1-5

AND

StratifyECOG PS 0-1 vs 2

PPI 0 1 vs 2 5 Placebo po daily d 1-5 q35 + Prednisone

DOMIPPI 0-1 vs 2-5

PSA vs tumor progression

p y q5 mg po BID continuously + placebo anti-emetic daily d 1-5

IZE

2:1

950 patients accrued in 170 centers in 16 countries on 4 continents

Cabazitaxel: selected to overcome taxane resistancetaxane resistance

Cabazitaxel:P ffi it f th P P• Poor affinity for the PgP

efflux pump• greater penetration of the

H

R

• greater penetration of the blood brain barrier compared with docetaxel and paclitaxel

Taxane

p• Active in vitro and in vivo on tumors resistant to

• Docetaxel and paclitaxel have a strong affinity for the PgP pump

Docetaxel • If the PgP pump is overexpressed, it drives drug out of tumor cell

Mita AC et al, Clin Cancer Res. 2009, 15, 723-730

TROPIC: Phase III registration study146 Sit i 26 C t i146 Sites in 26 CountriesmCRPC patients who progressed during and after p p g g

treatment with a docetaxel‐based regimen (N=755)

Stratification factorsECOG PS (0, 1 vs. 2) • Measurable vs. non‐measurable disease

cabazitaxel 25 mg/m² q 3 wk+ prednisone* for 10 cycles

mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 cycles

(n=378) (n=377)*Oral prednisone/prednisolone: 10 mg daily.

Primary endpoint: Overall SurvivalSecondary endpoints: Progression‐freesurvival (PFS), response rate, and safety

Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progressionPSA progression

De Bono J et al. Lancet, 2010, 376:1147-54

Patient characteristics MP (n=377) CBZP (n=378)

Age Median (years) 67.0 68.0≥75 (%) 19.0 18.0

ECOG PS (%)( )0, 1 91.2 92.62 8.8 7.4

PSA (ng/mL)PSA (ng/mL)Median 127.5 143.9

Measurability of disease (%)M bl di 54 1 53 2Measurable disease 54.1 53.2

Disease Site (%)Bone 87.0 80.2

ECOG PS: ECOG performance status; PSA: Prostate‐specific antigen.

Lymph node 44.8 45.0Visceral 24.9 24.9


Population with a very advanced disease

TROPIC trial: Pre-protocol treatments

MP (n=377) CBZP (n=378)Total prior docetaxel dose (mg/m²)

Median 529.2 576.6Months from last docetaxel dose to progressionMonths from last docetaxel dose to progression

Median 0.70 0.80Number of patients progressed (%)

During last docetaxel treatment 27.6 30.4<3 months since last docetaxel dose 48.0 41.8≥3 months since last docetaxel dose 24.0 27.0

Chemotherapy (%)1 regimen 71.1 68.82 regimens 21.0 24.93 regimens 8.0 6.3

A heavily pretreated population who progressedidl ft fi t li d t l


rapidly after first line docetaxel

TROPIC Trial: overall survival (Primary endpoint)(Primary endpoint)

100

80

MP CBZP

Median OS (months) 12.7 15.1

Hazard ratio 0.72

of O

S (%

)

80

60

95% CI 0.61–0.84

P-value <.0001

CensoredMP

Prop

ortio

n

40

MPCBZP

Combined medianfollow-up: 13.7 months

20

0Time (months)

377378

299321

195241

94137

3160

919

00 6 12 18 24 30

Numberat Risk

MPCBZP


28% reduction in the risk of death

Factor SubgroupPatientNumber

Hazard ratio (95%CI)

favors CBZP favors MP 0 0 5 1 1 5 2Factor Subgroup Number (95%CI)

ITT population All patients 755 0.72 (0.61–0.84)ECOG status 0,1 694 0.71 (0.60–0.84)ECOG status 2 61 0.78 (0.46–1.33)M bl di N 350 0 72 (0 56 0 92)

