Il trattamento del carcinoma della prostata
in fase di resistenza alla castrazione
Giuseppe Procopio, MD,
Treatment options for patients with CRPC
Zoledronic
Acid1
Sipuleucel-T3
Cabazitaxel4
Docetaxel2
2002
2004 . . . . . . . . . . . . . . .
Denosumab5
.
.
2010
Abiraterone6
2011
The near future
MDV3100 7
Alpharadin8
1Saad
et al. J Natl Cancer Inst 2002; 94: 1458–1468
et al. N Engl J Med 2004;351(15): 1502-1512
3Kantoff et al. N Engl J Med 2010; 363(5): 411-422
4de Bono et al. Lancet. 2010; 376(9747): 1147-1154
5Fizazi et al. Lancet 2011; 377(9768): 813-822
2Tannock
6de
Bono et al. N Engl J Med 2011; 346(21): 1995-2005
7Scher HI et al. N Engl J Med. 2012 Aug 15.
8
] Parker C. et al. ESMO 2011: Abstract 2, and ASCO GU 2012
Prostate Cancer Clinical States
Noncastrate
Castration resistant
Diagnoses: 217,730
Clinically
Localized
Disease
Rising PSA
Deaths: 32,050
Clinical
Metastases:
Noncastrate
Rising PSA:
Castrate
Clinical
Clinical
Metastases: Metastases:
Castrate
Castrate
Pre-
1st-Line
Provenge
Docetaxel
Clinical
Metastases:
Castrate
PostCabazitaxel
Abiraterone
MDV3011
Radium 223
With detectable metastases:
deaths from cancer exceed
those from other causes
Modified from Scher and Heller. Urology. 2000.
TAX 327
Updated Survival Analysis
Probability of Survival
1.0
Docetaxel q3wk
Docetaxel qwk
Mitoxantrone q3wk
0.8
Median
survival
(months)
Docetaxel q3wk: 19.2
Docetaxel qwk:
17.8
Mitoxantrone q3wk 16.3
0.6
0.4
Hazard
ratio
0.79
0.87
–
P-value
0.004
0.086
–
0.2
0.0
0
1
2
3
4
5
6
7
Years
Berthold DR et al. J Clin Oncol. 2008;26:242-245.
Tannock I. N Engl J Med. 2004;351:1502-1512.
Phase III Trials
Docetaxel plus for CRPC
•
•
•
•
•
•
•
•
Oblimersen sodium1
OGX-0112
Bevacizumab
Aflibercept
Lenalidomide6
Dasatinib3
Atrasentan4
1. Sternberg CN et al. Ann Oncol. 2009 Jul;20(7):1264-9
Zibotentan5
2 .Chi KN et al, J Clin Oncol. 2010 Sep 20;28(27):4247-54
3. Araujo JC et al, Cancer. 2012 Jan 1;118(1):63-71
4.Quinn DI, J Clin Oncol 30, 2012 (suppl; abstr 4511)
