Diapositiva 1 - Società Urologia Nuova

Opinioni a confronto fra Urologo ed Oncologo
Il carcinoma della prostata:
cosa fare dopo chemio-resistenza
Il punto di vista dell’Oncologo
Dott.ssa M. RIZZO
A.O.R.N. “A. Cardarelli”, Napoli
The evolution of the cancer niche
no validated
predictive models
Nature Reviews|Cancer volume 13, July 2013
Prostate cancer disease continuum: before 2004
Palliative Therapy
Castration
Tumour
volume
2nd-line
hormonal
therapies
Local
therapy*
Symptoms
Non-metastatic
Hormone-sensitive
*e.g. Radiotherapy
Metastatic
Androgen-Independence
adapted by O. Caffo presentation-AIOM Prostata-Milano, 30 nov 2012
Trattamento chemioterapico nel CP
S PHASE SPECIFIC
Antimetabolites
Hydroxyurea
Podophyllotoxin
Campotecine
SPECIFIC
Bleomycin
Check point
G1/S
p53
apoptosis
drug resistance
G2 PHASE
NON PHASE SPECIFIC
Alkylating agents
Alkylating related agents
Intercalating
Antibiotics (mitoxantrone)
M PHASE
SPECIFIC
(antimitotic)
vincristine
vinblastine
paclitaxel
vinorelbina
docetaxel
cabazitaxel
Docetaxel in Prostate Cancer
adapted by O. Caffo presentation-AIOM Prostata-Milano, 30 nov 2012
Prostate cancer disease continuum: after 2004
Docetaxel/chemotherapy
Castration
Tumour
volume
2nd-line
hormonal
therapies
Local
therapy*
Symptoms
Non-metastatic
Hormone-sensitive
*e.g. Radiotherapy
Metastatic
Androgen-Independence
Principi Di Chemioterapia:
Meccanismi di Resistenza
Molecular targets and mechanisms of resistance in PC
 resistance to hormone-therapy (?)
 resistance to chemotherapy (?)
 resistance to immunotherapy (?)
Agarval N. European Urology 61 (2012)
Prostate cancer disease continuum: after 2005
Docetaxel/chemotherapy
Castration
Tumour
volume
2nd-line
hormonal
therapies
Local
therapy*
Rechallenge of Docetaxel
Symptoms
Non-metastatic
Hormone-sensitive
*e.g. Radiotherapy
Metastatic
Androgen-Independence
Prostate cancer disease continuum: after 2012
Docetaxel/chemotherapy
Castration
Tumour
volume
2nd-line
hormonal
therapies
Local
therapy*
Rechallenge of Docetaxel
Cabazitaxel
Symptoms
Non-metastatic
Hormone-sensitive
*e.g. Radiotherapy
Metastatic
Androgen-Independence
TROPIC: phase III registration trial of second-line Cabazitaxel
Stratified by ECOG PS
(0,1 vs 2) and measurable vs
nonmeasurable disease
Patients with
metastatic
CRPC progressing
on docetaxel
(N = 755)
•
•
Mitoxantrone 12 mg/m2 IV q3w +
Prednisone 10 mg/day PO for 10 courses
(n = 377)
Cabazitaxel 25 mg/m2 IV q3w +
Prednisone 10 mg/day PO for 10 courses
(n = 378)
Primary endpoint: OS
Secondary endpoints: PFS, response rate, safety
de Bono JS, et al. Lancet. 2010;376:1147-1154.
Chemotherapy with Docetaxel
Not more than once
adapted by O. Caffo presentation-AIOM Prostata-Milano, 30 nov 2012
Cabazitaxel vs Docetaxel
Cabazitaxel
•
•
•
•
Blocco del fuso mitotico
Bassa affinità P-gp
Pre-clinica attività in tumori refrattari a docetaxel
In vitro: blocco del trasporto intracellulare del
recettore androgenico
Microtubule
stabilization
Darshan M.S. et al Can Res 2011;15; 71(18): 6019-29
Cabazitaxel: key differences with docetaxel
Docetaxel
Cabazitaxel
Stabilization of microtubules
✔
✔
Activity in taxane-sensitive cell lines
✔
✔
Activity in taxane-sensitive in vivo tumor models
✔
✔
Orally bioavailable in murine models
✔
Crosses blood-brain-barrier in vivo
✔
Active in chemotherapy-resistant or insensitive
cell lines
✔
Active in chemotherapy-resistant or insensitive
in vivo tumor models
✔
Active in chemotherapy-resistant or insensitive
patients
RECHALLENGE (?)
TROPIC (?)