0 0.5 1 1.5 2

Overall Survival—Updated Subgroup Analysis

Measurable disease No 350 0.72 (0.56–0.92)Measurable disease Yes 405 0.71 (0.57–0.88)No. of prior chemo 1 528 0.71 (0.58–0.86)No. of prior chemo ≥2 227 0.73 (0.54–0.99)Age <65 295 0 81 (0 62 1 05)AnalysisAge <65 295 0.81 (0.62–1.05)Age ≥65 460 0.66 (0.53–0.81)Rising PSA at baseline No 159 0.85 (0.60–1.20)Rising PSA at baseline Yes 583 0.68 (0.56–0.82)Total docetaxel dose* <225 mg/m² 59 1.02 (0.55–1,87)g ( , )Total docetaxel dose ≥225 to 450 mg/m² 206 0.61 (0.44–0.84)Total docetaxel dose ≥450 to 675 mg/m² 217 0.81 (0.59–1.10)Total docetaxel dose ≥675 to 900 mg/m² 131 0.77 (0.52–1.12)Total docetaxel dose ≥900 mg/m² 134 0.57 (0.39–0.84)Progression During last docetaxel treatment 219 0.71 (0.53–0.96)Progression <3 months since last docetaxel dose 339 0.70 (0.56–0.89)Progression ≥3 and <6 mos since last docetaxel dose 108 0.76 (0.48–1.20)

Progression >6 months since last docetaxel dose 84 0.77 (0.43–1.38)

3

*The protocol was amended after the first 59 patients were enrolled in order tomandate that eligible patients had to have received >225 mg/m² of docetaxel.

TROPIC Trial: Progression-free survival

)

100

80

MP CBZP

Median PFS (months) 1.4 2.8

Hazard ratio 0.75n

of P

FS (%

)

60

95% CI 0.65–0.87

P-value 0.0002

PFS composite endpoint: PSA progression,

Prop

ortio

n

40

20

CensoredMP

pain progression, tumor progression, symptom deterioration, or death.

20

0Time (months)0 6 12 18 213 9 15

CBZP

Combined medianfollow-up: 13.7 months

377378

5592

1218

61

41

Time (months)0 6 12 18 213 9 15

117168

3055

96

Numberat Risk

MPCBZP

25% d i i i k f i

35De Bono J et al. Lancet, 2010, 376:1147-54

25% reduction in risk of progression

TROPIC Trial: Response rate and time to progressionResponse rate and time to progression

MP ( 377)

CBZP ( 378)

Hazard ratio(95% CI)

P-value(n=377) (n=378) (95% CI)

Tumor assessment

R t * (%) 4 4 14 4 0 0005Response rate* (%) 4.4 14.4 – 0.0005

Median TTP (months) 5.4 8.8 0.61 (0.49–0.76) <0.0001

PSA assessment

0 0010.75 6 43 1Median TTP (months)

PSA assessment

Response rate* (%) 17.8 39.2 – 0.0002

(174)(168)(N patients)

Pain response rate

0.001(0.63–0.90)6.43.1Median TTP (months)

(174)(168)(N patients)

0.630.91

(0.69-1.19)9.27.7Response rate (%)

36

TTP: time to progression ; *50% decrease or more in PSA


Treatment exposure on study drug y g

MP CBZP (n=371) (n=371)

Number of cyclesMedian 4.0 6.0(Range) (2-7) (3-10)

Treatment delays≤9 days 6% 7%≤9 days>9 days

6%2%

7%2%

Dose reduction* 5% 10%

Relative dose intensity (%)Median 97.3 96.1

*as percentage of total number of treatment cycles

An excellent dose intensitywith few dose reductions or treatment delayswith few dose reductions or treatment delays


Most Frequent Treatment-EmergentAdverse Events*

MP (n=371) CBZP (n=371)Grade 3/4 Grade 3/4

All grades (%)Grade 3/4

(%) All grades (%)Grade 3/4

(%)Any adverse event 88 39 96 57

F b il t i 1 1 8 8Febrile neutropenia 1 1 8 8Neutropenia* 88 58 94 82Diarrhea 11 <1 47 6Fatigue 27 3 37 5Back pain 12 3 16 4

N 23 <1 34 2Nausea 23 <1 34 2Vomiting 10 0 23 2Hematuria 4 1 17 2

*Sorted by ≥2% incidence rate for grade ≥3 events in the cabazitaxel arm.