5.Trump DL, Prostate. 2011 Sep;71(12):1264-75
6. Petrylak D et al, ESMO 2012 LBA24.
Overall Survival with 2nd line
Chemotherapy for mCRPC
Treatment
Setting
Patients
(N)
Response and overall
survival
950
Median OS: 14.3 months
vs 14.3 months
HR = 0.98
p = 0.7999
755
Median OS: 15.1 months
vs 12.7 months
HR = 0.72
p<.0001
SPARC
Satraplatin +
prednisone
vs
Placebo +
prednisone
Progression after
1 prior
chemotherapy
regimen
TROPIC
Cabazitaxel +
prednisone
vs
Mitoxantrone
+ prednisone
Prior Docetaxel
Sternberg CN, et al. J Clin Oncol 2009;27:5431−8
de Bono J, et al. Lancet. 2010 Oct 2;376(9747):1147-54
TROPIC: Study Design (n=720)
mCRPC
Progression
after docetaxel
•
Stratification factor :
–
ECOG PS (0,1 vs 2)
–
Measurable/nonmeasurable
•
Primary Endpoint:
–
Overall survival (OS)
•
Secondary Endpoint:
–
PSA response, PSA
progression, PFS, RR, pain
progression, safety, PK of
cabazitaxel
R
R
A
A
N
N
D
D
O
O
M
M
I
I
Z
Z
E
E
n=360
Cabazitaxel 25mg/m2 q3w
Prednisone 10mg qd
Mitoxantrone 12mg/m2 q3w
Prednisone 10mg qd
n=360
Reduction of 25% in the risk of death
or median OS=10.67 months for cabazitaxel vs 8 months
511 events, duration 36 months
de Bono et al. Lancet 2010; 376(9747): 1147-1154
Cabazitaxel Approved as Second-Line
Chemotherapy
30% reduction in risk of death
Median OS, Mos
MP
CBZP
12.7
15.1
HR
0.70
95% CI
0.59-0.83
p value
<0.0001
Combined median
follow-up: 12.8 months
de Bono et al. Lancet 2010; 376(9747): 1147-1154
Androgen
biosynthesis
inhibitors:
Abiraterone,
TAK700
2nd
generation
AR inhibitors:
MDV3100,
ARN509
Chen Y, et al. Lancet Oncol. 2009;10:981-991.
Abiraterone Inhibits Androgen Biosynthesis
Through CYP17
• Androgens produced at 3
critical sites
– Testes
– Adrenal gland
– Prostate tumor cells
• Abiraterone inhibits
biosynthesis of androgens that
stimulate tumor cell growth
• PSA and radiographic
responses in Phase 2 studies
of CRPC
– Chemo-naïve and
post-chemo patients1-6
1. Attard G et al. J Clin Oncol. 2008;26:4563-4571; 2. Attard G et al. J Clin Oncol. 2009;27:3742-3748; 3. Reid AH et al. J
Clin Oncol. 2010;28:1489-1495; 4. Ryan CJ et al. J Clin Oncol. 2010;28:1481-1488; 5. Danila DC et al. J Clin Oncol.
2010;28:1496-1501; 6. de Bono JS et al. Ann Oncol. 2010;21(suppl 8): Abstract LBA5.
Abiraterone Acetate
Phase III Post-Chemo Study Design
Efficacy endpoints (ITT)
• 1195 patients
progressive
mCRPC
• Failed 1 or 2
chemotherapy
regimens, 1
with docetaxel
R
A
N
D
O
M
I
Z
E
D
Abiraterone 1000 mg daily
Prednisone 5 mg bid
n = 797
2:1
Placebo daily
Prednisone 5 mg bid
n = 398
1° endpoint:
• OS (25%
improvement; HR
0.8)
2nd endpoints:
• TTPP
• rPFS
• PSA response
•
Phase 3 multicenter, randomized, double-blind, placebo-controlled study
(147 sites in 13 countries; USA, Europe, Australia, Canada)
•
Stratification by:
ECOG performance status
0-1 vs 2
Worst pain over previous 24 hours
BPI short form; 0-3 (absent) vs 4-10 (present)
Prior chemotherapy
1 vs 2
Type of progression
PSA only vs radiographic with or without PSA
de Bono JS et al. N Engl J Med. 2011;364:1995-2005
Overall Survival: Second Pre-planned Analysis
Median benefit 4.6 months
100
HR =0.74 (0.638-0.859) P<0.0001
26% reduction in risk of death
Survival (%)
80
AA median OS (95% CI):
15.8 months (14.82-17.02)
60
40
Placebo median OS (95% CI):
11.2 months (10.41-13.14)
20
Placebo
AA
Median follow-up 20.2 months
0
0
AA 797
Placebo 398
6
657
306
12
18
24
Time to Death (Months)
473
273
15
183
6
100
30
0
0
Scher HI et al. J Clin Oncol 2011; 29 (suppl): LBA4517
Fizazi K et al, Lancet Oncol, in press
Adverse Events of Special Interest
AA (n = 791)
All Grades
Grades 3/4
Placebo (n = 394)
All Grades
Grades 3/4
Fluid retention
30.5%
2.3%
22.3%
1.0%
Hypokalemia
17.1%
3.8%
8.4%
0.8%
LFT
abnormalities
10.4%
3.5%
8.1%
3.0%
Hypertension
9.7%
1.3%
7.9%
0.3%
Cardiac
disordersa
13.3%
4.1%
10.4%
2.3%
aMost
frequently reported cardiac terms were tachycardia and atrial fibrillation.
