Download Abiraterone acetate

The New era of CRPC:
few targets for a pletora of agents!
Cabazitaxel
Sipuleucel-T
Alpharadin
ADT
PD
Docetaxel
PD
Abiraterone
Legend:
MDV3100
Hormonal therapy
Chemotherapy
Radiometabolic therapy
TAK700
Immunotherapy
New Hormonal Therapies
Roberto Iacovelli
Current strategies for androgen inibition in CRPC
LH-RHa
Abiraterone
TAK700
Bicalutamide
MDV3100
New Hormonal Therapies
AR
Roberto Iacovelli
Molecular basis for Androgen inibition in CRPC
Hormon
sensitive
PCa
CRPC
cells
Negative
control
Il recettore per l’androgeno (AR) è
espresso (RNA) sia nei tumori sensibili
che resistenti alla castrazione
Dillard et al. Mol Cell Endocrinol. 2008
New Hormonal Therapies
Roberto Iacovelli
Molecular basis for Androgen inibition in CRPC
Metastasis of CRPC
H&E
AR staining
BP=benign prostate
tissue;
CP=Prostate cancer;
METS=castrationresistant metastatic
tumor
PSA staining
Montgomery et al. Cancer Res 2008;68:4447-4454.
New Hormonal Therapies
Roberto Iacovelli
Molecular basis for Androgen inibition in CRPC
Control
Normal
epithelium
CYP17 is not expressed in
normal prostatic epithelium
New Hormonal Therapies
CRPC cells
CYP17 is expressed in
CRPC cells.
Hormon
sensitive
PCa
CRPC
cells
CYP17 is not expressed in
hormone sensitive cells.
Roberto Iacovelli
Molecular basis for Androgen inibition in CRPC
Expression of steroidogenic enzyme
transcripts in primary and metastatic
prostate tumors
BP=benign prostate tissue;
CP=Prostate cancer;
METS=castration-resistant
metastatic tumor
Montgomery et al. Cancer Res 2008;68:4447-4454.
New Hormonal Therapies
Roberto Iacovelli
Molecular basis for Androgen inibition in CRPC
CRPC cell acquires the ability to
product itself testosterone from
cholesterol by CYP17
New Hormonal Therapies
Roberto Iacovelli
Molecular basis for Androgen inibition in CRPC
Testosterone
CYP17
Hormone sensitive
PCa cell
ENDOCRINE
Pathway
CRPC cell
PARACRINE
Pathway
AUTOCRINE
Pathway
Increase of malignancy
New Hormonal Therapies
Roberto Iacovelli
Molecular basis for Androgen inibition in CRPC
Efstathiou E. Clin Cancer Res 2010;16:1100-1107
New Hormonal Therapies
Roberto Iacovelli
Targeting CYP17
CYP17
inhibitor
CYP17
Iacovelli et al. Anti-Cancer Drugs 2011.
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate
A new molecule who meet oncological need in prostate cancer:
Proved efficacy in post
docetaxel patients
Increase the time to
chemotherapy
Pain
Baseline
PSA
Progression
Tumor/Bone
Progression
ECOG PS Decline
Death
Chemotherapy
Increase OS
24-48 months
Adapted from Halabi S. J Clin Oncol. 2009;27: 2766-2771
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate: proves of efficacy
Abiraterone
acetate
CRPC
chemo- naïve
1 phase III Trial
CRPC
TXT pretreated
1 phase III Trial
3 phase II Trials
1 phase I Trial
Iacovelli et al. Anti-Cancer Drugs 2011.
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate
• Abiraterone acetate: selective inhibitor of androgen biosynthesis
that blocks CYP17 activity
• Primary endpoint: OS
Randomized 2:1
Patients with mCRPC
progressing after 1-2
chemotherapy regimens,
1 of which contained docetaxel
Abiraterone acetate 1000 mg/day +
Prednisone 5 mg BID
(n = 797)
Stratified by ECOG PS, worst pain over previous
24 hrs, previous chemotherapy, type of progression
Placebo +
Prednisone 5 mg BID
(n = 398)
(N = 1195)
Study stopped at planned interim analysis at 534 events because
OS improvement crossed predetermined stopping boundary
de Bono JS et al. N Engl J Med. 2011;364:1995-2005.
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate
OS
Median OS, mos
HR
PFS
Pbo
ABI
10.9
14.8
0.65
Median PFS, mos
HR
Pbo
ABI
3.6
5.6
0.58
95% CI
0.54-0.77
95% CI
0.46-0.73
P value
< .0001
P value
< .0001
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate
Adverse Events
Treatment-Related AEs, %
Abiraterone Acetate
(n = 791)
Placebo
(n = 394)
All Grades
Grade 3/4
All Grades
Grade 3/4
All treatment-related AEs
99
55
99
58
Fluid retention
31
2
22
1
Hypokalemia
17
3
8
1
Cardiac disorders*
13
3
11
2
Hypertension
10
1
8
<1
LFT abnormalities
10
3
8
3
*Most frequent cardiac disorders were tachycardia and atrial fibrillation.
de Bono JS, et al. N Eng J Med. 2011;364:1995-2005. Scher HI, et al. ASCO GU 2011. Abstract 4.
