Manejo del cáncer de próstata metastásico en el 2014 · Introducción II •Denominamos cáncer de próstata resistente a la castración (CPRC) al cáncer de próstata que progresa

PROGRAMA CIENTÍFICO

ID d

el e

vento

:

Hotel AC Palma Plaça del Pont 3

07014 Palma de Mallorca

15 de mayo de 2013 • 19:00h – 22:00h

Abordaje del paciente con Cáncer de

Próstata Resistente a Castración (CPRCm)

Dra. Aránzazu González del Alba Servicio de Oncología Médica

Hospital Universitario Son Espases Palma de Mallorca

Barcelona, 18 de marzo de 2014

Manejo del cáncer de próstata metastásico en el 2014


ID del evento:



15 de mayo de 2013 • 19:00h – 22:00h



Introducción

• 15% de pacientes diagnosticados de CaP fallecerán a causa de enfermedad avanzada

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

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


ID del evento:



15 de mayo de 2013 • 19:00h – 22:00h



Introducción II

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

1984-1989

Evolución histórica del tratamiento del cáncer de próstata avanzado

However, this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy

1. The Leuprolide Study Group. N Engl J Med. 1984;311:1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321:419-424. 3. Tannock IF, et al. J Clin Oncol. 1996;14:1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. 5. Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520. 6. Tannock IF, et al. N Engl J Med. 2004;351:1502-1512. 7. de Bono JS, et al. Lancet. 2010;376:1147-1154. 8. Kantoff PW, et al. N Engl J Med. 2010;363:411-422. 9. Fizazi K, et al. Lancet. 2011;377:813-822. 10. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 11. Scher HI, et al. ASCO GU 2012. Abstract LBA1. 12. Parker C, et al. ASCO GU 2012. Abstract 8.

1996 2002 2004 .... 2010 2011

Mitoxantrone[3] Docetaxel*[5,6]

Sipuleucel-T*[8]

LHRH agonists*[1,2]

Abiraterone*[10]

Reversible AR blockers[1,2]

Cabazitaxel*[7] Denosumab[9] Zoledronic Acid[4]

Enzalutamida[11]

Radium-223[12]

* Approved agent for PCa

Revisar Terminología

• “Cáncer de próstata hormono-refractario”

• “Cáncer de próstata andrógeno-independiente”

• “Cáncer de próstata resistente a castración”

Evidencia clara de que segundas maniobras hormonales (antiandrógenos, ketoconazol, estrógenos y nuevos agentes) consiguen respuesta clínica incluso en pacientes refractarios a TDA

The FDA approved mitoxantrone-prednisone as palliative treatment for patients with

symptomatic HRPC

• Improvement in pain control

• No difference in survival

Median survival

(months) HR P

Docetaxel q3w

18.9 0.76 0.009

Docetaxel q1w

17.3 0.93 0.3

Mitoxantrone q3w

16.4 - -

2004: Docetaxel improves OS vs mitoxantrone

Tannock IF et al. N Engl J Med 2004;351:1502-12. Berthold D et al. J Clin Oncol 2008;26:242-5. * Data 2006 7

Docetaxel q3w (N=335)

Docetaxel q1w (N=334)

Mitoxantrone q3w (N=337)

3-year survival rate* 18.6% 16.8% 13.5%

mCPRC tratamiento de primera línea

Docetaxel 75 mg/m2 cada 3 semanas

estándar en primera línea de CRPC metastático

1Heidenreich 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;25:1–6 4Horwich A, et al. Ann Oncol 2009;20(Suppl 4):76–8

ASINTOMATICO MINIMAMENTE SINTOMATICO

SINTOMATICO

PROGRESION PSA PROGRESION GGO PROGRESION VISCERAL

BAJA CARGA TUMORAL

ALTA CARGA TUMORAL

Distintas situaciones clínicas en CPRC


ID del evento:



15 de mayo de 2013 • 19:00h – 22:00h



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

Criterios de progresión en CP

•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 ↓

La vía de señal androgénica

Molecular states framework for androgen

receptor (AR) activation in prostate cancer.

Nelson P S JCO 2012 feb ;30:644-646

Evolución natural del cáncer de próstata

Volumen tumoral

Tiempo

ADT / Castración

Docetaxel

Terapia local*

Metastásico

Síntomas

Resistente a la castración

No metastásico

Asintomático

Sensible a hormonas

Terapias hormonales de 2ª línea

Bicalutamida Flutamida Nilutamida

Muerte

Cabazitaxel

Abiraterona

Rad 223

Enzalutamida

*por ejemplo, cirugía, radioterapia

Kohli & Tindall. Mayo Clin Proc 2010;85:77–86.