The rate of grade 5 lethal cardiac events was identical in the 2 study arms: 1.3% (10 pts) in AA
and 1.3% (5 pts) in placebo.
MDV3100 (Enzalutamide, XTANDI)
• Oral drug rationally
designed to target AR
signaling, impacting
multiple steps in AR
signaling pathway.
T
T
1
Enzalutamide
Inhibits Binding of
Androgens to AR
AR
• No demonstrated
agonist effects in preclinical models.
Cell cytoplasm
2
Inhibits Nuclear
Translocation of AR
Cell nucleus
3
Tran et al. Science 2009;324:787–90.
And Uniquely
AR
Inhibits Association
Of AR with DNA
14
5
AFFIRM Phase III Trial Design
Patient Population:
1199 patients with
progressive CRPC
*Failed docetaxel
chemotherapy
R
A
N
D
O
M
I
Z
E
D
Enzalutamide
160 mg daily
n = 800
Placebo
n = 399
2:1
Corticosteroids were not required, but allowed
Stratification: PS and BPI score, PCWG2 criteria used
156 centers from 15 countries and 5 continents
September 2009 - November 2010
Primary
Endpoint:
Overall Survival
90% power to
detect a 24%
reduction in
mortality
Enzalutamide Overall Survival
Median benefit 4.8 months
HR = 0.631 (0.529, 0.752) P <0.0001
37% reduction in risk of death
Enzalutamide: 18.4 months
(95% CI: 17.3, NYR)
Placebo: 13.6 months
(95% CI: 11.3, 15.8)
enzalutamide
800
775
701
627
400
211
72
7
0
Placebo
399
376
317
263
167
81
33
3
0
Scher HI et al. N Engl J Med. 2012 Aug 15, Sternberg CN et al. Global Can Prost, Brussels June 2012
Survival Benefit Across All Subgroups
Hazard Ratio for Death Overall Survival median (mo)
Enzalutamide / Placebo
(95% CI)
Favors Enzalutamide*
Favors Placebo*
Scher HI et al. N Engl J Med. 2012 Aug 15, Sternberg CN et al. Global Can Prost, Brussels June 2012
Adverse Events of Special Interest
Grade ≥3 Events
All Grades
Enzalutamide
(n = 800)
Placebo
(n = 399)
Enzalutamide
(n = 800)
Placebo
(n = 399)
Fatigue
33.6%
29.1%
6.3%
7.3%
Cardiac Disorders
6.1%
7.5%
0.9%
2.0%
Myocardial Infarction
0.3%
0.5%
0.3%
0.5%
LFT Abnormalities*
1.0%
1.5%
0.4%
0.8%
Seizure
0.6%
0.0%
0.6%
0.0%
*Inchyperbilirubinemia, AST increased, ALT increased, LFT abnormal, transaminases
increased, and blood bilirubin increased.
FDA-ApprovedcAugust 31, 2012
Radium-223 Targets Bone Metastases
Range of alpha-particle
Radium-223
Bone surface
• Alpha-particles induce double-strand DNA breaks in
adjacent tumour cells1
• Short penetration of alpha emitters (2-10 cell diameters) =
highly localised tumour cell killing and minimal damage to
surrounding normal tissue
1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.
