Tratamiento sistémico del cáncer de próstata hormono ... · Tratamiento sistémico del cáncer de próstata hormono-sensible metastásico Hasta 2014: Deprivación androgénica:

Dr Pablo MarotoHospital Sant Pau

Tratamiento sistémico del cáncer de próstata hormono-sensible metastásico

➢ Hasta 2014: Deprivación androgénica: tratamiento standard del mHSPC2014-2019: Introducción de terapias que prolongan la Sv en la fase Resistente a Castración:

Docetaxel especialmente con alta carga tumoralAbiraterona, DE DEBUT con alta y baja carga

tumoral>2019: Llegan los antiandrógenos de última generación

mHSPC. Estado del Arte

2014-2019

Abiraterona: Stampede/Latitude

Docetaxel: Chaarted, Stampede

2014-2019



James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session

|

|

James, N. D. et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an

adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 387, 1163–1177 (2016).

Relapsing after previous RP or RT with ≥1 of: • PSA ≥4ng/ml and rising with

doubling time <6m• PSA ≥20ng/ml• Node-positive• Metastatic

Newly-diagnosedAny of:• Metastatic • Node-Positive• ≥2 of: Stage T3/4

PSA≥40ng/mlGleason 8-10

ADT = 71 m (IQR 32 to not reached)ADT + DCT = 81 m (41 to not reached)HR 0.78, 95% CI 0·66–0·93; p=0·006

CHAARTED

Sweeney, C. J. et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N. Engl. J. Med. 2015; 373, 737–746

DEPRIVACIÓN ANDROGÉNICA

CARCINOMA DE PRÓSTATA METASTÁSICO SENSIBLE A CASTRACIÓN RECIENTE

DIAGNÓSTICO

DOCETAXEL

ALTO VOLUMEN: Visceral metastases

or ≥4 bone lesions with ≥1 beyond the vertebral

bodies and pelvis

Type of patients: Patient A: Localized PC at diagnosis that received local treatment. After a while these pts develop metastaseswithout previous treatment with ADT for the metastaticdisease*

Patient B: Patient diagnosed with metastatic prostate cancer

N = 790

mFOLLOW UP = 29m

Sweeney, C. J. et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N. Engl. J. Med. 373, 737–746 (2015).

mCSPC

Sweeney, C. J. et al. Long term efficay and …. J Clin Oncol 2018

(A) High-volume total patient population, (B) Low-volume total patient population, (C) High-volume de novo metastatic patients, (D) Low-volume de novo metastatic patients, (E) High-volume patients with prior local therapy, (F) Low-volume patients with prior local therapy

✓ Conclusión Docetaxel en CPMHS:

Retrasa el tiempo a castraciónMejoría en supervivencia Global

Limitado al subgrupo de pacientes con alto volumen de enfermedad

Mayor evidencia en los pacientes de debut con metástasis

2014-2019



LATITUDE

- Adc Próstata M1 RECIENTE DIAGNÓSTICO: SENSIBLE CASTRACIÓN

- ALTO RIESGO. 2 de:- GLEASON 8 -10 - 3 O MÁS LESIONES

ÓSEAS- METÁSTASIS

VISCERALES (MEDIBLES)

RAMDOM 1:1

ADT + PLACEBO

VS

ADT + ABIRATERONA 1000mg + PREDNISONA

5mg

OP:- mOS- SLP RADIOGRÁFICA.

OS:- TIEMPO A :

- EVENTO ESQUELÉTICO,

- PROGRESIÓN PSA,- SIGUIENTE

TRATAMIENTO- QT - PROGRESIÓN DEL

DOLOR

Fizazi, K. et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N. Engl. J. Med. NEJMoa1704174 (2017). doi:10.1056/NEJMoa1704174

FIRST INTERIM ANALYSISMedian follow-up of 30.4m

ABIRATERONA +ADT : NRADT: 34.7m

ABIRATERONA +ADT : 33mADT: 14.8

Fizazi, K. et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N. Engl. J. Med. NEJMoa1704174 (2017). doi:10.1056/NEJMoa1704174

James, N. D. et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N. Engl. J. Med. NEJMoa1702900 (2017).

doi:10.1056/NEJMoa1702900

Todos los pacientes: N= 1917 Median follow-up = 40m.