RA, receptor de

andrógenos

Señalización AR continuada

Sipuleucel T Abiraterona Enzalutamida

3/22/2014 SOGUG, Madrid

Oblimersen

AT-101

Custirsen

Sunitinib

Sorafenib

Bevacizumab

Aflibercept

Talidomida

Lenalidomida Atrasentan

Zibotentan

Dasatinib

Negative studies

Docetaxel-HD-Calcitriol1

Docetaxel-Bevacizumab2

Docetaxel-GVAX3

Docetaxel-Oblimersen4

Docetaxel-Lenalidomide

Docetaxel-Atrasentan5

Docetaxel-Aflibercept6

Docetaxel-Zibotentan7

Since 2004, many attempts to further improve docetaxel efficacy have failed

1. Scher HI et al. J Clin Oncol 2010;28:15s (Abstract 4509). 2. Kelly WK et al. J Clin Oncol 2010;28:18s (Abstract

LBA4511). 3. Small E et al. ASCO GU symposium 2009 (Abstract 7). 4. Sternberg C et al. Annals Oncol 2009;20:1264-69.

5. University of Michigan press release (April 2011). 6. Press release Sanofi-Regeneron 2012. 7. Nelson JB et al. J Clin Oncol 2011;29 (suppl 7):Abst 117.

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

Agents with overall survival benefit in mCRPC

Cortesia Dr J.Carles

Sipuleucel T

Sipuleucel-T

Coste = $93,000

No aprobado en Europa

Pacientes asintomáticos o mínimamente sintomáticos

Cabazitaxel: selected to overcome taxane resistance

• Cabazitaxel: Poor affinity for the PgP efflux pump

Greater penetration of the blood brain barrier compared with docetaxel and paclitaxel

Active in vitro and in vivo on tumors resistant to Docetaxel

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

Taxane

H

R

• Docetaxel and paclitaxel

have a strong affinity for

the PgP pump

• If the PgP pump is

overexpressed, it drives

drug out of tumor cell

Second-line Cabazitaxel in mCRPC patients: TROPIC – Study design

de Bono JS et al. Lancet 2010;376:1147-54 * or prednisolone, when prednisone was

unavailable 24

146 Sites in 26 Countries (North America, Europe, India, Latin America, Asia, South Africa)

mCRPC patients who progressed during or after treatment

with a docetaxel-based regimen (N=755)

Stratification factors ECOG PS (0, 1) vs ECOG PS (2)

Measurable vs non-measurable disease

Cabazitaxel 25 mg/m2 q3w + 10 mg oral prednisone* daily

10 cycles

Mitoxantrone 12 mg/m2 q3w + 10 mg oral prednisone* daily

10 cycles

Primary endpoint: OS Secondary endpoints: Progression-free survival (PFS), response rate, and safety

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

N=378 N=377

TROPIC trial: Pre-protocol treatments

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

Total prior docetaxel dose (mg/m²)

Median 529.2 576.6

Months from last docetaxel dose to progression

Median 0.70 0.80

Number 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 68.8

2 regimens 21.0 24.9

3 regimens 8.0 6.3

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

A heavily pretreated population who progressed

rapidly after first line docetaxel

Beneficio SG en todos los subgrupos

De Bono et al. The lancet 2010; 376: 1147-54

*El protocolo se enmendó tras los primeros 59 pacientes incluídos, para asegurar que los pacientes incluídos hubiesen recibido >225 mg/m² de docetaxel

Factor Subgroup Hazard ratio

(95% CI)

Población ITT Todos los pacientes 0.70 (0.59–0.83)

ECOG status 0, 1 0.68 (0.57–0.82)

2 0.81 (0.48–1.38)

Enfermedad medible

No 0.72 (0.55–0.93)

Si 0.68 (0.54–0.85)

No. tratamientos previos

1 0.67 (0.55–0.83)

≥2 0.75 (0.55–1.02)

Edad <65 0.81 (0.61–1.08)

≥65 0.62 (0.50–0.78)

Dolor basal No 0.57 (0.43–0.77)

Si 0.76 (0.59–0.98)

Aumento PSA No 0.88 (0.61–1.26)

Si 0.65 (0.53–0.80)