ALSYMPCA (ALpharadin in SYMptomatic
Prostate CAncer) Phase III Study Design
PATIENTS
• Confirmed
symptomatic
CRPC
• ≥ 2 bone
metastases
• No known
visceral
metastases
STRATIFICATION
• Total ALP:
< 220 U/L vs ≥ 220 U/L
• Bisphosphonate use:
Yes vs No
• Prior docetaxel:
Yes vs No
• Postdocetaxel or
unfit for
docetaxel
TREATMENT
R
A
N
D
O
M
I
S
E
D
6 injections at
4-week intervals
Radium-223 (50 kBq/kg)
+ Best standard of care
Placebo (saline)
+ Best standard of care
2:1
N = 921
Planned follow-up is 3 years
Clinicaltrials.gov identifier: NCT00699751
Parker C, ESMO 2011 and ASCO 2012
ALSYMPCA Updated Analysis
Time To First SRE*
100
HR = 0.636
90
95% CI, 0.519, 0.780
80
P = 0.0001
70
60
%
Radium-223, n = 614
Median: 12.2 months
50
40
30
Placebo, n = 307
Median: 6.7 months
20
10
0
Month
0
3
6
9
12
15
18
21
24
27
30
Radium-223 614
487
332
193
125
62
31
8
8
1
0
Placebo 307
207
108
51
33
17
8
6
3
1
0
*Provisional data
Parker C, ASCO 2012
ALSYMPCA Updated Analysis
Overall Survival
100
90
HR = 0.695
80
95% CI, 0.581, 0.832
70
P = 0.00007
60
%
50
Radium-223, n = 614
Median OS: 14.9 months
40
30
20
Placebo, n = 307
Median OS: 11.3 months
10
0
Month 0
3
6
9
12
15
18
21
24
27
30
33
36
39
Radium-223 614
578
504
369
274
178
105
60
41
18
7
1
0
0
Placebo 307
288
228
157
103
67
39
24
14
7
4
2
1
0
Parker C, ASCO 2012
OS Benefit in Recent CRPC Trials
Trial/
Agent
Mechanism
Comparator
Survival
(months)
Hazard
Ratio
P-value
AFFIRM
Enzalutamide
Androgen
Receptor
Signaling
Inhibitor
Placebo
18.4 vs. 13.6
0.631
<0.0001
COU-AA-301
Abiraterone +
prednisone
CYP17 Inhibitor
Placebo +
prednisone
14.8 vs. 10.9
0.646
<0.0001
Cytotoxic
Mitoxantrone +
prednisone
15.1 vs. 12.7
0.70
<0.0001
Alpha-particle
emitting
radionuclide
Placebo
14.9 vs 11.3
0.69
0.0018
TROPIC
Cabazitaxel +
prednisone
ALSYMPCA
Radium 223*
* Only 60% of these patients were post-docetaxel patients
Clinical Need in CRPC
Pre - Chemotherapy
• An intervention with little or no toxicity compared
with chemotherapy for treatment of asymptomatic
or mildly symptomatic CRPC
• Aim to prevent or delay the onset of pain related
to metastatic disease and disease progression
• Prolong survival
Overall Study Design of COU-AA-302
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
(cancer-related 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
25
25
25
PRESENTED
PRESENTEDAT
AT
Abiraterone Doubled Time to rPFS
Subjects Without Progression
or Death (%)
100
Abiraterone (median, mos):
16.5
Prednisone (median, mos):
8.3
HR (95% CI):
80
p Value:
0.53 (0.45-0.62)
< 0.0001
60
40
20
0
Abiraterone
Prednisone
0
3
6
9
12 15 18 21 24 27
Months From Randomization
Abiraterone 546 485 389 311 240 195 157 131 117
Prednisone 542 406 244 176 133 99 78 62 45
IA3 data. rPFS assessed by investigator review at prespecified IA.