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate
Patients
• Progressive chemonaïve mCRPC patients
(Planned N = 1088)
• Asymptomatic or
mildly symptomatic
R
A
N
D
O
M
I
Z
E
D
Efficacy end points
AA 1000 mg daily
Prednisone 5 mg BID
(Actual n = 546)
Placebo daily
Prednisone 5 mg BID
(Actual n = 542)
1:1
Co-Primary:
• rPFS by central review
• OS
Secondary:
• Time to opiate use (cancerrelated pain)
• Time to initiation of
chemotherapy
• Time to ECOG-PS
deterioration
• TTPP
• Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites
in 12 countries; USA, Europe, Australia, Canada
• Stratification by ECOG performance status 0 vs. 1
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate
Treatment Arms Evenly Matched
AA + P
(n = 546)
Placebo + P
(n = 542)
71 (44-95)
70 (44-90)
Median time from initial diagnosis to first dose (years)
5.5
5.1
Median PSA (ng/mL)
42.0
37.7
Median testosterone (ng/dL)
4.0
4.0
Median alkaline phosphatase (IU/L)
93.0
90.0
Median hemoglobin (g/dL)
13.0
13.1
Median lactate dehydrogenase (IU/L)
187.0
184.0
Gleason score (≥8) at initial diagnosis
54%
50%
83%
80%
48%
47%
49%
50%
0-1
66%
64%
2-3
32%
33%
Median age, years (range)
Extent of disease
Bone metastases
>10 bone lesions
Soft tissue or node
Pain (BPI Short Form)
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
New Hormonal Therapies
Roberto Iacovelli
Progression-Free (%)
Abiraterone acetate: PFS
100
AA + P (median, mos):
PL + P (median, mos):
HR (95% CI):
80
P value:
NR
8.3
0.43 (0.35-0.52)
< 0.0001
60
40
20
0
AA + P
PL + P
0
3
6
9
12
15
18
Time to Progression or Death (Months)
AA 546
PL 542
489
400
340
204
164
90
46
30
12
3
0
0
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate: OS
AA + P (median, mos):
PL + P (median, mos):
HR (95% CI):
100
P value:
Survival (%)
80
NR
27.2
0.75 (0.61-0.93)
0.0097
60
40
20
0
AA + P
PL + P
3
0
6
9
12
15
18
21
24
27
30
33
0
2
0
0
Time to Death (Months)
AA 546
PL 542
538 524
534 509
503
493
482
465
452 412
437 387
258
237
120
106
27
25
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate: secondary end-points
AA + P
Median
(months)
Placebo + P
Median
(months)
NR
23.7
Time to chemotherapy
initiation
25.2
16.8
Time to ECOG PS
deterioration
12.3
10.9
Time to PSA
progression
11.1
5.6
Time to opiate use
(cancer related pain)
HR (95% CI)
0.69
(0.57, 0.83)
0.58
(0.49, 0.69)
0.82
(0.71, 0.94)
0.49
(0.42, 0.57)
P Value
0.0001
<0.0001
0.0053
<0.0001
Note: All secondary end points remain significant after adjusting for multiplicity testing
Patient Reported Outcomes favored AA +P vs. Placebo +P
Full data to be reported
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate: Subsequent
Therapy Was Common
AA + P
(n = 546)
n (%)
Placebo + P
(n = 542)
n (%)
242 (44.3)
327 (60.3)
207 (37.9)
287 (53.0)
Cabazitaxel
45 (8.2)
52 (9.6)
Ketoconazole
39 (7.1)
63 (11.6)
Sipuleucel-T
27 (4.9)
24 (4.4)
Abiraterone acetate*
26 (4.8)
54 (10.0)
No. with selected
subsequent therapy for
mCRPC
Docetaxel
Despite 16% of patients did not receive subsequent therapy
compared to placebo, AA increase OS!
*Prior to unblinding (e.g. not per protocol)
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate
Adverse Events
Treatment-Related AEs, %
COU-AA-301
(n = 791)
COU-AA-302
(n = 542)
All Grades
Grade 3/4
All Grades
Grade 3/4
All treatment-related AEs
99
55
NA
NA
Fluid retention
31
2
28
0.7
Hypokalemia
17
3
17
2
Cardiac disorders*
13
3
19
6
Hypertension
10
1
22
4
LFT abnormalities
10
3
10
4
12
5.4
11
3
ALT increase
AST increase
*Most frequent cardiac disorders were tachycardia and atrial fibrillation.
de Bono JS, et al. N Eng J Med. 2011;364:1995-2005. Scher HI, et al. ASCO GU 2011. Abstract 4.