Dosis total docetaxel

<225 mg/m² 0.96 (0.49–1.86)

≥225 to 450 mg/m² 0.60 (0.43–0.84)

≥450 to 675 mg/m² 0.83 (0.60–1.16)

≥675 to 900 mg/m² 0.73 (0.48–1.10)

≥900 mg/m² 0.51 (0.33–0.79)

Progresión Durante tto con docetaxel 0.65 (0.47–0.90)

<3 meses desde la última dosis de DTX 0.70 (0.55–0.91)

≥3 meses desde la última dosis de DTX

0.75 (0.51–1.11)

0.25 1 2 0.5 1.5 A Favor CBZP A Favor MP

28

TROPIC Trial: Progression-free survival

Pro

po

rtio

n o

f P

FS

(%

)

377

378

55

92

12

18

6

1

4

1

100

80

60

40

20

0

Time (months) 0 6 12 18 21 3 9 15

117

168

30

55

9

6

MP CBZP

Median PFS (months) 1.4 2.8

Hazard ratio 0.75

95% CI 0.65–0.87

P-value 0.0002

Number

at Risk

MP

CBZP

Censored MP CBZP

Combined median follow-up: 13.7 months

PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death.


25% reduction in risk of progression

29

TROPIC Trial: Response rate and time to progression

(174) (168) (N patients)

Pain response rate

0.001 0.75

(0.63–0.90) 6.4 3.1 Median TTP (months)

0.63 0.91

(0.69-1.19)

9.2 7.7 Response rate (%)

MP (n=377)

CBZP (n=378)

Hazard ratio (95% CI)

P-value

Tumor assessment

Response rate* (%) 4.4 14.4 – 0.0005

Median TTP (months) 5.4 8.8 0.61

(0.49–0.76) <0.0001

PSA assessment

Response rate* (%) 17.8 39.2 – 0.0002

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


30

Most Frequent Treatment-Emergent Adverse Events*

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

Low rate of grade 3-4 peripheral neuropathy (1% in each group)


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

All grades (%) Grade 3/4

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

(%)

Any adverse event 88 39 96 57

Febrile neutropenia 1 1 8 8

Neutropenia* 88 58 94 82

Diarrhea 11 <1 47 6

Fatigue 27 3 37 5

Back pain 12 3 16 4

Nausea 23 <1 34 2

Vomiting 10 0 23 2

Hematuria 4 1 17 2

Abdominal pain 4 0 12 2

Síntesis de andrógenos

Abiraterona

Nacusi et al Nature Publishing Group 2011;8:378–384

COU-AA-301 Study Design

Abiraterone acetate

1000 mg daily

Placebo daily

Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study

(147 sites in 13 countries; USA, Europe, Australia, Canada)

OS (25% improvement; HR 0.8) Primary endpoint:

• 1195 patients with progressive,

mCRPC

• Failed 1 or 2 chemotherapy

regimens, one of which

contained docetaxel

• Randomised 2:1

T

R

E

A

T

U

N

T

I

L

P

R

O

G

R

E

S

S

I

O

N

Prednisone 5mg twice daily

Prednisone 5mg twice daily

de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Stratification by:

• ECOG performance

status (0-1 vs. 2)

• Worst pain over

previous 24 hours (BPI

short form; 0-3 [absent]

vs. 4-10 [present])

• Prior chemotherapy (1

vs. 2)

• Type of progression

(PSA only vs.

radiographic progression

with or without PSA

progression)

Updated Analysis (775 Events): OS Benefit of

AA Increased From 3.9 to 4.6 Months

Median duration of follow-up: 20.2 months

Median duration of treatment: 8 months with AA vs. 4 months with placebo

HR (95% CI): 0.74 (0.64-0.86)

p < 0.0001

AA median OS (95% CI):

15.8 months (14.8-17.0)

Placebo median OS (95% CI):

11.2 months (10.4-13.1)

100

80

60

40

20

0

0

Su

rviv

al (%

)

6 12 18 24

797

398

657

306

473

183

273

100

15

6

Time to Death (Months)

30

0

0

AA

Placebo

AA

Placebo

Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

Survival Benefit Observed With AA Is

Consistent for Majority of Subgroups

0.5 0.75 1 1.5

Region

Baseline ALK-P above median

Baseline LDH above median

Baseline PSA above median

Visceral disease at entry

Age, years

Type of progression

No. prior chemo regimens

Baseline BPI

Baseline ECOG

All subjects

Other

N.A.

