03 mcrpc first and second line elena verzoni.ppt [modalità ... · crpc psa response or failed...
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mCRPC: First andmCRPC: First and Second lineElena VerzoniOncologia Medica Fondazione IRCCS Istituto Nazionale TumoriMilano
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Landmarks of disease progression in CRPC
30 months2-10 years
Failed l h h th lli tilocalized
therapyHormonal therapy chemotherapy palliation
LHRH analogues, antiandrogenis, ADT…
rden
death
Tumou
r bu
r
C t ti i t t P t t CH iti P t t C
diagnosis Symptomatic Asymptomatic PSA rises
M0 M+
Castration‐resistant Prostate Cancer* (CRPC)
Hormone‐sensitive Prostate Cancer(HSPC)
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Castration‐Resistant Prostate Cancer
NONMETASTATIC diseaseNON METASTATIC disease
OLIGOMETASTATIC disease /asymptomatic or mildly
symptomatic patientssymptomatic patients
METASTATIC disease/symptomatic
‐> Chemo‐naïve patients‐> Chemo‐naïve patients
‐> After docetaxel
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NON METASTATIC
CASTRATION‐RESISTANT disease
N t d d t t t• No standard treatment
• Non efficacy data available from docetaxel‐based chemo
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CASTRATION‐RESISTANTCASTRATION RESISTANTOLIGOMETASTATIC disease:
A t ti / Mildl S t ti P ti tAsymptomatic/ Mildly Symptomatic Patients
PRE DOCETAXELPRE‐DOCETAXEL
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ABIRATERONE –ENZALUTAMIDEABIRATERONE ENZALUTAMIDEPRE‐DOCETAXEL
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PREVAIL
End points di efficaciaPazienti mCRPC chemo-naïve
Enzalutamide 160 mg QD
Co-Primari:• rPFS (central review)
OS
RAND
• Progressione del PSA in
naïvein progressione
(N = 1717)Enzalutamide 160 mg QD
(n=872)• OS
Secondari:Tempo all’uso di oppiacei (dolore
DOMIZ
gaccordo con i criteri PCWG2 o progressione radiologica
• Terapia di deprivazione oppiacei (dolore correlato al tumore)Tempo all’inizio della chemioterapiaPlacebo QD
8 )
ZATIO
p pandrogenica in corso
• ECOG PS di grado 0 o 1 p
Tempo al primo evento scheletricoTempo alla
(n =845)ON
1:1
• Asintomatici o lievemente sintomatici, in accordo con BPI-SF(scores da 0 a 1 [asintomatico] progressione PSA(scores da 0 a 1 [asintomatico]o da 2 a 3 [paucisintomatico])
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Enzalutamide: Analisi OS
OS 32.4 mos
OS 30 2 mosOS 30.2 mos
St d t fi t i t i PFS 12 65%
Beer T et al. N Engl J Med 2014;
Stopped at first interim rPFS 12 mo: 65% vs 14%
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COU-AA-302
End points di efficaciaPazienti mCRPC chemo-naïve
Abiraterone acetato 1000 mg QDP d i BID
Co-Primari:• rPFS (central review)
efficaciaRAND
• Progressione del PSA in
in progressione(N = 1088)
Prednisone 5 mg BID(n = 546)
• OSSecondari:
Tempo all’uso di oppiacei
OMIZA
Progressione del PSA in accordo con i criteri PCWG2 o progressione radiologica
• Terapia di deprivazione(dolore correlato al tumore)Tempo all’inizio della chemioterapiaT l d t i t
Prednisone 5 mg BIDPlacebo QD
(n = 542)
ATION
• Terapia di deprivazione androgenica in corso
• ECOG PS di grado 0 o 1 Tempo al deterioramento dell’ECOG PSTTPP
( )N
1:1• Asintomatici o lievemente
sintomatici, in accordo con BPI-SF( d 0 1 [ i t ti ](scores da 0 a 1 [asintomatico]o da 2 a 3 [paucisintomatico])
Ryan et al, N Engl J Med 2013
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Abiraterone: Analisi OS
Median follow-up of 49.2 monthsAbiraterone treatment effect more pronounced when adjusting for 44% of prednisone patients who received subsequent abiraterone (HR = 0.74)
Ryan C et al. ESMO 2014; Abstract 7530 (oral presentation)
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CASTRATION‐RESISTANTCASTRATION RESISTANTOLIGOMETASTATIC disease:
S t ti P ti tSymptomatic Patients
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2004: First‐line Docetaxel: Overall Survival
TAX 327 SWOG 9916
Docetaxel therapy led to improved survival and Docetaxel/estramustine improved median survival by 2 monthsDocetaxel therapy led to improved survival and rates of response in terms of pain, PSA level, and quality of life compared with mitoxantrone/prednisone
Docetaxel/estramustine improved median survival by 2 months compared with mitoxantrone/prednisone
1. Tannock IF et al NEJM 20042. Petrylak DPet al NEJM 2004
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I Linea: Docetaxel +?