Abdominal pain 4 0 12 2

38

Low rate of grade 3-4 peripheral neuropathy (1% in each group)De Bono J et al. Lancet, 2010, 376:1147-54

TROPIC Trial: Fatal Events

MP CBZPMP(n=371)

CBZP(n=371)

Total deaths during study 275 (81.9%) 270 (72.8%)

Due to progression 264 (71.2%) 218 (58.8%)

Due to AE 7 (1.9%) 18 (4.9%)Due to other reasons 15 (4 0%) 12 (3 2%)15 (4.0%) 12 (3.2%)Cause unknown (> 3 mo following last dose)

11 (3.0%) 20 (5.4%)

39

Cabazitaxel: cuestiones para el futuro

• ¿Qué dosis usar 25 o 20 mg/m2?¿Qué dosis usar 25 o 20 mg/m ?

• Actividad en primera línea

• ¿Es más o menos tóxico a nivel hematológico que docetaxel?hematológico que docetaxel?

• Evaluación en estadios precoces

40

Abiraterone in second-line metastatic CRPC COU AA 301 study

Abiraterone: 1000 mg daily

CRPC – COU-AA-301 studyRA Abiraterone: 1000 mg daily

Prednisone 5 mg BIGn=797

ANDO

PatientsProgressive mCRPCFailed 1 or 2 chemo

MIZE

regimen, including 1 with docetaxel Placebo daily

Prednisone 5 mg BIGE

2:1Stratification factors:

• ECOG PS [0-1 versus 2]

• Worst pain over previous24 hours (BPI short form;

n=797

147 sites in 13 countries(US, Europe, Australia, Canada)

24 hours (BPI short form;0-3 [absent] vs 4-10 [present]

• Prior chemotherapy[1 vs 2]

•Type of progression [PSA onlyvs radiographic progression]vs radiographic progression]

Primary endpoint: Overall SurvivalSecondary end points: TTPP rPFS PSA responseSecondary end points: TTPP, rPFS, PSA response

De Bono J et al. ESMO 2010

Comparison of Cabazitaxel and Abiraterone phase III studies

Pts characteristics & Outcome Cabazitaxel (/MP) Abiraterone (/P)Age (years) 68 (62-73) 69 (42-95)Age (years) 68 (62 73) 69 (42 95)

ECOG PS 2 7% 10.7%

Pain at baseline 46% 44 3%Pain at baseline 46% 44.3%

Median PSA (υg/L) 143.9 129

Visceral mets 25% 24 3%Visceral mets 25% 24.3%

Measurable disease 53% 69%

Number of line of CT > 2 31% 28 2%Number of line of CT > 2 31% 28.2%

PSA response rate 39.2% (34-44.5) 29.1%

Pain response rate 9 2% (4 9-13 5) NRPain response rate 9.2% (4.9 13.5) NR

Tumour response rate 14.4% (9.6-19.3) NR

PFS (months) cPFS (1 4-2 8 mths) rPFS (3 6-5 6 mths)PFS (months) cPFS (1.4 2.8 mths) rPFS (3.6 5.6 mths)

Overall Survival (months) 12.7 —› 15.1 10.9 —› 14.8

Randomized, placebo‐controlled, phase III trial of sunitinib in combination with prednisone (SU‐P) versus prednisone (P) alone in men with progressive

t t ti t ti i t t t t ( CRPC)metastatic castration‐resistant prostate cancer (mCRPC).

Abstract 4515 Michaelson et al , ASCO 2011

clinicaloptions.com/oncologyProtecting Bone for Men With Prostate Cancer

C b ti ib D l MET/VEGFR TKICabozantinib, Dual MET/VEGFR TKI, vs Placebo in mCRPC

PR or CR

(n = 79)

Open-Label ExtensionCabozantinib

100 mg/day PO

12 wks

CabozantinibRandomization

(n 79)

Lead-in StageCabozantinib

Patients with mCRPC and measurable SD

100 mg/day PO(n = 14)

U til PD*Cabozantinib100 mg/day PO

(n = 171)

measurabledisease; rising

PSA only, not eligible

SD(n = 31)

Placebo daily(n = 17)

Until PD*

*At progression, patients on placebo could

(n 17)

PD Di ticross-over to cabozantinib (n = 14). PD(n = 61)

Discontinue cabozantinib

Hussain M, et al. ASCO 2011. Abstract 4516.