NO

YES

NO

YES

NO

YES

NO

YES

≥ 75

≥ 65

< 65

Radiographic

PSA only

2

1

≥ 4

< 4

2

0-1

ALL

15.1

16.4

19.5

12.4

20.8

10.4

18.2

13.6

17.1

12.9

15.6

16.2

15

14.8

18.3

14.2

17.1

13.3

18.4

7.3

17

15.8

11.5

11.1

18

8.1

18

8

15.3

8.8

12.3

8.3

9.3

11.1

11.2

10.5

13.6

10.4

11.7

9.3

13.9

7

12.3

11.2

0.80

0.68

0.88

0.60

0.75

0.77

0.79

0.65

0.69

0.79

0.64

0.76

0.69

0.78

0.63

0.80

0.71

0.78

0.69

0.77

0.74

0.74

(0.64-1.00)

(0.56-0.83)

(0.69-1.12)

(0.50-0.74)

(0.59-0.96)

(0.63-0.93)

(0.63-0.99)

(0.53-0.79)

(0.58-0.82)

(0.59-1.05)

(0.48-0.85)

(0.63-0.90)

(0.53-0.91)

(0.65-0.93)

(0.47-0.84)

(0.61-1.03)

(0.59-0.85)

(0.63-0.96)

(0.56-0.85)

(0.50-1.17)

(0.63-0.86)

(0.64-0.86)

Variable Subgroup

Median (months)

AA Placebo HR 95% CI

Favors

AA

Favors

Placebo

Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

AEs of Special Interest

de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

AA (n = 791)

Placebo (n = 394)

All Grades Grade 3 Grade 4 All

Grades Grade 3 Grade 4

Fluid retention and

edema 31% 2% <1% 22% 1% 0

Hypokalemia 17% 3% <1% 8% 1% 0

Cardiac disorders 13% 3% 1% 11% 2% <1%

LFT abnormalities 10% 3% <1% 8% 3% <1%

Hypertension 10% 1% 0 8% <1% 0


ID del evento:



15 de mayo de 2013 • 19:00h – 22:00h



Radionúclidos y tratamiento paliativo

• Hasta la fecha actual 3 radionúclidos habían sido aprobados para el tratamiento del dolor óseo:

• Radionúclidos de primera generación: Fósforo 32

• Radionúclidos de segunda generación: Stroncio 89

• Radionúclidos de tercera generación: Samario 153

• Sr 89 demostró aumento del tiempo a recurrencia del dolor

• Sm 153: Alivio del dolor y disminución del consumo de analgésicos con menor toxicidad hematológica

Climent MA, 2012 Crit Rev and Hematology

Radium Ra 223 Dichloride (Alpharadin)

• Metal alcalino

térreo

• Afinidad ósea por

su “parecido” al

Calcio

• Emisor alfa

Ra 88

56

Ba

Sr 38

20

Ca

1. Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s.

Características Físicas

Rotura simple Reparables Baja letalidad

Rotura doble Apoptosis Alt. Mitótica Fase G0

Cortesía Dr Vallejo

Bone Targeted Localized Mechanism

of Action – α-Pharmaceuticals

Henriksen G, et al. Cancer Res. 2002;62:3120–25 42

Bone marrow

Tumor Range of α-particle (small volume)

Range of β-particle (large volume)

Bone Bone surface

Radionuclide

ALSYMPCA Trial Design (Alpharadin in symptomatic PC)

M36 M16 M24 M12 M0

R 2:1

Radium Ra 223 dichloridea 50 kBq/kg

Saline* (placebo)

FOLLOW-UP PHASE TREATMENT PHASE 6 injections at

4-week intervals

M28 M6 M20 M32 M8 M10

Stratification factors •Total ALP < 220 U/L vs ≥ 220 U/L •Bisphosphonate use (yes vs no) •Prior docetaxel (yes vs no)

Monthe

Assessments

ALP, alkalinphosphatase; ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer; R, randomization

aPlus best standard of care.

Parker C, et al. J Clin Oncol. 2012;30(suppl). Abstract LBA4512. Clinical Trials.gov identifier # NCT00699751.