30
66 20
20 7
33
36
4
0
0
0
Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)
OS Favors Abiraterone
Subjects Without Death (%)
100
Abiraterone (median, mos):
35.3
Prednisone (median, mos):
30.1
HR (95% CI):
p Valuea:
0.79 (0.66-0.95)
0.0151
80
60
40
20
0
Abiraterone
Prednisone
12 15 18 21 24 27 30 33 36
Months From Randomization
Abiraterone 546 538 524 503 482 452 421 393 333 175 68
15
0
Prednisone 542 534 508 492 465 437 400 361 283 153 67
9
0
IA3 data. aPrespecified significance level by O’Brien-Fleming Boundary
Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)
0
3
6
9
Subsequent Therapy Was Common
Abiraterone
(n = 419)
n (%)
Prednisone
(n = 482)
n (%)
274 (65)
347 (72)
Docetaxel
239 (57)
304 (63)
Cabazitaxel
60 (14)
70 (15)
Ketoconazole
39 (9)
63 (13)
Abirateroneb
38 (9)
78 (16)
Sipuleucel-T
33 (8)
28 (6)
No. with selected subsequent
therapy for mCRPCa
aFirst
patient crossover after unblinding on 7 May 2012. IA3 data clinical cutof f date on 22 May 2012.
bPrior to unblinding (eg. not per protocol). IA3 data.
Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)
Maximal Decline From Baseline (%)
Abiraterone Doubled the Maximal Decline in PSA (≥ 50%)
Relative to Prednisone Alone
Abiraterone
Prednisone
100
75
50
25
0
-25
-50
-75
-100
• 29% of patients in the prednisone control arm had a decline in PSA of ≥ 50%
• 69% of patients in the abiraterone arm had a decline in PSA of ≥ 50%
IA3 data. A negative percent indicates a decline in PSA. A positive percent indicates that the
subject never has a decline in PSA.
Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)
TAK 700 : Pre-Chemo Study
Bone scan flare up in patient with decrease PSA
Pre treatment : January 23 2012
PSA 80 mildly symptomatic
Week 13: April 14, 2012
PSA 49 asymptomatic
What’s next?
Cabozantinib (XL-184) in mCRPC
Baseline
12 weeks
Cabozantinib
Dual inhibition
MET
VEGFR2
74%
Soft tissue lesion
regression
19%
Docetaxel-pretreated patients
Complete resolution
of bone metastases
(similar results obtained in docetaxal-naïve patients)
56%
*Partial response or stable disease
†Randomization stopped due to cabozantinib efficacy
PFS, progression-free survival
Partial resolution of
bone metastases
Hussain M, et al. J Clin Oncol. 2011;29(15S): Abst 4516
Change in Bone Scan Lesion Area
Patients with ≥1 post-baseline bone scan (n = 84)
Prior therapies:
Docetaxel
Docetaxel + Abiraterone or MDV3100
C Cabazitaxel
Radionuclide
C C
100 +++
% Change from Baseline
80
60
*
40
20
CC
0
C
C
C
**
CC
CC
CC
CC C
**C C
C
-20
-40
-60
-80
-100
Median change in bone scan lesion area: 60% reduction
Smith M et al, ASCO 2012 Abst #4513
New Agents and Trials for CRPC
•
•
•
•
•
•
•
•
Tasquinimod
• OGX-0113
• Abiraterone4
Abiraterone
• Dasatinib
• Cabazitaxel5
Sipuleucel-T1
• Aflibercept
• MDV31006
PROSTVAC2
• Ipilimumab
MDV3100
• TAK-700
Ipilimumab
• Alpharadin7
Alpharadin7
• Cabozantinib
TAK-700 1Kantoff PW, N Engl J Med. 2010 Jul 29;363(5):411-22,2Kantoff PW, J Clin Oncol 2010; 28:1099–105
3CHi
KN, J Clin Oncol; 28:4247-4254, 4 de Bono JS et al. N Engl J Med. 2011;364:1995-2005,
5 de Bono et al. Lancet 2010; 376(9747): 1147-1154, 6Scher HI et al. N Engl J Med. 2012 Aug 15.
7Parker C et al, ESMO LBA 2 and ASCO 2012
Progress and Conclusions in mCRPC
• Unequivocal evidence of continued involvement
of the AR signaling axis
• Non toxic therapies pre-chemotherapy of
interest
• Need to address prostate cancer heterogeneity
to move the field forward
• Need to evaluate the best sequence and
combination of agents
Conclusioni
Prospettive per il paziente mCRPC
Miglioramento sopravvivenza
Riduzione degli eventi scheletrici
Miglioramento della quality of life
Thank you for your attention and your
kind invitation