James, N. D. et al. Abiraterone for Prostate Cancer Not Previously

Treated with Hormone Therapy. N. Engl. J. Med 2017

HR Todos OS: 0.63, 0.52 to 0.76; P<0.001)No mets: HR 0.75 I Mets: HR 0.61 HR SLP: 0.29; 95% CI, 0.25 to 0.34; P<0.001No mets: 0.21 Mets: 0.31

ESMO 2018

ESMO 2018

Alto riesgo: ¿Abi o Docetaxel?

(criterios puramente médicos)

James et al. ESMO 2017




Dudas

• Docetaxel o terapia dirigida al AR

• Pacientes de bajo volumen

• Potencial de mejora combinando Docetaxel + Terapia dirigida al AR

• Pacientes no de debut

2019: Antiandrógenos

Apalutamida: TITAN

Enzalutamida: ARCHES, ENZAMET

TITAN Study Design

TITAN rPFS: Apalutamide Significantly Reduced Risk of Radiographic Progression or Death by 52%

TITAN rPFS Benefit Consistent Across Subgroups

TITAN OS: Apalutamide Significantly Reduced the Risk <br />of Death by 33%

TITAN OS Benefit Consistent Across Subgroups

• Primary endpoint

• rPFS: time from randomisation to first objective evidence of radiographic progression assessed centrally, or death from any cause within 24 weeks of treatment discontinuation, whichever occurs first

• Radiographic disease progression was defined by RECIST, version 1.1, criteria for soft tissue disease or by appearance of ≥2 new lesions on bone scan compared to baseline (at week 13) or versus the best response on treatment (week 25 or later). New bone scan lesions observed at week 13 required confirmation of ≥2 additional new bone lesions on subsequent scans

ARCHES study design

OS final

analysis

Key eligibility criteria

• mHSPC (confirmed by bone scan, CT or MRI),

histologically confirmed adenocarcinoma

• ECOG PS score of 0 or 1

• Current ADT duration ≤3 months unless prior docetaxel, then ≤6 months

Stratification factors

• Volume of disease (low vs high*)

• Prior docetaxel therapy for mHSPC

(none, 1–5 or 6 cycles)

n=1150

Enzalutamide

160 mg/day +

ADT

Placebo + ADT

R

1 : 1

Key discontinuation criteria

Radiographic progression, unacceptable

toxicity or initiation of an investigational

agent or new therapy for prostate cancer

14 October

2018

rPFS final analysis

OS interim analysis

First

patient

enrolled

21 March

2016

*Defined as metastases involving the viscera or, in the absence of visceral lesions, ≥4 bone lesions, ≥1 of which must be in a

bony structure beyond the vertebral column and pelvic bone

CT=computed tomography; ECOG PS=Eastern Cooperative Oncology Group Performance Status;

MRI=magnetic resonance imaging; OS=overall survival; R=randomised

• At data cut-off, there were 262 events of radiographic progression (enzalutamide + ADT, 77; placebo + ADT, 185) and 25 deaths without radiographic progression (enzalutamide + ADT, 12; placebo + ADT, 13)

• Median follow-up time was 14.4 months; median duration of therapy was 12.8 (range 0.2–26.6) months for enzalutamide + ADT and 11.6 (range 0.2–24.6) months for placebo + ADT

• As of October 14, 2018 (cut-off date), 769 patients were still on treatment; 437 (76%) for enzalutamide + ADT and 332 (58%) for placebo + ADT

ARCHES: Overall rPFS (primary endpoint)

100

80

70

60

50

40

30

20

10

0

90

0 3 6 9 12 15 21 27 33

Time (months)

Fre

e o

f rP

FS

ev

en

t (%

)

574 493 257 63 5ENZA + ADT

No. at risk

576 445 192 39 0PBO + ADT

18 24 30

0

0

ENZA + ADT

PBO + ADT

ENZA + ADT (n=574)

PBO + ADT (n=576)

Median, months(95% CI)

NR(NR, NR)

19.4 (16.6, NR)

12-month eventfree rate estimate

0.84 0.64

HR (95% CI) 0.39 (0.30, 0.50)p<0.0001

CI=confidence interval; HR=hazard ratio; NR=not reached

Subgroup analysis of rPFS

Hazard ratio (95% CI)Subgroup

All patients

Geographic region – Europe

Geographic region – North America

Geographic region – rest of the world

ECOG PS score 0 at baseline

ECOG PS score 1 at baseline

Gleason score at initial diagnosis <8

Gleason score at initial diagnosis ≥8

Disease localisation at baseline – bone only

Disease localisation at baseline – soft tissue only

Disease localisation at baseline – bone and soft tissue

Low volume of disease

High volume of disease

No prior docetaxel therapy

Prior docetaxel therapy

574 (89) / 576 (198)