Key inclusion criteria •Confirmed symptomatic CRPC •≥ 2 bone metastases •No known visceral metastases •Post-docetaxel or unfit for docetaxel

Primary endpoints: overall survival Secondary endpoints: time to first SRE, time to total ALP progression, total ALP response, total ALP normalization, time to PSA progression, safety, PS and HRQoL

Month

Radium 223 614 578 504 369 274 178 105 60 41 18 7 1 0 0

Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0

ALSYMPCA: Radium Ra 223 Dichloride Significantly Prolonged Overall Survival Compared With Placebo

0

20

40

60

80

100

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

Surv

ival

(%

)

Radium 223 Placebo

Median OS (months) 14.9 11.3

Hazard ratio 0.695

95% CI 0.581-0.832

P < 0.0001

ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer; CI, confidence interval; OS, overall survival.

Parker C, et al. J Clin Oncol. 2012;30(suppl). Abstract LBA4512.

Radium 223 Placebo

Median OS Δ: 3.6 months

Prior docetaxel use NO prior docetaxel use

ALSYMPCA Updated Analysis

OS by Stratification Variables:

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



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



Baseline ALP

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

ALSYMPCA: Adverse Events of Interest

All Grades Grades 3 or 4

n (%) Radium 223

(n = 600) Placebo (n = 301)

Radium 223 (n = 600)

Placebo (n = 301)

Hematologic

Anemia 187 (31.2) 92 (31) 77 (13) 40 (13)

Neutropenia 30 (5) 3 (1) 13 (2) 2 (1)

Thrombocytopenia 69 (11.5) 17 (5.6) 38 (6.3) 6 (2)

Nonhematologic

Bone pain 300 (50) 187 (62) 125 (21) 77 (26)

Diarrhea 151 (25) 45 (15) 9 (1.5) 5 (1.7)

Nausea 213 (35.5) 104 (35) 10 (2) 5 (2)

Vomiting 111 (18.5) 41 (14) 10 (2) 7 (2)

Constipation 108 (18) 64 (21) 6 (1) 4 (1)

ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer.

Parker C, et al. J Clin Oncol. 2012;30(suppl.). Abstract LBA4512.

Data on file. Wayne, NJ: Bayer HealthCare Pharmaceuticals. ClinicaTrials.gov identifier # NCT00699751.

Enzalutamide (MDV3100): Mechanism of action

• AR signalling inhibition at three levels:

– Blocks binding of testosterone to the AR

– Inhibits nuclear translocation of AR

– Inhibits binding of the AR to DNA

Enzalutamide

T

Cell nucleus

Inhibits binding of androgens to AR

Inhibits nuclear translocation of AR

Inhibits association of AR with DNA

AR

Cell cytoplasm

T, testosterone

1

2

3

Tran C et al. Science 2009;324:787–790; Baskin-Bey ES et al. ASCO GU 2011 abstr 177;

Watson PA et al. Proc Natl Acad Sci USA 2010;107:16759–65

T

AR

Phase III: AFFIRM trial of enzalutamide in mCRPC patients post-chemotherapy

Scher et al. NEJM Aug 15. [Epub ahead of print] (2012).

n = 1199 mCRPC

1–2 prior chemotherapy

regimens*

R 2:1

Enzalutamide 160 mg qd (n = 800)

Placebo per qd (n = 399)

*≥ 1 docetaxel (glucocorticoids were allowed but not required)

• AFFIRM is a phase III randomised, double-blind, placebo-controlled trial

mCRPC, metastatic castrate-resistant prostate cancer; qd, once per day; R, randomisation

Recruitment in 156 centres from 15 countries across 5 continents between September 2009 and November 2010

• Stratification variables:

• ECOG performance status (0–1 vs 2)

• Mean Brief Pain Inventory Q#3 score (<4, ≥ 4)

Primary endpoint: Overall survival

AFFIRM: Overall survival


3 6 9 18 21 24 15

100

80

60

40

20

0 0

Surv

ival

(%

)

Duration of overall survival (months) 12

775 701 627 72 7 0 211 800 400 Enzalutamide, n =

376 317 263 33 3 0 81 399 167 Placebo, n =

Placebo: 13.6 months (95% CI: 11.3–15.8)

Enzalutamide: 18.4 months (95% CI: 17.3–NYR)

HR = 0.63 (95%CI: 0.53–0.75); p<0.001 37% reduction in risk of death

4.8 month difference in

median overall survival

CI, confidence interval; HR, hazard ratio; NYR, not yet reached

No at risk:

AFFIRM: Secondary endpoints


Enzalutamide (n = 800)

Placebo (n = 399)