C b ti ib Pl b i CRPCCabozantinib vs Placebo in mCRPC: Efficacy and Safety

Authors concluded that cabozantinib has substantial antitumor activity in progressiven Fr

ee

1.00

0.75

Cabozantinib (n = 14)Placebo (n = 17)

Median PFS, Wks21 6

antitumor activity in progressive mCRPC

– Disease control at Wk 12: 68%Prop

ortio

Prog

ress

ion

0.50

0.25(HR 0 13; log rank P = 0007)

– Measurable disease regression: 74%

-12 0 10 20 30 40 50 60PFS per mRECIST,

Postrandomization (Wks)12-Wk

Lead-in Stage

P (HR 0.13; log-rank P = .0007)

– Evidence of improvement on bone scan: 76%

Pain impro ement 67%

Postrandomization (Wks)Lead-in Stage

– Pain improvement: 67%

– Moderate but manageable toxicity profile; similar to other y p ;TKIs

Hussain M, et al. ASCO 2011. Abstract 4516.

F t t t i tFactores pretratamiento• Dolor• PS

Predictores de supervivencia tras progresión

• Fosfatasa alcalina• Nº localizaciones metastáticas• M1 hepáticas

• Nº factores de progresión (PSA, dolor, radiológica)

• Duración de QT primera líneap• Hb• PSA• Tiempo desde diagnóstico

• Duración de QT primera línea• Momento en que se produce

la progresión durante QT i líTiempo desde diagnóstico primera línea

Armstrong et al CCR 16 jan 2010

Tratamientos anti diana frenteTratamientos anti-diana frente a metástasis óseasa metástasis óseas

Zoledronic Acid in Castration‐Resistant Prostate Cancer

Zoledronic acid 4 mg q3 wks(n = 214)

RA

Eligibility Criteria

Patients with prostate cancerCastration resistant

(n 214)NDOM

Zoledronic acid 4 mg q3 wks(initially 8 mg)Bone metastases

(N = 643)Pl b 3 k

MIZE

(initially 8 mg)(n = 221)

• Patients in 8‐mg arm reduced to 4 mg owing to renal toxicity

Placebo q3 wks(n = 208)

D

• Patients in 8‐mg arm reduced to 4 mg owing to renal toxicity

• Primary outcome: proportion of patients having ≥ 1 SRE

• Secondary outcomes: time to first on‐study SRE, proportion of patients with SREs, d i di iand time to disease progression

Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.

Time to First SRE

SREs: Zol 4 mg 38%; placebo 49% (P = .028)• 11% absolute risk reduction in ≥ 1 SRE 100

nt

Pain/analgesia scores increased less with Zol

No improvement in tumor progression, QoL, OS60

80

hout

Eve

n

20

40Median, Days P Value

cent

With

0

20

0 120 240 360 480 600 720

Zol 4 mg 488 .009Placebo 321Pe

rc

0 120 240 360 480 600 720Days

Zol 4 mg 214 149 97 70 47 35 3Placebo 208 128 78 44 32 20 3Placebo 208 128 78 44 32 20 3

Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. Saad F, et al. ASCO 2003. Abstract 1523. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.


St d D i I t ti l R d i dStudy Design: International, Randomized, Double-Blind, Active-Controlled StudyKey Inclusion

Hormone refractory (castration

Denosumab 120 mg SC and Placebo IV* q4 wks

(n = 950)Hormone-refractory (castration-resistant) prostate cancer and bone metastases

Key Exclusion

(n = 950)

Key Exclusion

Current or previous IV bisphosphonate treatment

Zoledronic acid 4 mg IV* and Placebo SC q4 wks

(n = 951)

Calcium and vitamin D supplemented in both treatment groups

Accrual period from May 2006 - December 2008

*Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine clearance and

Accrual period from May 2006 December 2008

Analysis cutoff date: October 2009

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.