New Hormonal Therapies
Roberto Iacovelli
Abiraterone acetate: Correct timing
INDIPENDENTE
da T circolante autoproduzione T
DIPENDENTE
da T circolante
20-50 ng/dl
IPERSENSIBILE
Totalmente
dipendente
da T circolante
>20-50 ng/dl
• AR stimolato anche
aspecificamente
• sintesi enzimi
produzione T
• AR ipersensibile o iperespresso
• sintesi di TUTTI gli enzimi produzione T
• AR ipersensibile o iperespresso
• sintesi di alcuni enzimi produzione T
• AR normale
• No enzimi produzione T
New Hormonal Therapies
Roberto Iacovelli
Cytoreduction and androgen signaling modulation by abiraterone acetate
(AA) plus leuprolide acetate (LHRHa) versus LHRHa in localized high-risk
prostate cancer (PCa): Preliminary results of a randomized preoperative
study.
Patients
• high risk PCa
(clinical stage
≥T1c and biopsy
Gleason score
≥8, or ≥T2b,
Gleason ≥ 7 and
PSA > 10ng/ml).
R
A
N
D
O
M
I
Z
E
D
Efficacy end points
AA 1000 mg daily
Prednisone 5 mg BID +
LHRHa for 12 wks
S
U
R
G
E
R
Y
LHRHa
For 12 wks
2:1
Results:
AA+LHRHa
LHRHa
ypT2N0
60%
33%
Near pCR
24%
8%
N+
28%
50%
R1
8%
33%
Co-Primary:
• difference in down
staging (≤ ypT2)
• safety
Secondary:
• difference in androgen
biosynthesis, androgen
signaling, proliferation
apoptosis and
candidate treatment
resistance pathways.
Abiraterone acetate
35% of patients had PD as best
response a 3 mos with Abiraterone.
What is the mechanism of resistance?
New Hormonal Therapies
Roberto Iacovelli
Enzalutamide (MDV3100)
New Hormonal Therapies
Roberto Iacovelli
Enzalutamide (MDV3100)
New Hormonal Therapies
Roberto Iacovelli
Enzalutamide (MDV3100)
Antitumor activity of Enzalutamide in Phase I/II study
Activity seems to be independent of previous chemotherapy
Scher HI, et al. Lancet 2010;375:1437
New Hormonal Therapies
Roberto Iacovelli
Enzalutamide (MDV3100)
The AFFIRM Trial Design
Primary End-Point: OS
Stratification variables: ECOG-PS, meand BPI (<4, ≥4)
Statistical design: power 90% to detect a 24% reduction in mortality (target HR= 0.76).
New Hormonal Therapies
Roberto Iacovelli
Enzalutamide (MDV3100)
Baseline patient demographics:
New Hormonal Therapies
Roberto Iacovelli
Enzalutamide (MDV3100)
RESULTS:
The AFFIRM study was halted and unblinded after the interim analysis (520 events).
Target 0.76!
New Hormonal Therapies
Roberto Iacovelli
Enzalutamide (MDV3100)
RESULTS:
PSA response rate, PSA-PFS and Time To First Skeletal Event
*Smith MR et al. Lancet 2012
HR denosumab vs placebo 0.84!*
New Hormonal Therapies
Roberto Iacovelli
Enzalutamide (MDV3100)
RESULTS:
Survival benefit across all subgroups
New Hormonal Therapies
Roberto Iacovelli
Enzalutamide (MDV3100)
RESULTS:
Safety
New Hormonal Therapies
Roberto Iacovelli
Conclusions
Androgen pathways is the driver of tumor progression of
prostate cancer.
Resistance to LHRHa don’t mean resistance to all hormonal
strategies.
CYP17 and AR are the main targets of new hormonal therapies
The sequential use of these agents may be feasible but not
proven in large prospective trial.
Precocious use of new agents seems to be more active.
Hormonal strategies in CRPC: it’s only the beginning…
Q&A
Durante il trattamento l’analogo deve essere proseguito?
È Possibile rinunciare al trattamento con prednisone?
In controllo con placebo o Prednisone è idoneo?
New Hormonal Therapies
Roberto Iacovelli
Is prednisone an active control for CRPC?
AA + P
(n = 546)
Placebo + P
(n = 542)
RR (95% CI)
P Value
62%
24%
NA
<0.0001
N=220
N=218
RECIST: Defined
objective response
36%
16%
2.273
(1.591, 3.247)
<0.0001
Complete response
11%
4%
Partial response
25%
12%
Stable disease
61%
69%
Progressive disease
2%
15%
PSA decline ≥50%
The AFFIRM study reported a PSA decline >50% in 2% of patients
treated with placebo alone!
New Hormonal Therapies
Roberto Iacovelli