Hazard ratio p-value

Confirmed PSA response rates

≥50% reduction from baseline (%) 54 2 – p<0.001

≥90% reduction from baseline (%) 25 1 – p<0.001

PSA progression

Median time to PSA progression (months) 8.3 3.0 0.25 p<0.001

Soft tissue response*

Soft tissue response rate (%) 29 4 – p<0.001

Progression-free survival

Radiographic progression-free survival (months) 8.3 2.9 0.40 p<0.001

Skeletal-related events

Time to first skeletal-related event (months) 16.7 13.3 0.69 p<0.001

Health-related quality of life

Functional Assessment of Cancer Therapy - Prostate (FACT-P) quality of life response rate (%)

43 18 – p<0.001

PSA, prostate-specific antigen

Percentages relate to patients with baseline and postbaseline assessments *n=446 and n=208 for enzalutamide and placebo arms respectively

AFFIRM: Overall survival

Subgroup Hazard ratio for death (95% CI)

Median overall survival (months)

Enzalutamide/placebo

All subjects 0.63 (0.53–0.75) 18.4/13.6

Age < 65 ≥ 65

0.63 (0.46–0.87) 0.63 (0.51–0.78)

–/12.4

18.4/13.9

Baseline ECOG performance status 0–1 2

0.62 (0.52–0.75) 0.65 (0.39–1.07)

–/14.2

10.5/7.2

Baseline mean pain score on BPI-SF (question #3) < 4 ≥ 4

0.59 (0.47–0.74) 0.71 (0.54–0.94)

–/16.2

12.4/9.1

Geographical region North America Other

0.63 (0.47–0.83) 0.64 (0.51–0.80)

17.4/12.3

–/14.4

Number of prior chemotherapy regimens 1 ≥ 2

0.59 (0.48–0.73) 0.74 (0.54–1.03)

–/14.2

15.9/12.3

Type of progression at study entry PSA progression only Radiographic progression PSA progression

0.62 (0.46–0.83) 0.64 (0.52–0.80)

–/19.5

17.3/13.0

Baseline value > median PSA LDH

0.62 (0.50–0.78) 0.61 (0.50–0.76)

15.3/10.3 12.4/8.5


0 0.5 1.0 1.5 2.0

Favours Enzalutamide Favours placebo

The size of the circles is proportional to the size of the subgroup

BPI-SF, Brief Pain Inventory - short form; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PSA, prostate-specific antigen

AFFIRM: resumen de AA

AA, acontecimiento adverso; LFT, pruebas de función hepática

*las anomalías en las LFT eran hiperbilirrubinemia y aumento de los niveles de aspartato aminotransferasa o alanina aminotransferasa

El periodo de notificación de acontecimientos adversos para el grupo de enzalutamida fue más del doble que el correspondiente al grupo placebo

Acontecimientos adversos, n (%)

Acontecimientos totales (todos los grados)

Acontecimientos de grado ≥ 3

Enzalutamida (n = 800)

Placebo (n = 399)

Enzalutamida (n = 800)

Placebo (n = 399)

≥ 1 acontecimientos adversos 785 (98) 390 (98) 362 (45) 212 (53)

Cualquier acontecimiento adverso grave

268 (34) 154 (39) 227 (28) 134 (34)

Interrupciones debidas a acontecimientos adversos

61 (8) 39 (10) 37 (5) 28 (7)

Acontecimientos causantes de muerte

23 (3) 14 (4) 23 (3) 14 (4)

Acontecimientos adversos de interés, n (%)

Cansancio 269 (34) 116 (29) 50 (6) 29 (7)

Trastornos cardíacos (cualquiera) 49 (6) 30 (8) 7 (1) 8 (2)

Infarto de miocardio 2 (<1) 2 (<1) 2 (<1) 2 (<1)

Alteración transaminasas* 8 (1) 6 (2) 3 (<1) 3 (<1)

Convulsiones 7 (<1) 0 5 (<1) 0

N Engl J Med 2012; 367: 1187–1197

Zoledronic Acid in Castration-Resistant Prostate Cancer

• 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, and time to disease progression

Patients with prostate cancer

Castration resistant Bone metastases

(N = 643)

Zoledronic acid 4 mg q3 wks

(n = 214)

Placebo q3 wks

(n = 208)

R

A

N

D

O

M

I

Z

E

D

Eligibility Criteria

Zoledronic acid 4 mg q3 wks

(initially 8 mg)

(n = 221)

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

Study Design: International, Randomized, Double-Blind, Active-Controlled Study

Key Inclusion

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

Key Exclusion

Current or previous IV bisphosphonate treatment

*Per protocol and zoledronic acid 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.