Time to First On-Study SRE1.00

out S

RE HR: 0.82 (95% CI: 0.71-0.95;

P = .0002, noninferiority;P = .008, superiority)

18%Risk

reduction

ects

With

o

0 50

0.75

on o

f Sub

je

0.25

0.50

KM Estimate ofMedian Mos

0Prop

ortio

0 3 6 9 12 15 18 21 24 27

DenosumabZoledronic acid

20.717.1

Zoledronic acid 951 733 544 407 299 207 140 93 64 47Pts at Risk, n

Study Mo0 3 6 9 12 15 18 21 24 27

Denosumab 950 758 582 472 361 259 168 115 70 39

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


Adverse Events of Interest

Subject Incidence, n (%) Zoledronic Acid(n = 945)

Denosumab(n = 943)

Infectious adverse events 375 (39 7) 402 (42 6)Infectious adverse events 375 (39.7) 402 (42.6) Infectious serious adverse events 108 (11.4) 130 (13.8) Acute-phase reactions (first 3 days) 168 (17.8) 79 (8.4) Renal adverse events* 153 (16.2) 139 (14.7) Cumulative rate of ONJ† 12 (1.3) 22 (2.3)

Yr 1 5 (0.5) 10 (1.1)Yr 2 8 (0.8) 22 (2.3)

Hypocalcemia 55 (5.8) 121 (12.8)New primary malignancy 10 (1.1) 18 (1.9)New primary malignancy 10 (1.1) 18 (1.9) *Includes renal failure, increased blood creatinine, acute renal failure, renal impairment, increased blood urea, chronic renal failure, oliguria, hypercreatinemia, anuria, azotemia, decreased creatinine renal clearance, decreased urine output, abnormal blood creatinine, proteinuria, decreased glomerular filtration

t d h iti

Fizazi K, et al. ASCO 2010. Abstract LBA4507. Fizazi K, et al. Lancet. 2011;377:813-822.

rate, and nephritis.†P = .09.

R di 223 T B MRadium-223 Targets Bone Metastases

Range of alpha-particle

Radium-223

B f

• Alpha-particles induce double-strand DNA breaks in adjacent tumour cells1

Bone surface

adjacent tumour cells1

– Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissue

1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.

ALSYMPCA (ALpharadin in SYMptomatic P CA ) Ph III S d D i

TREATMENT

Prostate CAncer) Phase III Study DesignTREATMENT

6 injections at 4-week intervalsR

A

PATIENTS

• ConfirmedSTRATIFICATION

Radium-223 (50 kBq/kg) + Best standard of care

ANDO

Confirmed symptomatic CRPC

• ≥ 2 bone metastases

• Total ALP: < 220 U/L vs ≥ 220 U/L

Placebo (saline) + B t t d d f

MISE

metastases• No known

visceral metastases

< 220 U/L vs ≥ 220 U/L• Bisphosphonate use:

Yes vs No• Prior docetaxel:

Yes vs No + Best standard of careED

2:1

• Post-docetaxel or unfit for docetaxel

Yes vs No

N = 922docetaxel

Planned follow-up is 3 years

Clinicaltrials.gov identifier: NCT00699751.

p y

A SYMPCA O ll S i lALSYMPCA Overall Survival100

80

90 HR 0.695; 95% CI, 0.552-0.875P = 0.00185

50

60

70

%Radium-223, n = 541Median OS 14 0 months

30

40

50% Median OS: 14.0 months

Pl b 268

0

10

20 Placebo, n = 268Median OS: 11.2 months

Month 0 3 6 9 12 15 18 21 24 27

Radium- 223 541 450 330 213 120 72 30 15 3 0

0

Placebo 268 218 147 89 49 28 15 7 3 0

ALSYMPCA Time to Fi Sk l l R l d EFirst Skeletal-Related Event

100

80

90 HR 0.610; 95% CI, 0.461-0.807P = 0.00046

50

60

70

hout

SR

E Radium-223, n = 541Median: 13.6 months

30

40

50

% W

ith

Placebo, n = 268Median: 8.4 months

0

10

20Median: 8.4 months

Month 0 3 6 9 12 15 18 21

Radium-223 541 379 214 111 51 22 6 0

0

Placebo 268 159 74 30 15 7 2 0

Nuevos agentes en mCPRC A t d l i i t iAntes de la quimioterapia

• Aprobados • EmergentesAprobados

– Leuprolide• Emergentes

– Abiraterone– Goserelin

– Bicalutamide– MDV3100

– Ipilimumab– Flutamide

– Ketoconazole

p

– Orteronel (TAK700)

