i trattamenti successivi

IRCCS Azienda Ospedaliera Universitaria San Martino –
IST
Istituto Nazionale per la Ricerca sul Cancro
A progressione da docetaxel, quali
razionali e quali evidenze per i
trattamenti successivi?
Giuseppe Fornarini
U.O. Oncologia medica 1
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OT
ABI
taxotere
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COU 301 AA+P vs P OS 15.8 vs 11.2
ADT-> TXT
AFFIRM ENZA vs placebo OS 18.4 vs 13.6
TROPIC Caba vs mitoxantrone OS 15.1 vs 12.7
AFFIRM ENZA vs placebo OS 18.4 vs 13.6
ADT-> ABI-> TXT
TROPIC Caba vs mitoxantrone OS 15.1 vs 12.7
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COU 301 AA+P vs P OS 15.8 vs 11.2
ADT-> TXT
AFFIRM ENZA vs placebo OS 18.4 vs 13.6
TROPIC Caba vs mitoxantrone OS 15.1 vs 12.7
AFFIRM ENZA vs placebo OS 18.4 vs 13.6
ADT-> ABI-> TXT
TROPIC Caba vs mitoxantrone OS 15.1 vs 12.7
…i trattamenti successivi: come scegliere?
AA
ENZA
CABA
CABA
ENZA
ENZA
CABA
CABA
ABI
ABI
CABA
ENZA
ABI
ABI
ENZA
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innumerevoli combinazioni di sequenze e a
complicare la scelta subentrano ulteriori variabili:
sintomatico
Malattia viscerale
asintomatico
PS
LDH/Hb/ALP
…i trattamenti successivi:
come scegliere?
 Nessuno studio Head to Head
 No confronti: differente popolazione inserita negli studi
 Anticipo nei trattamenti
 Diversa gestione dei pazienti
 Aumento del PSA o riduzione non corrisponde sempre
a risposta
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and….
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CAST:
63 pts CAB-> ABI
69 pts ABI-> CAB
OS was 19.1 month - PFS 8.1 month
OS was 17.0 months - PFS 6.5 month
Although partial responses to cabazitaxel occurred in both groups, Abi→Cab treated
patients had a significantly decreased antitumor response from cabazitaxel than Cab→Abi
treated patients (median PFS 5.0 versus 2.6 months, p < 0.001).
Wissing MD et all. Int J Cancer 2014 Sep 20. doi: 10.1002/ijc.29231. [Epub ahead of print]
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Azad A. ESMO 214
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Azad A. ESMO 214
Retrospective cohort of 275 consecutive
patients treated with cabazitaxel
• Treatment sequences received:
– DOC  CAB only (n=158)
– DOC  ABI or ENZ  CAB (n=68)
– DOC  CAB  ABI or ENZ (n=43)
SAGB.CAB.14.08.0382c 25/11/2014
• Prognostic factors of overall survival analysed
by multivariate stepwise logistic regression
Oudard S et al, ESMO 2014 (poster 789P)
Retrospective cohort of 275 consecutive
patients treated with cabazitaxel
Prognostic factors of survival
Variable
HR (CI 95%)
P
Ref
<0.001
Metastatic site
Bone only
Visceral
2.19 (1.42-3.38)
Bone + lymph node
1.43 (0.01-2.03)
Lymph node only
0.34 (0.15-0.75)
Duration of response to 1st ADT
> 12 months
Ref
≤ 12 months
1.66 (1.19-2.32)
0.003
SAGB.CAB.14.08.0382c 25/11/2014
Number of active therapies
DOC  CAB only
Ref
DOC  CAB  ART
0.33 (0.20-0.54)
DOC  ART  CAB
0.56 (0.40-0.80)
Oudard S et al, ESMO 2014 (poster 789P)
<0.001
24
SAGB.CAB.14.08.0382c 25/11/2014
Clinical characteristics of patients by
treatment sequence
DOC  CAB
(n=158)
DOC  CAB  ART
(n=43)
DOC  ART CAB
(n=74)
Median age (yr)
69.0
66.0
68.0
Gleason 8-10 (%)
52.7
45.9
48.5
Duration of response to 1st
ADT ≤ 12 mths (%)
36.7
18.6
21.6
ECOG 2 or more (%)
16.2
20.5
4.5
Pain (%)
66.5
62.8
38.7
Hb, median (g/dL)
11.8
12.6
12.9
ALP, median (UI/mL)
140.5
185.0
96.0
PSA, median (ng/mL)
108.0
86.0
88.0
Patients treated with DOCCABABI or ENZ more likely to have
poor PS and pain at initiation of first life-extending therapy post-DOC
Oudard S et al, ESMO 2014 (poster 789P)
25
Overall survival from initiation of next
life-extending therapy post-docetaxel
100%
90%
DOC ABI or ENZ  CAB (n=68)
80%
DOC CAB  ABI or ENZ (n=43)
70%
DOC CAB only (n=158)
60%
50%
40%
30%
20%
10%
0%
SAGB.CAB.14.08.0382c 25/11/2014
0
3
6
9
12
15
18
21
24
27 30 33
Months
36
39
42
45
48
51
54
57
Trend for better OS (p=0.06) in patients treated with DOCCABAABI or ENZA
Oudard S et al, ESMO 2014 (poster 789P)
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… come identificare la miglior
sequenza…fattori predittivi-prognostici
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120%
100%
Who are 100%
the non-responders to enzalutamide
80%
67%
60%
50%
40%
40%
33%
25%
17%
20%
9%
0%
0%
High AR nuclear + CYP17
expression
ARv7 presence
ERG presence
Retrospective analysis in 153 mCRPC patients treated with cabazitaxel plus