Patients who progressed while receiving docetaxel
Proportion of Overall Survival
100
90
80
70
MTX
CBZ
10.9
13.8
60
50
40
30
Symbols = Censors
20
MTX + PRED
CBZ + PRED
10
0
Number at Risk
0
6
12
18
24
30
MTX + PRED
CBZ + PRED
ASCO 2011
230
239
172
194
98
130
33
44
2
9
1
0
Time (Months)
ASCO GU 2011
Patients who progressed after completion of docetaxel
Proportion of Overall Survival
100
90
80
70
MTX
CBZ
15.6
18
60
50
40
30
Symbols = Censors
20
MTX + PRED
CBZ + PRED
10
0
Number at Risk
MTX + PRED
CBZ + PRED
0
6
12
18
24
30
147
139
128
127
90
101
34
46
9
19
0
4
Time (Months)
ASCO GU 2011
Prostate cancer disease continuum: today
Death
Docetaxel/chemotherapy
Castration
2nd-line
hormonal
therapies
Bicalutamide
Flutamide
Nilutamide
Tumour
volume
Cabazitaxel
Local
therapy*
Abiraterone
Continued AR
signalling
Symptoms
Asymptomatic
Non-metastatic
Hormone-sensitive
Metastatic
Castration-resistant
*e.g. Radiotherapy
Kohli & Tindall. Mayo Clin Proc 2010;85:77–86.
Terapia ormonale nel carcinoma prostatico (2)
Il testosterone guida la crescita delle cellule tumorali prostatiche
 Ruolo del diidrotestosterone (DHT)
nell’attivazione delle pathway tumorali della
cellula prostatica [Huggins]
HSPC
La crescita tumorale dipende
 Centralità del recettore androgenico nella
modulazione dei processi tumorali [Jensen]
dal testosterone circolante prodotto
da surrene e testicoli
ADT mantiene la testosteronemia sotto
la soglia di castrazione
blocco della crescita tumorale
Dillard et al, Mol Cell Endocrinol 2008
Castration-Resistance Prostate Cancer
Il testosterone guida la crescita delle cellule tumorali prostatiche
HSPC
CRPC
La crescita tumorale dipende
il TUMORE RIPRENDE A CRESCERE
dal testosterone circolante prodotto
anche se la testosteronemia è sotto la
da surrene e testicoli
soglia di castrazione (< 20-50 ng/dl)
ADT mantiene la testosteronemia sotto
la soglia di castrazione
IPERSENSIBILIZZAZIONE DEL RECETTORE TESTOSTERONE
- Aumento della sensibilità / affinità del AR vs testosterone
- Aumento del numero e/o stabilizzazione del AR
blocco della crescita tumorale
IL TUMORE si svincola dal testosterone circolante
perchè AUTOPRODUCE TESTOSTERONE
Dillard et al, Mol Cell Endocrinol 2008
Advanced prostate cancer: future management
Pre-chemotherapy
LHRH analogues
Anti-androgens
Additional
hormonal
approaches
First line
chemotherapy
Docetaxel
Post-chemotherapy
Cabazitaxel
Abiraterone
Enzalutamide*
Radium-223*
Abiraterone*
*Not currently licenced in Italy
mCRPC=metastatic castration-resistant prostate cancer; LHRH=luteinising hormone-releasing hormone.
Castration-Resistance Prostate Cancer
3 molecole con risultati positivi e apparentemente simili ma non confrontabili
TROPIC
COU-AA-301 trial
AFFIRM trial
1. De Bono JS at al.Lancet 2010; 376: 1147–54
2. Fizazi K et al. Lancet Oncol 2012; 13: 983–92.
3. Scher HI et al. N Engl J Med 2012;367(13):1187-97
Disegno degli studi: le differenze (1)
Cabazitaxel
designed to detect a 25%
improvement in survival
Mitoxantrone arm
Abiraterone
designed to detect a 20%
improvement in survival
Placebo arm
Interim
analysis
Disegno degli studi: le differenze (2)
Cabazitaxel
designed to detect a 25%
improvement in survival
Mitoxantrone arm
Enzalutamide
designed to detect a 24%
improvement in survival
Placebo arm
Interim
analysis
Disegno degli studi: le differenze (3)
Abiraterone
designed to detect a 20%
improvement in survival
Placebo arm
Interim
analysis
Enzalutamide
designed to detect a 24%
improvement in survival
Placebo arm
Interim
analysis
Paesi coinvolti negli studi registrativi
Paesi Partecipanti
TROPIC
(cabazitaxel)
COU-AA-301
(Abiraterone)
AFFIRM
(Enzalutamide)
USA, EU, Canada,
Australia
USA, EU, Canada,
Australia
USA, EU, Canada, ,
Australia
South America, Africa,
India, Asia, Russia
South America, Africa
Caratteristiche basali dei pazienti:
PSA, pain e precedenti linee di CT
(>75Y %)
PSA
basal
Pain
Pts 2L
Pts 3L
Pts > 3L
Cabazitaxel
68 (18%)
144
45%
69%
25%
6%
Abiraterone
69 (28%)
129
44%
70%
30%
0%
Enzalutamide
69 (25%)
107
Asintom.