Agent Target Summary of trial StatusBevacizumab VEGF Docetaxel vs
Docetaxel+BevacizumabNEGATIVE
Aflibercept VEGF-trap Docetaxel vs D t l Aflib t
NEGATIVEDocetaxel+Aflibercept
Lenalidomide Antiangiogenic Docetaxel vs Docetaxel+Lenalidomide
NEGATIVE
Atrasentan Endothelin receptor
Docetaxel vs Docetaxel+Atrasentan
OPEN TO ACCRUAL
Zibotentan Endothelin receptor
Docetaxel vs Docetaxel+Zibotentan
NEGATIVEreceptor Docetaxel+Zibotentan
Dasatinib Src kinase, BCR-ABL, ckit, PDGFR
Docetaxel vs Docetaxel+Dasatinib
NEGATIVE
C ti (OGX) Cl t i D t l NEGATIVECustirsen (OGX) Clusterin Docetaxel vs Docetaxel+ Cutrirsen
NEGATIVE
DN-101 Vitamin D receptor Docetexel vs Docetaxel+DN-101 NEGATIVE
GVAX Whole-cell vaccine Docetaxel vs Docetaxel+GVAX NEGATIVE
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METASTATIC CASTRATION‐RESISTANT disease
POST‐DOCETAXEL
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Post‐docetaxel Options available
What’s the best sequence to maximize survival?What s the best sequence to maximize survival?
Abiraterone
ADT Docetaxel CabazitaxelPDPD
CYP 17 i hibiDocetaxel
CYP‐17 inhibitor
Chemo
rechallenge
Enzalutamide
No data available for the
New generation antiandrogenEnzalutamide
best sequencing
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TROPIC Trial: OSTROPIC Trial: OS
100
80f O
S (%
)
80
60
Prop
ortion
of
40
P
20
Time (months)
377 299 195 94 31 9
00 6 12 18 24 30
377378
299321
195241
94137
3160
919
De Bono JS et al. Lancet 2010;
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Abiraterone post‐docetaxel: COU‐AA‐301
De Bono NEJM 2011 analisi ad interim studio 301
Fizazi Lancet Oncology 2012 analisi finale studio 301
Logothetis Lancet Oncology 2012S tt li i t di 301 D l SRE
Sternberg Annals of Oncology 2012SECONDARY
Sottoanalisi studio 301 su Dolore e SRE
Sternberg Annals of Oncology 2012Sottoanalisi studio 301 su Fatigue
SECONDARYENDPOINTS
Harland abstract ASCO 2011Sottoanalisi studio 301 su QoL
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COU‐AA‐301 Study DesignPhase 3, multinational, multicenter, randomized, double‐blind, placebo‐controlled study
(147 sites in 13 countries; USA, Europe, Australia, Canada)
FI
ABIRATERONE ACETATO 1000 mg QD
•1195 pts con mCRPC in progressione
•Fallimento 1 o 2 precedenti regimi di CT, uno dei quali a base Docetaxel
NO
A
•Randomizzazione 2:1
•Stratificazione per: •ECOG PS (0‐1 vs. 2)
PROG
Prednisone 5 mg BID
Placebo QD
•Maggior intensità di dolore nelle ultime 24 ore (BPI short form; 0‐3 [assente] vs. 4‐10 [presente])
RESSIQ
•Precedente chemioterapia (1 vs. 2)
•Tipo di progressione (solo PSA vs. Rx PD con o senza PSA PD)
IONEPrednisone 5 mg BID
OS Primary Endpoint:
de Bono et al. NEJM 2011; 364:1995‐2005
(miglioramento del 25%; HR 0.8)
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COU AA 301: Overall SurvivalCOU‐AA‐301: Overall Survival
H d R ti (95% CI) 0 74 (0 638 0 859) P < 0 0001Hazard Ratio (95% CI): 0.74 (0.638-0.859) P < 0.0001
80
100al
(%)
60
80 Abiraterone + prednisone: OS 15.8 mesi
(95% CI; 14.82-17.02)
Braccio Abiraterone+ 4.6 Mesi Su
rviv
a
40
Placebo +
0
20Placebo +
prednisone OS 11.2 mesi
(95% CI; 10.41-13.14)
797 657 473 273 15 0
0
Time to Death (Months)0 6 12 18 24 30
AA/Pdn398 306 183 100 6 0
273 15 0Placebo/Pdn
Fizazi et al. Lancet Oncol 2012; 13(10): 983‐992
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MDV3100 Phase 3 AFFIRM study: post docetaxelMDV3100 Phase 3 AFFIRM study: post‐docetaxel
P ti tPrimary end point:
MDV3100 160mg daily
Patient Population
OS
Secondary endpoints:160mg daily (n=800)1199 patients
with progressive CRPC
Secondary endpoints:
PSA response
OR
Placebo
CRPC
Failed docetaxel h h
TTPSA progression
rPFS
Time to 1st SRE
(n=399)chemotherapy
Randomised 2:1
QoL
* Glucocorticoids were not required but allowed
Scher HI et al. NEJM 2012; 367:1187‐97
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AFFIRM Overall survival: Median benefit 4.8 months
Scher HI et al. NEJM 2012; 367:1187‐97
mOS 18.4 mo vs 13.6 mo (p<0.0001)HR 0.63
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Radium‐223 Targets Bone Metastases
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ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design
TREATMENT
6 injections at 4‐week intervalsR
PATIENTS4‐week intervals
Radium‐223 (50 kBq/kg) + Best standard of care
RAND
• Confirmed symptomatic CRPC
STRATIFICATION
DOMI
• ≥ 2 bone metastases
• No known
• Total ALP: < 220 U/L vs ≥ 220 U/L
• Bisphosphonate use: Yes vs No
Placebo (saline) + Best standard of care
ISED
visceral metastases
• Post-
Yes vs No• Prior docetaxel:
Yes vs No
2:1
N = 922
docetaxel or unfit for docetaxel
N = 922
Planned follow‐up is 3 years
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ALSYMPCA Time to First Skeletal‐Related Event
90
100
HR 0.610; 95% CI, 0.461‐0.807P = 0.00046
60
70
80
RE
P 0.00046
Radium‐223, n = 541
40
50
60
Witho
ut SR
Median: 13.6 months
20
30
40
% W
Placebo, n = 268Median: 8.4 months
0
10
Month 0 3 6 9 12 15 18 21
Radium-223 541 379 214 111 51 22 6 0
Placebo 268 159 74 30 15 7 2 0
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ALSYMPCA Overall Survival
90
100
HR 0.695; 95% CI, 0.581‐0.873P < 0 001
60
70
80 P < 0.001
40
50
60
%Radium‐223, n = 541Median OS: 14.9 months
20
30
40
Placebo, n = 268M di OS 11 3 h
0
10Median OS: 11.3 months
Month 0 3 6 9 12 15 18 21 24 27
Radium- 223 541 450 330 213 120 72 30 15 3 0
Placebo 268 218 147 89 49 28 15 7 3 0
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Which drug for which patient?g pDo we have any choice criteria?
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Caratteristiche dei pazienti dello studio PREVAIL/COUAA302
Characteristics Enzalutamide(n=872)
Placebo(n=845) Characteristics Abiraterone
(n = 546)Prednisone
(n = 542)
Median age≥75-84≥85
72 (43-93)31.4%4.9%
71 (42-93)28.4%6.2%
Median age, years (range) 71 (44-95) 70 (44-90)
Median time from initial diagnosis to first dose (years) 5.5 5.1
Gleason score ≥8 at initial diagnosis
50.6% 52.4%
Distribution of disease at
diagnosis to first dose (years)
Median PSA (ng/mL) 42.0 37.7
Gleason score (≥ 8) at initial 54% 50%Distribution of disease at screeningBone Lymph nodeVisceral disease (lung or li )
85.0%50.1%11.2%4.6%7 3%
81.7%51.4%12.5%4.0%8 9%
Gleason score (≥ 8) at initial diagnosis 54% 50%
Extent of disease
liver)Visceral liverVisceral lungVisceral lung or liverOther soft tissue†
7.3%0.7%
13.0%
8.9%0.4%
12.4%
Bone metastases 83% 80%
> 10 bone metastases 49% 47%
Other soft tissue†
No. of bone metastases at screening 32.7% 32.2%
Soft tissuea 49% 50%
Pain (BPI-SF)g
>10% %
Baseline pain 0-1 on BPI SF-Q3
66.2% 67.5%
0-1 66% 64%
2-3 32% 33%
Beer T et al. N Engl J Med 2014; epub (Supplementary Data)BPI‐SF, Brief Pain Inventory‐Short Form (scale 0‐10).
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Caratteristiche dei pazienti dello studio COUAA301
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Cabazitaxel: TROPIC ‐ Caratteristiche dei pazienti al basale
De Bono JS, et al. Lancet 2010; 376: 1147–54
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Cabazitaxel: malattia aggressiva (PD: PSA + dolore + radiologia)
Fattori predittivi di efficacia nel CRPC progredito al Docetaxel.
De Bono JS, et al. Lancet 2010; 376: 1147–54
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Caratteristiche dei pazienti dello studio AFFIRM
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Take home messagesTake home messages
• New drugs are now available in differentsetting ‐> OS improvement!!
• No comparative data
• No data about sequencing
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Take home messagesTake home messages
f d• Sites of disease
B d• Burden
S t• Symptoms
Diff t f t fil /• Different safety profile/os‐ev
A PS C bidit• Age, PS, Comorbidity
Multidisciplinary approach is mandatory!!