341 (55) / 344 (121)

86 (12) / 77 (28)

147 (22) / 155 (49)

448 (65) / 443 (143)

125 (24) / 133 (55)

171 (21) / 187 (47)

386 (63) / 373 (148)

268 (33) / 245 (81)

51 (5) / 45 (12)

217 (50) / 241 (102)

220 (13) / 203 (46)

354 (76) / 373 (152)

471 (68) / 474 (164)

103 (21) / 102 (34)

0.39 (0.30, 0.50)

0.43 (0.31, 0.59)

0.27 (0.14, 0.54)

0.41 (0.25, 0.68)

0.38 (0.28, 0.51)

0.43 (0.27, 0.70)

0.42 (0.25, 0.70)

0.36 (0.27, 0.48)

0.31 (0.21, 0.47)

0.42 (0.15, 1.20)

0.44 (0.31, 0.61)

0.24 (0.13, 0.45)

0.44 (0.33, 0.57)

0.36 (0.27, 0.48)

0.53 (0.31, 0.92)

Enzalutamide + ADT / placebo + ADT

N (E)

Favours placebo + ADTFavours enzalutamide + ADT0.0 0.5 1.0 2.01.5

ENZAMET

STRATIFICATION

Volume of metastases*-High vs LowPlanned Early DocetaxelYes vs NoECOG PS- 0-1 vs 2Anti-resorptive therapy-Yes vs NoComorbiditiesACE-27**: 0-1 vs 2-3 Study Site

R

A

N

D

O

M

I

Z

E

ARM A:Testosterone Suppression + standard NSAA

ARM B:Testosterone Suppression+ Enzalutamide (160 mg/d)

Evaluate every 12 weeks

Evaluate every 12 weeks

CRPC therapy at investigator’s discretion at progression

Follow for time to progression and overall survival

• Prior to randomization testosterone suppression up to 12 weeks and 2 cycles of docetaxel was allowed.

• Intermittent ADT and cyproterone were not allowed• NSAA: bicalutamide; nilutamide; flutamide• *High volume: visceral metastases and/or 4 or more bone

metastases (at least 1 beyond pelvis and vertebral column)• **Adult Co-morbidity Evaluation-27

Christopher Sweeney, MBBS

36

Primary endpoint: Overall survival


Proportion alive at 36 months (95% CI)

NSAA Enzalutamide

0.72 (0.68 to 0.76) 0.80 (0.75 to 0.83)

Secondary Endpoints: Progression–free survival (PCWG2)

37

Time to PSA rise, clinical progression or death Time to clinical progression (imaging, symptoms, signs, change of therapy or death)


Concurrent Docetaxel: Prespecified Subgroup of Interest(Biology and Treatment Implications)


Clinical Progression-Free Survival Overall Survival

TestosteroneSuppression

+Docetaxel

N=503 (71% High Volume)

TestosteroneSuppression

+No Docetaxel

N=622(37% High Volume)

Selected docetaxel-relevant adverse events:

Limited to First 6 months

TS + NSAADocetaxel

N=246

TS + ENZADocetaxel

N=254

TS + NSAANo Docetaxel

N=312

TS + ENZANo Docetaxel

N=309

Neutropenic Fever 32 (13%) 35 (14%) 0 1 (<1%)

Sensory neuropathy Gde 2 7 (3%) 24 (9%) 2 (<1%) 0

Gde 3 1 (<1%) 3 (1%) 0 0

Motor Neuropathy G2 1 (<1%) 4 (2%) 0 0

Gde 3 0 0 0 1 (<1%)

Nail discoloration 13 (5%) 25 (10%) 0 0

G1 or 2 Watery eyes 15 (6%) 52 (20%) 0 0

G2 fatigue 35 (14%) 52 (20%) 9 (3%) 32 (10%)


Conclusiones

Las terapias dirigidas al receptor androgénico son el standard of care del CPMHS

Prolongan tiempo a progresión y supervivencia en todos los subgrupos de pacientes

Docetaxel alternativa SOLO en pacientes de alto riesgo y penalizado por toxicidad

Gracias!!!

Documents

Tratamiento sistémico del cáncer de próstata hormono ... · Tratamiento sistémico del cáncer de próstata hormono-sensible metastásico Hasta 2014: Deprivación androgénica: