New Agents in mCRPC

optimal use in an evolving

landscape?
Nicholas James
@Prof_Nick_James
#NJProstatecancer

1
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Anterior Pituitary
LH
Testis
Leydig
cells
Testosterone
Prostate
Androgen pathways in human prostate
ACTH

Adrenal
cortex
DHEA
Prostate
DHT
Effect of castration on androgen levels
Labrie F. Nature Reviews Urology 2011
Overview
How best to manage hormone sensitive
disease?
Key data about new agents
What do we know about sequencing
multiple agents?
How might we select patients for differing
therapies?
Hormone therapy
Hormones are a multi-component system:
Regulation of synthesis
Synthesis
Secretion
Ligand receptor binding
Actions of activated ligand/receptor on the
target gene expression paterns
Hormone therapy strategies
Block synthesis
At level of regulation GnRH agonists, antagonists
At level of synthetic pathways abiraterone
Block binding to receptor bicalutamide,
enzalutamide
Block post-receptor effects enzalutamide
Add alternative hormones to alter environment
diethylstilboestrol, dexamethasone
ADT and Cardiovascular Disease (CVD)
Risk of CV event associated with LHRH
agonist or orchidectomy
Treatment
Incident diabetes Incident CHD Myocardial infarction Sudden cardiac death
Adjusted
HR
95%
CI
p
Adjusted
HR
95%
CI
p
Adjusted
HR
95%
CI
p
Adjusted
HR
95%
CI
p
No treatment 1 (ref) 1 (ref) 1 (ref) 1 (ref)
LHRH agonist 1.44
1.34
1.55
<0.001 1.16
1.10
1.21
<0.001 1.11
1.01
1.21
0.03 1.16
1.05
1.27
0.004
Orchiectomy 1.34
1.20
1.50
<0.001 0.99
0.91
1.07
0.74 0.94
0.82
1.09
0.44 1.01
0.87
1.18
0.85
CHD, coronary heart disease; HR, hazard ratio
LHRH, lueteinising hormone-releasing hormone
ref, reference
Keating NL, et al. JCO 2006
Risk of CV event associated with LHRH
agonist or orchidectomy
Treatment
Incident diabetes Incident CHD Myocardial infarction Sudden cardiac death
Adjusted
HR
95%
CI
p
Adjusted
HR
95%
CI
p
Adjusted
HR
95%
CI
p
Adjusted
HR
95%
CI
p
No treatment 1 (ref) 1 (ref) 1 (ref) 1 (ref)
LHRH agonist 1.44
1.34
1.55
<0.001 1.16
1.10
1.21
<0.001 1.11
1.01
1.21
0.03 1.16
1.05
1.27
0.004
Orchiectomy 1.34
1.20
1.50
<0.001 0.99
0.91
1.07
0.74 0.94
0.82
1.09
0.44 1.01
0.87
1.18
0.85
CHD, coronary heart disease; HR, hazard ratio
LHRH, lueteinising hormone-releasing hormone
ref, reference
Keating NL, et al. JCO 2006
Risk of CV event associated with LHRH
agonist or orchidectomy
Treatment
Incident diabetes Incident CHD Myocardial infarction Sudden cardiac death
Adjusted
HR
95%
CI
p
Adjusted
HR
95%
CI
p
Adjusted
HR
95%
CI
p
Adjusted
HR
95%
CI
p
No treatment 1 (ref) 1 (ref) 1 (ref) 1 (ref)
LHRH agonist 1.44
1.34
1.55
<0.001 1.16
1.10
1.21
<0.001 1.11
1.01
1.21
0.03 1.16
1.05
1.27
0.004
Orchiectomy 1.34
1.20
1.50
<0.001 0.99
0.91
1.07
0.74 0.94
0.82
1.09
0.44 1.01
0.87
1.18
0.85
CHD, coronary heart disease; HR, hazard ratio
LHRH, lueteinising hormone-releasing hormone
ref, reference
Keating NL, et al. JCO 2006
CV Events over time
Duration of
treatment
(months)
Incident diabetes Incident CHD Myocardial infarction Sudden cardiac death
Adjusted
HR
95%
CI
p Adjusted HR 95% CI p
Adjusted
HR
95%
CI
p
Adjusted
HR
95%
CI
p
None 1 (ref) 1 (ref) 1 (ref) 1 (ref)
14 1.29
1.12
1.49
<0.001 1.14
1.04
1.25
0.007 1.12
0.94
1.34
0.19 1.07
0.82
1.28
0.47
512 1.45
1.30
1.61
<0.001 1.19
1.11
1.28
<0.001 1.23
0.94
1.31
0.21 1.31
1.11
1.55
<0.001
1324 1.54
1.35
1.76
<0.001 1.11
1.01
1.22
0.04 1.11
0.90
1.30
0.42 1.18
0.91
1.42
0.10
25 1.49
1.30
1.71
<0.001 1.18
1.07
1.30
0.001 1.08
0.94
1.29
0.24 1.06
0.90
1.26
0.47
Keating NL, et al. JCO 2006
CHD, coronary heart disease; HR, hazard ratio
LHRH, lueteinising hormone-releasing hormone
ref, reference
CV Events over time
Duration of
treatment
(months)
Incident diabetes Incident CHD Myocardial infarction Sudden cardiac death
Adjusted
HR
95%
CI
p Adjusted HR 95% CI p
Adjusted
HR
95%
CI
p
Adjusted
HR
95%
CI
p
None 1 (ref) 1 (ref) 1 (ref) 1 (ref)
14 1.29
1.12
1.49
<0.001 1.14
1.04
1.25
0.007 1.12
0.94
1.34
0.19 1.07
0.82
1.28
0.47
512 1.45
1.30
1.61
<0.001 1.19
1.11
1.28
<0.001 1.23
0.94
1.31
0.21 1.31
1.11
1.55
<0.001
1324 1.54
1.35
1.76
<0.001 1.11
1.01
1.22
0.04 1.11
0.90
1.30
0.42 1.18
0.91
1.42
0.10
25 1.49
1.30
1.71
<0.001 1.18
1.07
1.30
0.001 1.08
0.94
1.29
0.24 1.06
0.90
1.26
0.47
Keating NL, et al. JCO 2006
CHD, coronary heart disease; HR, hazard ratio
LHRH, lueteinising hormone-releasing hormone
ref, reference
Discussion point
Do we need to consider cardiovascular risk
factors when commencing ADT for prostate
cancer?
WHAT IS THE PROGNOSIS FOR
NEWLY DIAGNOSED HIGH RISK
PROSTATE CANCER?