prednisone
2nd ADT included anti-androgens, DES, estramustine, ketoconazole, abiraterone,
enzalutamide
Efstathiou E et al. Eur Urol 2014 (epub ahead of print)
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Constitutively active splice variant
SAGB.CAB.14.08.0382c 25/11/2014
AR-FL
ARv7
Antonarakis et al. NEJM 2014 (epub ahead of print on 4 Sept); Guo Z et al. Int J Biol Sci 2011; 7: 815-822
AR-FL: Full-Length Androgen Receptor; NTD: N-Terminal Domain; DBD: DNA-Binding Domain; LBD: LigandBinding Domain; U: Unique N- or C-terminal sequence
ARv7 and resistance to ABI or ENZ
Clinical or radiological PFS
Enzalutamide
AR-V7 Negative
1.0
1.0
HR 8.5
(95% CI 2.8 – 25.4)
p<0.001
0.8
AR-V7 Negative
0.8
0.6
0.6
0.4
0.4
0.2
0.2
HR 16.5
(95% CI 3.3 – 82.9)
p<0.01
AR-V7 Positive
AR-V7 Positive
0.0
0.0
0
SAGB.CAB.14.08.0382c 25/11/2014
Abiraterone
3
6
9
12
0
3
6
9
62 US patients prospectively enrolled to receive enzalutamide (n=31) or abiraterone (n=31)
Antonarakis et al. NEJM 2014 (epub ahead of print on 4 Sept) Antonarakis, ESMO
2014 (abstract 7980)
ARv7 and resistance to ABI or ENZ
Updated overall survival (all combined)
1.0
AR-V7 negative
Median OS >16.0 mo
(CI 95%: 16.0-NR)
Overall survival
0.8
0.6
AR-V7 Positive
Median OS 9.9 mo
(CI 95%: 4.5-13.8)
0.4
HR 5.5
(CI 95%, 2.5-12.0)
P<0.001
0.2
0.0
0
3
6
9
12
15
18
21
SAGB.CAB.14.08.0382c 25/11/2014
Time (months)
62 US patients prospectively enrolled to receive enzalutamide (n=31) or abiraterone (n=31)
Antonarakis et al. NEJM 2014 (epub ahead of print on 4 Sept); Antonaralis, ESMO 2014
(abstract 7980)
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Prevalence di AR – V7 in CRPC (n° 62)
• Pre Enza, Pre ABI: 11.6%
• Post Enza only: 25.0%
• Post Abi only: 51.2%
• Post Enza and Post Abi: 66.7%
AR-V7, the most important AR transcriptional variant, is expressed at
detectable in CTCs in a significant proportion of mCRPC patients
Detection of AR- V7 may be associated with primary and acquired
resistance to Enzalutamide and abiraterone
Antonarakis E.S. NEJM 2014
Docetaxel refractory patients
Cabazitaxel
Abiraterone
• Retrospective review of 186
mCRPC patients
• Retrospective study of 44
patients with mCRPC
• 33 (17.7%) docetaxel refractory*
• Treated with docetaxel → ABI
• Subsequent therapies:
• 7/44 patients docetaxel refractory
– cabazitaxel
– AR-targeted agents (ABI or ENZ)
• No PSA, radiological or clinical
response to ABI
SAGB.CAB.14.08.0382c 25/11/2014
• Multivariate analysis: significant
OS benefit with cabazitaxel versus
new AR-targeted agents
*Docetaxel refractoriness defined as disease progression occurring within 3 mths from docetaxel
initiation and after adequate exposure to docetaxel (ie cumulative dose of ≥225 mg/m2).
Di Lorenzo et al. Eur Urol 2014, 65: 502-507
De Bono Mukherji D. ASCO 2012
NLR and activity of docetaxel
VENICE (1224 patients)
TAX327 (1006 patients)
• dNLR ≥2 & duration of 1st ADT are
prognostic for OS (MVA analysis)
HR
• OS benefit particularily marked for
high dNLR vs mitoxantrone
P
dNLR <2
(CI 95%)
Age (≥ median)
1.24
(1.06-1.44)
0.006
ALP (≥ median)
1.65
(1.41-1.93)
<0.001
Duration of initial
ADT (< median)
1.41
(1.21-1.64)
<0.001
dNLR (≥ median)
1.29
(1.44-1.50)
<0.001
Hemoglobin
(<median)
1.45
(1.24-1.69)
<0.001
Pain at baseline
(PPI ≥2)
1.56
(1.33-1.82)
<0.001
Median OS
Difference
HR
[95% CI]
dNLR ≥2
DOC
M
DOC
M
(n=156)
(n=181)
(n=176)
(n=155)
20.8
18.6
17.4
13.1
2.2 mths
4.3 mths
0.80
[0.59-1.09]
0.72
[0.54-0.95]
• Confirmed PSA decrease ≥50% with
docetaxel:
• dNLR <2: 70%
• dNLR ≥2: 55%
*Posthoc analyses
Van Soest R et al. ESMO 2014 (poster P786)
dNLR: derived neutrophil lymphocyte ratio; ALP: Alkalin Phosphatase; M: mitoxantrone
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conclusioni
• Assenza di studi comparativi
• La ridotta risposta alla ADT in prima linea ( non la
durata della terapia ormonale) e un alto NLR sembra
rappresentare un fattore prognostico e predittivo di
bassa risposta agli AR-TA
• la sequenza ABI-ENZA e viceversa non sembra essere
attiva.
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conclusioni
• La ricerca della variante AR-V7 nelle CTC sembra essere
promettente ma richiede un validazione prospettica
• La sopravvivenza è correlata al numero di linee di trattamento
attive ricevute
• La chemioterapia impatta decisamente sulla sopravvivenza
globale il corretto posizionamento va valutato sul singolo
malato.
Grazie per l'attenzione!!!!