72%
25%
3%
Età
Differenti metodologie
Progression
based on
Timing
IMAGING
Criteria
Efficacy on PAIN
compared
Cabazitaxel
Imaging or
PSA or
Pain
8 weeks
( 2 mo)
PCWG 1
vs mitoxantrone
Abiraterone
PSA and
Imaging and
Pain
4 mo or
7 mo or
10 mo
different
vs placebo
Enzalutamide
Imagin/Bone/SRE
AND new Therapy
12 weeks
(3 mo)
PCWG2
vs placebo
Differenze nei risultati e durata trattamento
Time to PSA
progression
Time to
imaging
progression
OS
Sperimental
OS
Comparator
HR
PFS
Treatment
Cabazitaxel
6.4 mo
PSA-r 39%
8.8 mo
ORR 14%
15.1 mo
Final
12.7 mo
Final
0.70 Final
2.8 mo
4.5 mo
Abiraterone
10.2 mo
PSA-r 38%
5.6 mo
ORR 14%
14.8 mo IA
15.8
10.9 mo IA
11.2
0.65 IA
0.74
Final
5.6 mo
PFS-imag
8 mo
Enzalutamide
8.3 mo
PSA-r 54%
8.3 mo
ORR 29%
18.4 mo IA
13.6 mo IA
0.63 IA
IA= intermin analysis
PSA-r= biochemical response
PFS-imag= PFS radiological
8 mo
Treatment Choice
Age
- Younger than 60 yrs
- 60-80 yrs
- Older than 80 yrs
Performance Status Score
- 0/1
-2
-3
Pain
- None
- Moderate
- Severe
PSA doubling time
< 3 mos
> 3 mos
PSA DT
(t2 - t1)log(2)/log(P2/P1)
Pt’ Comorbidities
- Elevated LFTs
- Diabetes
- Cardiac Disease
- Neuropathy
- Anemia/cytopenia
Comorbidities are the most important prognostic factor for 3-yr survival in pts younger
than 70 yrs [1]. Presence of ≥ comorbidities significantly increase the risk of death [2]
1. Hall WH, et al. Prostate Cancer Prostatic Dis 2005; 8:22-30; 2. Houterman S, et al. Crit Rev Oncol Hematol. 2006; 58:60-67.
Cabazitaxel and Abiraterone phase III studies
Pts characteristics &
Outcome
Cabazitaxel (/MP)
Abiraterone (/P)
Age (years)
68 (62-73)
69 (42-95)
ECOG PS 2
7%
10.7%
Pain at baseline
46%
44.3%
Median PSA (ug/L)
143.9
129
Visceral mets
25%
24.3%
Measurable disease
53%
69%
Number of line of CT > 2
31%
28.2%
PSA response rate
39.2% (34-44.5)
29.1%
Pain response rate
9.2% (4.9-13.5)
NR
Tumour response rate
14.4% (9.6-19.3)
NR
cPFS (1.4-2.8 mths)
rPFS (3.6-5.6 mths)
12.7 —› 15.1
10.9 —› 14.8
PFS (months)
Overall Survival (months)
COU-AA-301: Final OS by subgroup analyses
Fisazi et al , Lancet Oncol 2012; 13: 983–92
TROPIC: final results
De Bono et al , Lancet Oncol 2010; 376: 1147–54
….è mandatorio nel CRPC
↑ sopravvivenza
Preservare/
Migliorare QoL
Abiraterone ritarda il tempo al deterioramento della QoL
Il tempo mediano al deterioramento della QoL (punteggio totale FACT-P) è stato di 12.1 mesi
nel gruppo abiraterone + prednisone e 8.4 mesi nel gruppo placebo + prednisone
Harland et al. ECCO 2011: Abstract 7001
Il braccio Abi+prednisone ha
evidenziato una percentuale di
palliazione significativamente
maggiore rispetto al braccio
placebo+prednisone
% of Patients Experiencing Palliation
Palliazione del dolore e tempo alla palliazione
70
60
P = 0.0005
50
45%
40
28.8%
30
20
10
0
Abiraterone + prednisone
Placebo + prednisone
AA
AA
Placebo
Placebo
Logothetis et al. The Lancet-Oncology 2012
Patient segments who are unsuitable for CT
Patient Type 0a
Unsuitable for
chemotherapy
Patient Type 0b
Discontinued
due to toxicity
Distribution of 1st line docetaxel patients
Patient Type 1
Received up to 4
cycles of
Taxotere and
has never
responded to the
treatment.
21%
Patient Type 2
Patient Type 3
Patient Type 4
Responding
during the initial
cycles of
treatment and
progresses while
on treatment
(patient received
between 4 to 10
consecutive
cycles).
Responding
during all
treatment
(patient received
up to 10 or more
cycles). Then
patient
progresses
within 6 months
after the last
cycle of Taxotere
Responding
during all
treatment
(patient received
up to 10 or more
cycles). Then
patient
progresses more
than 6 months
after the last
cycle of Taxotere
27%
34%
20%
In the past, present and future...
…clinical experience and multidisciplinary