STAMPEDE Trial

1. Multi-arm multi-stage trials
2. Design of STAMPEDE over time
3. Assessing new agents in hormone-naive
prostate cancer


Setting

New treatments often not as useful as hoped
Typical academic Phase III trial
Years of investment from the key players
5 - 10 years from idea to result
Hundreds or thousands of patients
Hundreds of research staff
Cost millions in development
Yet, high chance finding new treatment not better
Opportunity cost in continuing RCT which is not likely to
be positive?

Need Better Strategy For
Selection
What to take into phase III trials?
Single arm phase II trials arent reliable enough
Need: Test many new promising treatments
Need: Potential to discontinue unpromising arms
Need: Start to randomise as quickly as possible

Multi-Arm, Multi-Stage trials
Approach
Multi-arm, Multi-stage
T2 T3 T1 C T4
Phase II
Phase III
Multi-arm, Multi-stage
T2 T3 T1 C T4
Phase II
Phase III
Traditional Approach
Phase II
Phase III
T1
C T1
T2
T3
C T3
T4
C T4
Traditional Approach
Phase II
Phase III
T1 T1
C T1
T2
T3
C T3
T4
C T4
Advantages of MAMS trials
1. Fewer patients
Concurrent assessment of agents
Randomise from start
One seamless trial
One protocol Less bureaucracy
2. Less overall time
Multi-arm, Multi-stage
T2 T3 T1 C T4
Phase II
Phase III
Multi-arm, Multi-stage
T2 T3 T1 C T4
Phase II
Phase III
Traditional Approach
Phase II
Phase III
T1
C T1
T2
T3
C T3
T4
C T4
Traditional Approach
Phase II
Phase III
T1 T1
C T1
T2
T3
C T3
T4
C T4
Advantages of MAMS trials
3. Increased flexibility
Adapts to intermediate results
Focus on more promising arms
Multi-arm, Multi-stage
T2 T3 T1 C T4
Phase II
Phase III
Multi-arm, Multi-stage
T2 T3 T1 C T4
Phase II
Phase III
Traditional Approach
Phase II
Phase III
T1
C T1
T2
T3
C T3
T4
C T4
Traditional Approach
Phase II
Phase III
T1 T1
C T1
T2
T3
C T3
T4
C T4
Advantages of MAMS trials
4. Reduced costs
Limited resources for trials
Must use fairly and efficiently
Multi-arm, Multi-stage
T2 T3 T1 C T4
Phase II
Phase III
Multi-arm, Multi-stage
T2 T3 T1 C T4
Phase II
Phase III
Traditional Approach
Phase II
Phase III
T1
C T1
T2
T3
C T3
T4
C T4
Traditional Approach
Phase II
Phase III
T1 T1
C T1
T2
T3
C T3
T4
C T4
MAMS principles
Multi-arm
Test many relevant agents of interest

Multi-stage
Ask: are there reasons why we should
continue investigating a treatment?
Need encouraging activity to continue assessing
Focus away from insufficiently active regimens
STAMPEDE
Recruits men from 4 groups starting long-term ADT:
1. High-risk localised (T3/4, PSA >40 or Gleason 8-10)
2. Node-positive (N+) prostate cancer
3. Newly-diagnosed metastatic (M1)
4. High risk recurrence post surgery or RT
Tests addition of further treatments to standard care
Radical radiotherapy in standard care:
N+M0 patients; optional
N0M0 patients; optional Oct 2005 Nov 2011, mandatory
from Nov-2011



27
www.stampedetrial.org
STAMPEDE outcome measures
Outcome Measure
Stage Primary Secondary
Pilot Safety Feasibility
Activity Failure-free survival Overall survival
Intermediate Toxicity / safety
(phase II) Skeletal events
Efficacy Overall survival Failure-free survival
Final Toxicity / safety
(Phase III) Skeletal events
Quality of life
Accrual rates increase
Aug-2013:
5454 pts
Past 4m:
140 pts/m
End of
pilot phase
Arms D &
F close
Arm G
open
Arm H
open
Original
research
arms
close
Arm G
closes
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
C
u
m
u
l
a
t
i
v
e

r
a
n
d
o
m
i
s
a
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i
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s
O
c
t

0
5
J
a
n

0
6
J
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0
6
J
a
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0
7
J
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0
7
J
a
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0
8
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0
8
J
a
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0
9
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0
9
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a
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1
0
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1
0
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a
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1
1
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1
1
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1
2
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1
2
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a
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1
3
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1
3
J
a
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1
4
J
u
l

1
4
Date of randomisation
Cumulative randomisations overall
Accrual by comparison so far
A = ADT alone (+RT) E = A + docetaxel + zoledronic acid
B = A + zoledronic acid F = A + celecoxib + zoledronic acid
C = A + docetaxel G = A + abiraterone
D = A + celecoxib H = A + RT to the prostate (M1 pts only)
Why add arms to ongoing trial?
1. Can start recruiting quicker than a new trial
Update protocol = simple, substantial amendment
Scientific review = amendment
2. Efficient use of volunteers
Patients contribute to more than one comparison
Reduce competing trials
Seamless accrual: no gaps between trials
3. Efficient use of resources
Much quicker start-up time: Start at full speed
Much cheaper than separate trial
Get answers more quickly
Quick start-up times
Ready on activation Suspended until ready
A
c
t
i
v
a
t
i
o
n

d
a
y
0.0
0.2
0.4
0.6
0.8
1.0
P
p
n

s
i
t
e
s

r
e
a
d
y
:

R
&
D

a
p
p
r
o
v
a
l

c
o
n
f
i
r
m
e
d
104 98 (6) 77 (21) 58 (19) 47 (11) 21 (26) 13 (8) 13 (0) 12 (1) 11 (1) 7 (4) 7 (0) 7 (0) 7 (0) 6 (1) 3 (3) approval
Sites needing
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time (weeks) from notifying sites
Timely R&D approval for new protocol
Data from activation
of abiraterone
comparison
Criteria for new comparisons
Existing or pending license in prostate cancer
Acceptable safety profile
Deliverable across all (or most) trial centres
(Pharmaceutical partner willing to support with
drug and distribution costs)
New comparison in STAMPEDE or separate trial?
Why add arms to ongoing trial?
Reasonable to update ongoing trial rather than start up a
new trial if:
1. Trial going to continue recruiting for some time
2. In same population
3. With same outcome measures
4. In same sites
Clear advantages
Practically efficient
Financially efficient
Avoids competition
Discussion point
Should we set up programmatic trials and
continually modify a base framework
WHAT IS THE PROGNOSIS
FOR NEWLY DIAGNOSED
ADVANCED PROSTATE
CANCER?
Impact of node status and radiotherapy on
failure-free survival in patients with newly-diagnosed
non-metastatic prostate cancer: v
Data from >690 patients in the control arm of the
STAMPEDE trial (MRC PR08, CRUK/06/019)

Nicholas James , MR Spears, NW Clarke, MR Sydes, CC Parker,
DP Dearnaley, JM Russell, AWS Ritchie, G Thalmann, JS De
Bono, G Attard, C Amos, MK Parmar, MD Mason and the
STAMPEDE Investigators
60
RT in high-risk M0 prostate cancer
61
Adding RT to androgen deprivation therapy (ADT)
reduces risk of death (by about 50%)
SPCG7 - node-negative (N0) & largely at lower end of risk
spectrum (max PSA 80)
PR07 - no mandatory nodal staging, but only for N0 if done;
no PSA cap
Uncertainty about role of RT in pts with:
N0 PSA>80 disease
N+ disease
No RCT of RT in N+M0 patients

STAMPEDE
Recruits men from 4 groups starting long-term ADT:
1. High-risk localised (T3/4, PSA >40 or Gleason 8-10)
2. Node-positive (N+) prostate cancer
3. Newly-diagnosed metastatic (M1)
4. High risk recurrence post surgery or RT
Tests addition of further treatments to standard care
Radical radiotherapy in standard care:
N+M0 patients; optional
N0M0 patients; optional Oct 2005 Nov 2011, mandatory
from Nov-2011



62
www.stampedetrial.org
Aims
1. Describe prognosis for men with newly-
diagnosed high-risk M0 disease
2. Describe impact of planned radical RT on time to
progression
split by nodal status

63
Primary outcome measures
Overall survival [definitive]
Time from randomisation to death from any cause

Failure-free survival (FFS) [intermediate]
Time from randomisation to evidence of at least one of:
Biochemical failure
Progression: local, lymph nodes, distant metastases
Death from prostate cancer

64
Methods
Database frozen 01-May-2014
Cox models to look at effects by node status subgroups
Models adjusted for other prognostic factors:
Age at randomisation (<60, 60-64, 65-69, 70 years)
Log-transformed pre-ADT PSA (continuous)
WHO performance status (0 vs 1&2)
Initial Gleason sum score category (7, 8, unknown)
Subgroup analyses looked at regional lymph nodes
N0 randomised <15-Nov-2011
N+ randomised >1 year prior to data freeze

65
Results Aim 1
Prognosis of
newly-diagnosed
high-risk M0
disease
Cohort selection:

66
Allocated to control arm
N=1858
Allocated to research
arms
N=3,715
Non-
metastatic
N=788
Metastatic
N=1090
Randomised by 01-May-
2014
N=5,573
Diagnosed within
6m
pre-randomisation
N=721
Diagnosed more than
6m
pre-randomisation
N=67

Newly-diagnosed M0 patients
(randomised Oct-2005 to May-2014)
Number of patients 721
Median Age (years) 66 (61-77)
Median PSA pre ADT
(ng/mL)
40% (n=287/721)
Node-positive 74% (n=535/721)
Gleason summary score 8-
10
15% (n=110/721)
WHO Performance Status 1-
2
43 (IQR 18-88)
Planned for RT 75% (n=539/721)
Median follow-up (months) 17 (IQR 6-36)
FFS events 149
Deaths 40
M0 cohort demographics
67
63.3 (IQR 26.4-NR)
0.00
0.25
0.50
0.75
1.00
P
r
o
p
o
r
t
i
o
n

e
v
e
n
t
-
f
r
e
e
721 392 (7) 273 (10) 173 (6) 108 (6) 46 (9) 24 (2) 8 (0) Death
721 345 (74) 219 (32) 128 (18) 69 (14) 35 (6) 18 (3) 3 (2) FFS Event
N(risk)
0 12 24 36 48 60 72 84
Time from randomisation (Months)
FFS Event Death
Survival & FFS outcomes M0 cohort
68
Results Aim 2
Impact of planned RT on time to progression

Split by nodal status:
N0 randomised prior to 15-Nov-2011
N+ randomised at least 1 year prior to data freeze

69
Nodal subgroups
Data frozen
01-May-2014

70
FFS
Events
N=21
FFS
Events
N=30
FFS
Events
N=27
FFS
Events
N=40
RT not
planned
N=59
RT
planned
N=121
RT not
planned
N=80
RT
planned
N=98
Randomised >1yr ago
N=178
Randomised <15/11/2011
N=180
Nodal stage unknown
N=1
N+
N=287
N0
N=433
Diagnosed within 6m
pre-randomisation
N=721
Nodal subgroup demographics
71

Node-negative pts
(rand <15-Nov-2011)
Node-positive pts
(randomised >1 year)
Number of patients 180 178
Median Age (years) 66 (IQR 60-71) 65 (IQR 60-70)
Gleason summary score 8-10 75% (n=135/180) 75% (n=133/178)
WHO Performance Status 1-2 11% (n=19/180) 13% (n=24/178)
Median PSA pre-ADT (ng/mL) 26 (IQR 58-104) 35 (IQR 15-76)
Planned for RT 67% (n=121/180) 55% (n=98/178)
Median follow-up (months) 46 (IQR 35-59) 27 (IQR 19-45)
FFS events 51 67
Deaths 16 22
FFS by RT status: Node-negative
cohort
72
62% (95% CI 48-73)
87% (95% CI 79-92)
0.00
0.25
0.50
0.75
1.00
121 112 (5) 101 (3) 61 (6) 37 (5) 19 (2) 8 (0) 0 (0) +RT
59 48 (11) 39 (8) 29 (3) 13 (4) 4 (3) 2 (1) 2 (0) -RT
N(risk)
0 12 24 36 48 60 72 84
Time from randomisation (months)
-RT +RT
N0 Planned radical RT status
62% (95% CI 48-73)
87% (95% CI 79-92)
0.00
0.25
0.50
0.75
1.00
121 112 (5) 101 (3) 61 (6) 37 (5) 19 (2) 8 (0) 0 (0) +RT
59 48 (11) 39 (8) 29 (3) 13 (4) 4 (3) 2 (1) 2 (0) -RT
N(risk)
0 12 24 36 48 60 72 84
Time from randomisation (months)
-RT +RT
N0 Planned radical RT status
FFS by RT status: Node-negative cohort
73
HR 0.33
(95% CI 0.18-0.61)
Note landmark analysis of patients FFS event-free at 6m = same
47% (95% CI 33-59)
71% (95% CI 58-81)
0.00
0.25
0.50
0.75
1.00
98 75 (14) 42 (4) 23 (4) 10 (2) 7 (1) 4 (2) 0 (0) +RT
80 54 (18) 29 (13) 15 (4) 9 (3) 5 (0) 4 (0) 1 (2) -RT
N(risk)
0 12 24 36 48 60 72 84
Time from randomisation (months)
-RT +RT
N+ Planned radical RT status
FFS by RT status: Node-positive cohort
74
47% (95% CI 33-59)
71% (95% CI 58-81)
0.00
0.25
0.50
0.75
1.00
98 75 (14) 42 (4) 23 (4) 10 (2) 7 (1) 4 (2) 0 (0) +RT
80 54 (18) 29 (13) 15 (4) 9 (3) 5 (0) 4 (0) 1 (2) -RT
N(risk)
0 12 24 36 48 60 72 84
Time from randomisation (months)
-RT +RT
N+ Planned radical RT status
FFS by RT status: Node-positive cohort
75
HR 0.51
(95% CI 0.31-0.84)
Note landmark analysis of patients FFS event-free at 6m =
same
Survival better than anticipated at trial inception in 2005
In M0, control arm patients
Effect of RT in N0M0 patients consistent with effect seen
in previous large RCTs
Effect of RT in N+ patients similar to effect in N0
patients
Strongly supports routine use RT in node-positive
prostate cancer
How best to administer?

ND James et al Proc ASTRO 2014.
Conclusions
76
Discussion point
Should all cN+ patients be offered radical
RT?
STAMPEDE
Recruits men from 4 groups starting long-term ADT:
1. High-risk localised (T3/4, PSA >40 or Gleason 8-10)
2. Node-positive (N+) prostate cancer
3. Newly-diagnosed metastatic (M1)
4. High risk recurrence post surgery or RT



78
www.stampedetrial.org
Stampede
M1 control
arm
outcomes

ND James et al Eur Urol 2014, in
press
Key Trial Eligibility Criteria:
High risk newly-diagnosed non-metastatic node-negative disease
OR
Newly-diagnosed metastatic or node-positive disease
OR
Previously treated with radical surgery and/or radiotherapy, now
relapsing
AND
Fit for all protocol treatment and follow-up
Allocated to control arm
N=1,716
Allocated to research arms
N=3,556
Metastatic
N=976
Non-
metastatic
N=740



Randomised by 07-Jan-
2014
N=5,272
Newly-
diagnosed
N=929
Rapidly relapsing
after previous
treatment
N=47



Diagnosed more
than
6 months prior to
randomisation
N=12
Included in
these
analyses
N=917



Stampede M1 control arm outcomes
11.2 IQR 5.1, 28.8) 42.1 (IQR 22.7, 90.7)
0.00
0.25
0.50
0.75
1.00
P
r
o
p
o
r
t
i
o
n

e
v
e
n
t
-
f
r
e
e
0 12 24 36 48 60
Time from randomisation (Months)
917 523 (61) 283 (90) 148 (43) 71 (30) 20 (9) Death
917 272 (369) 107 (93) 50 (28) 25 (8) 8 (3) FFS Event
Number at risk
FFS Event Death
ND James et al Eur Urol 2014, in press
Stampede M1 control
arm FFS
Top left
Metastatic site bone vs
soft tissue vs both

Top Right
Gleason score: up to 7 vs
8 or more

Bottom Left
Performance status: 0 vs 1
or 2

Bottom Right
Age: <60 vs 60-64 vs 65-
69 vs 70 or more

Stampede M1 control
arm overall survival
Top left
Metastatic site bone vs
soft tissue vs both