AlpharadinKetoconazole

– DES

i l l ( )

– Alpharadin

– Cabozantinib– Sipuleucel‐T (2010) USA

No sigue en desarrollo: zibotentan (ZD4054)g ( )

Nuevos agentes en mCPRCPrimera línea de quimioterapiaPrimera línea de quimioterapia

• Aprobados • Emergentes (combinados• Aprobados– Docetaxel

Emergentes (combinados con docetaxel)

Aflib (VEGF T )– Mitoxantrone*

– Bisphosphonates*

– Aflibercept (VEGF‐Trap)

– Dasatinibp p

– RT* – Ipilimumab

– LenalidomideLenalidomide

– Custirsen (OGX‐011)

No siguen en desarrollo (cada uno en combinación con

*Palliative therapy

g (docetaxel):atrasentan, bevacizumab, DN101, zibotentan

Nuevos agentes en mCPRCSegunda línea de quimioterapia

• Aprobados

– Docetaxel

• Emergentes

– Alpharadin

– Mitoxantrone*

– Cabazitaxel

– MDV3100

– Orteronel (TAK‐700)– Cabazitaxel

– Abiraterone

– Orteronel (TAK‐700)

– Ipilimumab

– Cabozantinib

– Ixabepilone

– Custirsen (OGX‐011) + docetaxel

*Palliative therapy

No sigue en desarrollo: sunitinib

A Treatment Algorithm for mCRPCA Treatment Algorithm for mCRPC

Maintain castration serum levels of testosterone and use denosumab or zoledronic acid with vitamin D and calcium if bone metastases are present

SymptomaticVisceral diseaseNo Yes

DocetaxelMitoxantronePalliative radiotherapy or radionuclide (radium 233?) for symptomatic bone metastases

Sipuleucel‐TSecondary hormone therapy • Antiandrogen• Antiandrogen withdrawal 233?) for symptomatic bone metastases

Clinical trial• Antiandrogen withdrawal• Ketoconazole or abiraterone acetate (Level 2B)

• Steroids• DES or other estrogen

Mottet N et al Eur Oncol 2011;59:572‐583

DES or other estrogenClinical trial Abiraterone acetate

CabazitaxelSalvage chemotherapyDoceta el rechallenge

Secondary hormone therapyClinical trial

Mottet N, et al. Eur Oncol. 2011;59:572 583.NCCN. Clinical practice guidelines in oncology: prostate cancer. v.3.2011. Yap T, et al. Nat Rev Clin Oncol. 2011; [Epub ahead of print].

Docetaxel rechallengeMitoxantrone

Consideraciones finales

• En CPRC la vía de señal de AR continúa activa y promoviendo el crecimiento celular

• La quimioterapia consigue paliación y mejoría en supervivencia en CPRC (primera línea: docetaxel, p (p ,segunda línea: cabazitaxel) (nivel evidencia 1)

• Abirateronamejora supervivencia en pacientes• Abirateronamejora supervivencia en pacientes que han progresado a docetaxel (nivel 1)

Consideraciones finalesConsideraciones finales

• La inmunoterapia con sipuleucel‐Tmejora la supervivencia en pacientes asintomáticos o mínimamente sintomáticos (nivel 1)

• En pacientes con metástasis oseas sintomáticas pAlpharadinmejora la supervivencia en pacientes no tratados con docetaxel y tras progresión al mismoy p g

• Nuevos agentes están siendo evaluados en primera línea (combinados con docetaxel) y tras fallo alínea (combinados con docetaxel) y tras fallo a docetaxel

MUCHAS GRACIAS

Documents

Quimioterapia en Cáncer deQuimioterapia en Cáncer de ... · INTRODUCCION (II) • Denominamos cáncer de próstata resistente a la castración (CPRC) al cáncer de próstata que