Denosumab 120 mg SC and Placebo IV* q4 wks (n = 950)

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

Analysis cutoff date: October 2009

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

Zoledronic acid 951 733 544 407 299 207 140 93 64 47

Denosumab 950 758 582 472 361 259 168 115 70 39

Pts at Risk, n Study Mo

0

1.00

Pro

po

rtio

n o

f S

ub

jec

ts W

ith

ou

t S

RE

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

KM Estimate of Median Mos

Denosumab

Zoledronic acid

20.7

17.1

HR: 0.82 (95% CI: 0.71-0.95; P = .0002, noninferiority; P = .008, superiority)

18% Risk

reduction

Time to First On-Study SRE

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

Novel Study Design: Co-primary End Points

Abiraterone 1000 mg daily

+

Prednisone 5 mg BID

(actual n = 546)

Co-primary end points:

• rPFS (central review)

• OS

Placebo daily

+

Prednisone 5 mg BID

(actual n = 542)

Progressive mCRPC

without prior

chemotherapy;

Asymptomatic or

mildly symptomatic

Patient

Population

BID, twice daily; rPFS, radiographic progression free survival; OS, overall survival; HR-QoL, Health-related quality of

life; FACT-P, Functional Assessment of Cancer Therapy-Prostate; BPI-SF, Brief Pain Inventory-Short Form; ECOG

PS, Eastern Cooperative Oncology Group performance status; PSA, prostate-specific antigen.

5

aStratification by ECOG PS 0 vs 1.

R A N D O M I Z E D

1:1a

Secondary end points:

• Time to opiate use

• Time to initiation of

chemotherapy

• Time to ECOG PS

deterioration

• Time to PSA

progression

Exploratory end points:

• HR-QoL (FACT-P, BPI-SF)

Study COU-AA-302

Abiraterone Doubled Time to rPFS

IA3 data. rPFS assessed by investigator review at prespecified IA.

100

80

60

40

20

0

0

Su

bje

cts

Wit

ho

ut

Pro

gre

ss

ion

or

De

ath

(%

)

6 12 18 30 36 24

546

542

389

244

240

133

157

78

20

7

0

0

Abiraterone

Prednisone

117

45

Months From Randomization

Abiraterone

Prednisone

Abiraterone (median, mos): 16.5

Prednisone (median, mos): 8.3

HR (95% CI): 0.53 (0.45-0.62)

p Value: < 0.0001

15 9 3 21 27 33

485

406

311

176

195

99

131

62

66

20

4

0

11

OS Favors Abiraterone

IA3 data. aPrespecified significance level by O’Brien-Fleming Boundary = 0.0035.

100

80

60

40

20

0

0

Su

bje

cts

Wit

ho

ut

De

ath

(%

)

6 12 18 30 36 24

546

542

524

508

482

465

421

400

68

67

0

0

Abiraterone

Prednisone

333

283

Months From Randomization

Abiraterone

Prednisone

Abiraterone (median, mos): 35.3

Prednisone (median, mos): 30.1

HR (95% CI): 0.79 (0.66-0.95)

p Valuea: 0.0151

15 9 3 21 27 33

538

534

503

492

452

437

393

361

175

153

15

9

13

Improvement in All Clinical End Points

IA3 data. Note: All secondary end points remain significant after adjusting for multiplicity testing.

Abiraterone Prednisone

Median (months)

Median (months)

HR (95% CI) p Value

Secondary end points

Time to opiate use

(cancer-related pain) NR 23.7 0.71 (0.59-0.85) 0.0002

Time to chemotherapy

initiation 26.5 16.8 0.61 (0.51-0.72) < 0.0001

Time to ECOG PS

deterioration 12.3 10.9 0.83 (0.72-0.94) 0.0052

Time to PSA progression 11.1 5.6 0.50 (0.43-0.58) < 0.0001

Exploratory end points

Time to BPI-SF pain

interference progression 10.3 7.4 0.80 (0.68-0.93) 0.0049

Time to degradation in

FACT-P (total score) 12.7 8.3 0.79 (0.67-0.93) 0.0046

16

PREVAIL: A Phase 3 trial of enzalutamide after progression on ADT in men with mCRPC

Patient population:

• 1717 men with progressive mCRPC

• Asymptomatic/ mildly symptomatic

• Chemotherapy-naïve

• Steroids allowed but not required

Co-primary endpoints:

• OS

• rPFS

Enzalutamide 160 mg/day (capsules)

n=872

Placebo n=845

R A N D O M I Z E D

1:1

ADT=androgen-deprivation therapy; mCRPC=metastatic castration-resistant prostate cancer; OS=overall survival; rPFS=radiographic progression-free survival.