Top Right
Gleason score: up to 7 vs
8 or more

Bottom Left
Performance status: 0 vs 1
or 2

Bottom Right
Age: <60 vs 60-64 vs 65-
69 vs 70 or more

Time to subsequent therapy from
first FFS event
0.00
0.20
0.40
0.60
P
r
o
p
o
r
t
i
o
n

o
f

r
e
l
a
p
s
e
s

s
t
a
r
t
i
n
g

t
r
e
a
t
m
e
n
t
502 238 88 31 Abiraterone
502 205 83 27 Bisphosphonate
502 154 53 18 Chemotherapy
Number at risk
0 12 24 36
Time from FFS event (Months)
Chemotherapy Bisphosphonate Abiraterone
ND James et al Eur Urol 2014, in press
CASTRATE REFRACTORY
PROSTATE CANCER
Development of CRPC
Intraprostatic androgen synthesis
Increased expression of enzymes converting
DHEA to testosterone and DHT in tumour tissue
Increased androgen synthesis

Androgen receptor (AR) abnormalities
Increased AR expression
Mutation of AR ligand binding domain
Constitutively active AR mutants (truncated AR)

EU/US Approvals in CRPC
US approvals

EU approvals

Enzalutamide
(post chemotherapy)
2

Abiraterone*
(chemotherapy-naive-302)
9
Radium-223
2

Enzalutamide
(post chemotherapy)
8
Docetaxel
4
Abiraterone*
(chemotherapy-naive-302)
3

Sipuleucel-T
2

Abiraterone*
(post-chemotherapy-301)
2

Cabazitaxel
2

Docetaxel (1995)
2
Radium-223
10
2005 2004 2006 2007 2008 2009 2010 2011 2012 2014 2015 2013
Enzalutamide
(chemotherapy naive)
11
Abiraterone*
(post-chemotherapy-301)
7
Cabazitaxel
6
Sipuleucel-T
5












CRPC treatment up to 2010
Clinical trial
Observation
2nd-line hormone Rx*
No metastases
*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole
Symptomatic
Docetaxel
Mitoxantrone
Clinical trial

Metastases
Asymptomatic
Cabazitaxel:
TROPIC overall survival (ITT
analysis)
MP 377 300 188 67 11 1
CBZP 378 321 231 90 28 4
Number
at risk
P
r
o
p
o
r
t
i
o
n

o
f

O
S

(
%
)

80
60
40
20
0
100
0 months 6 months 12 months 18 months 24 months 30 months
15.1
12.7
Median OS (months)
0.590.83 95% CI
<.0001
P-value
0.70
Hazard Ratio
CBZP MP


















CRPC treatment 2010-2011
Clinical trial
Observation
2nd-line hormone Rx*
No metastases
*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole
Symptomatic
Docetaxel
Clinical trial

Cabazitaxel
2nd-line hormone
Rx*
Metastases
Asymptomatic
Mottet et al. Eur Urol 2011;59:57283. Horwich et al. Ann Oncol 2010;21(Suppl. 5):v12933. NICE. Prostate Cancer Diagnosis and Treatment (NICE Clinical Guideline 58)
2008. de Reijke et al. Ned Tijdschr Geneeskd. 2008;152:17715. NCCN clinical practice guidelines in oncology: prostate cancer, v.4.2011. http://www.nccn.org. Miller et al.
Aktuelle Urologie. 2006;37:2014.
Abiraterone






























CRPC treatment 2011- 2013
Clinical trial
Observation
2nd-line hormone Rx*
No metastases
*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole
Symptomatic
Docetaxel
Clinical trial

Cabazitaxel
Or
Abiraterone
Or
Enzalutamide
Metastases
Asymptomatic
Mottet et al. Eur Urol 2011;59:57283. Horwich et al. Ann Oncol 2010;21(Suppl. 5):v12933. NICE. Prostate Cancer Diagnosis and Treatment (NICE Clinical Guideline 58)
2008. de Reijke et al. Ned Tijdschr Geneeskd. 2008;152:17715. NCCN clinical practice guidelines in oncology: prostate cancer, v.4.2011. http://www.nccn.org. Miller et al.
Aktuelle Urologie. 2006;37:2014.






Cabazitaxel
Or
Abiraterone
Or
Enzalutamide
COU-302 Trial
98
COU-302 Progression Free and
Overall Survival
99
Progression Free Survival Overall Survival
Statistically significant survival benefit with
abiraterone + low-dose prednisolone reached at final
analysis
Median follow up of 49.2 months
Abiraterone treatment effect more pronounced when adjusting for 44% of placebo + low-dose
prednisolone patients who crossed over to abiraterone + low-dose prednisolone (HR=0.74)
100
80
60
40
20
0
0
O
S

(
%
)

9 21 30 48 60 39
546
542
525
509
422
401
296
261
59
42
0
0
202
148
Time to death (months)
24 12 3 36 45 54
538
534
453
438
359
322
189
132
15
10
HR (95% CI): 0.81 (0.700.93)
P value: 0.0033

Placebo + low-dose prednisolone, 30.3 months
6 15 18 27 33 42 51 57
0
1
118
84
218
176
504
493
483
466
394
363
330
292
273
227
235
201
FA
CI: confidence interval; FA: final analysis; HR: hazard ratio; OS: overall survival.






























