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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
Abiraterona: Stampede/Latitude
Docetaxel: Chaarted, Stampede
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
Abiraterona: Stampede/Latitude
Docetaxel: Chaarted, Stampede
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
James et al. ESMO 2017
James et al. ESMO 2017
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
Christopher Sweeney, MBBS
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)
Christopher Sweeney, MBBS
Concurrent Docetaxel: Prespecified Subgroup of Interest(Biology and Treatment Implications)
Christopher Sweeney, MBBS
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%)
Christopher Sweeney, MBBS
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!!!