Beer TM, et al. ASCO-GU 2014; Oral presentation; ClinicalTrials.gov identifier: NCT01212991.

Enzalutamide prolonged radiographic progression-free survival

3 6 15 18 21 12

100

80

60

40

20

0 0

rPFS

(%

)

Months

9

514 256 5 1 0 34 832 128 Enzalutamide, n

305 79 0 0 0 5 801 20 Placebo, n

Placebo

Enzalutamide

HR=0.186 (95% CI: 0.15–0.23); p<0.0001

CI=confidence interval; HR=hazard ratio; rPFS=radiographic progression-free survival.

Beer TM, et al. ASCO-GU 2014; Oral presentation.

Estimated median rPFS, months (95% CI): Enzalutamide: NYR (13.8, NYR); Placebo: 3.9 (3.7, 5.4) NYR = Not Yet Reached

Enzalutamide reduced the risk of death by 29%

3 6 30 33 36 12

100

80

60

40

20

0 0

Surv

ival

(%

)

Months

9

863 850 33 2 0 797 872 824 Enzalutamide, n

835 781 27 2 0 701 845 744 Placebo, n

Placebo

Enzalutamide

HR=0.706 (95% CI: 0.60–0.84); p<0.0001

15

745

644

18

566

484

21

395

328

24

244

213

27

128

102

CI=confidence interval; HR=hazard ratio.


Estimated median OS, months (95% CI): Enzalutamide: 32.4 (30.1, NYR); Placebo: 30.2 (28.0, NYR) NYR = Not Yet Reached

Enzalutamide delayed median time to chemotherapy by 17 months

3 6 30 33 36 12

100

80

60

40

20

0 0

Cyt

oto

xic

che

mo

the

rap

y fr

ee

(%

)

Months

9

854 799 21 2 0 665 872 751 Enzalutamide, n

734 518 9 0 0 324 845 415 Placebo, n

HR=0.35 (95% CI: 0.30–0.40); p<0.0001

15

575

257

18

388

165

21

252

103

24

158

64

27

78

25

Placebo: 10.8 months

Enzalutamide: 28.0 months

CI=confidence interval; HR=hazard ratio.


Metastásico, sin

quimioterapia previa,

asintomático

Metastásico, sin


sintomático

Metastásico,

Post-docetaxel

Ácido zoledrónico

Segunda línea hormonal Docetaxel

Docetaxel Mitoxantrone Otros (CTX, VNB)

El CPRCm hasta 2010

Metastásico, sin


asintomático

Metastásico, sin


sintomático

Metastásico,

Post-docetaxel

Ácido zoledrónico

Denosumab

2ª línea hormonal Docetaxel

Sipuleucel (USA) Abiraterona

Enzalutamida

Docetaxel Rad 223 (EAP)

Cabazitaxel Abiraterona

Mitoxantrone Rad 223 (EAP) Enzalutamida

CPRCm en 2014


ID del evento:



15 de mayo de 2013 • 19:00h – 22:00h



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, segunda línea: cabazitaxel) (nivel evidencia 1)

• Abiraterona y Enzalutamida mejoran la supervivencia en pacientes que han progresado a docetaxel (nivel 1) y antes de la QT


ID del evento:



15 de mayo de 2013 • 19:00h – 22:00h



Consideraciones finales

• La inmunoterapia con Sipuleucel-T mejora la supervivencia en pacientes asintomáticos o mínimamente sintomáticos (nivel 1)

• En pacientes con metástasis oseas sintomáticas Rad 223 mejora la supervivencia en pacientes no tratados con docetaxel y tras progresión al mismo

• Queda por definir la mejor secuencia terapéutica en el CPRCm

• La inclusión de pacientes en ensayo clínico sigue siendo primordial: facilita el acceso a fármacos y responde a preguntas relevantes en nuestra práctica clínica.

MUCHAS GRACIAS

Documents

Manejo del cáncer de próstata metastásico en el 2014 · Introducción II •Denominamos cáncer de próstata resistente a la castración (CPRC) al cáncer de próstata que progresa