CRPC treatment early 2013
Clinical trial
Observation
2nd-line hormone Rx*
No metastases
*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole
Symptomatic
Abiraterone

Docetaxel
Docetaxel
Or
Abiraterone
Or
Enzalutamide
Metastases
Asymptomatic
Mottet et al. Eur Urol 2011;59:57283. Horwich et al. Ann Oncol 2010;21(Suppl. 5):v12933. NICE. Prostate Cancer Diagnosis and Treatment (NICE Clinical Guideline 58)
2008. de Reijke et al. Ned Tijdschr Geneeskd. 2008;152:17715. NCCN clinical practice guidelines in oncology: prostate cancer, v.4.2011. http://www.nccn.org. Miller et al.
Aktuelle Urologie. 2006;37:2014.






Cabazitaxel
Or
Enzalutamide
Or
Abiraterone
Bone metastasis in prostate cancer
Bone: most frequent site of prostate cancer metastasis
Favorable microenvironment for prostate tumor cells
Lesions first appear in axial skeleton, then appendicular skeleton
Main source of prostate cancerassociated morbidity
1. Roodman GD, et al. N Engl J Med. 2004;15:1655-1664.
The vicious cycle
of bone metastases
and tumor cell growth
in the bone marrow
microenvironment
1
RANKL
PTHrP
IL-6
PGE
2
TNF
M-CSF
BMP
PDGF
FGFs
IGFs
TGF-
Radium-223
Alpharadin is Ra-223 salt in solution
Acts as a calcium mimic:
a natural bone-seeker
targets new bone growth in and
around metastases
incorporated into bony matrix
Emits alpha-particles that induce primarily non-reparable, double strand DNA
breaks in adjacent tumour cells



Targets new bone in metastases Irradiates adjacent tumour cells
Bone marrow
Tumor
cells
Osteoclast
Osteoblast
Newly
formed
bone
Radium-223
deposition
Alpha
particle
radiation
Alpharadin uptake and elimination
Cleared rapidly, directly into gut (no apparent hepatobiliary excretion)
Spares kidney radiation dose low

Baseline
Day 2 Day 6
99m
Tc - MDP
223
Ra
Imaging
based on
Alsympca trial
Alsympca overall survival
Parker et al ESMO 2011.
Bone events
Clinical effectiveness of strontium-89 and
zoledronic acid in patients with castrate-
refractory prostate cancer (CRPC) metastatic
to bone receiving docetaxel (TRAPEZE)
Nick James
On behalf of
Sarah Pirrie, Darren Barton, Janet Brown, Lucinda
Billingham, Stuart Collins, Adam Daunton, Alison Birtle,
Prabir Chakraborti, Daniel Ford, Syed Hussain, Helen Jones,
Ann Pope, Emilio Porfiri, Martin Russell, Andrew Stanley,
John Staffurth, Duncan McLaren, Chris Parker, James Wylie
and the TRAPEZE trial investigators

Phase III Study treatments
docetaxel +
prednisolone
(cycles 1-6)
Sr89 150
MBq
(day 28 cycle 6)
A
B
C
D
+ 28 Days
*
docetaxel +
prednisolone + ZA
(cycles 7-10)
+ 28 Days
*
ARMS B & D : Post chemotherapy, ZA will be administered at 4-weekly intervals until protocol defined disease
progression.
Docetaxel 75mg/m2 every 3 weeks + prednisolone 10mg od
(cycles 1-10)
docetaxel +
prednisolone +
ZA
(cycles 1-6)
docetaxel +
prednisolone
(cycles 7-10)
Sr89
(day 28 cycle 6)
* At least 28 days
docetaxel + prednisolone + ZA 4mg iv
(cycles 1-10)
SRE Free Interval: ZA comparison
Presented by: Nick James
Cost effectiveness of ZA


ZA no ZA
ICER ZA
vs no ZA
Mean Cost Mean
QALYs
Mean Cost Mean
QALYs
Base case
results
12,668 0.908 12,417 0.876 8,005
No
discounting
12,788 0.915 12,552 0.884 7,684
Total Skeletal Related Events by
type
Presented by: Nick James
Sr89 comparison
No Sr89 Sr89
ZA comparison
No ZA ZA
N (%) N (%) N (%)
N(%)
Symptomatic pathological
fractures
16 18 23 11
Spinal cord or nerve root
compression
39 45 52 32
Cancer related surgery to
bone
10 13 18 5
Radiation therapy to bone
317 258 337 238
Change in antineoplastic
therapy to treat bone pain
16 12 17 11
Hypercalcaemia
0 2 2 0
Other
1 1 0 2
Total
399 349 449 299
Skeletal Related Events per
patient
Presented by: Nick James
Sr89 comparison
No Sr89 Sr89
ZA comparison
No ZA ZA
N(%) N(%) N(%) N(%)
0 196 (52) 201 (53) 185 (49) 213 (56)
1 92 (25) 96 (25) 91 (24) 97 (26)
2 32 (8) 38 (10) 33 (9) 37 (10)
3 28 (7) 20 (5) 38 (10) 10 (3)
4 11 (3) 11 (3) 13 (3) 9 (2)
5 or more 19 (5) 12 (4) 21 (5) 10 (3)
Number of patients with
at least one SRE
182 (48) 177 (47) 196 (51) 163 (44)
Conclusions TRAPEZE trial
Presented by: Nick James
ZA significantly increased SRE free interval
and decreased total SRE numbers, mostly
post-progression
ICER and net acquisition costs favourable
No impact on overall survival


Dicussion point
What is role of bone protection agents with
increasing numbers of active anti-cancer
agents?
Presented by:






























CRPC treatment early 2013
Clinical trial
Observation
2nd-line hormone Rx*
No metastases
*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole
Symptomatic
Abiraterone

Docetaxel
Docetaxel
Or
Abiraterone
Or
Enzalutamide
Metastases
Asymptomatic






Cabazitaxel
Or
Enzalutamide
Or
Abiraterone
























CRPC treatment late 2013-2014
Clinical trial
Observation
2nd-line hormone Rx*
No metastases
*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole
Symptomatic
Abiraterone

Docetaxel
Docetaxel
Or
Abiraterone
Or
Enzalutamide
Metastases
Asymptomatic
Cabazitaxel
Or
Enzalutamide
Or
Abiraterone






Radium-223
PREVAIL trial
Randomized, double-blind, placebo-controlled,
multinational phase 3 study in chemotherapy-naive
patients with mCRPC
randomized 1:1 to enzalutamide 160 mg/day or
placebo.
OS and rPFS co-primary endpoints
Planned sample size 1,680 with 765 deaths to
achieve 80% power to detect a target OS hazard
ratio (HR) of 0.815
118
KaplanMeier Estimates of Radiographic Progression-free Survival and Overall Survival.
Beer TM et al. N Engl J Med 2014;371:424-433.
PREVAIL trial
























CRPC treatment late 2014
Clinical trial
Observation
2nd-line hormone Rx*
No metastases
*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole
Symptomatic
Abiraterone

Docetaxel
Enzalutamide
Docetaxel
Or
Abiraterone
Or
Enzalutamide
Metastases
Asymptomatic
Cabazitaxel
Or
Enzalutamide
Or
Abiraterone






Radium-223
CAN WE PREDICT RESPONSE
TO NEW HORMONE
THERAPIES?
Resistance to Enzalutamide
Presented By Emmanuel Antonarakis at 2014 ASCO Annual Meeting
Full-Length AR (AR-FL)
Presented By Emmanuel Antonarakis at 2014 ASCO Annual Meeting
AR-V7: Truncated, Lacks LBD
Presented By Emmanuel Antonarakis at 2014 ASCO Annual Meeting
Progression-Free Survival (Enzalutamide)
Presented By Emmanuel Antonarakis at 2014 ASCO Annual Meeting
Prevalence of AR-V7 in CRPC (n=62)
Presented By Emmanuel Antonarakis at 2014 ASCO Annual Meeting
Discussion point
Do these mutations also predict response to
other therapies how to test?
WHAT ABOUT EARLIER USE
OF ACTIVE AGENTS?
Timing of chemotherapy ADT
vs ADT + Docetaxel
Important results presented
CHAARTED High risk M1
GETUG-12 High risk M0
Previously published
GETUG-15 M1- positive for PFS, negative
for OS
Timing of chemotherapy ADT
vs ADT + Docetaxel
Important results presented at ASCO 2014
CHAARTED High risk M1- Positive for OS
GETUG-12 High risk M0 borderline for
PFS, negative for OS
Previously published
GETUG-15 M1- borderline positive for PFS, negative
for OS
Awaited - STAMPEDE
E3805 CHAARTED Treatment
Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
Primary endpoint: Overall survival
Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
Causes of Death
Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
OS by extent of metastatic disease at start of ADT
Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
Therapy beyond progression
Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
Timing of chemotherapy ADT
vs ADT + Docetaxel
Consensus view of STAMPEDE :
On review of all data, we recommended that the STAMPEDE
trial would best serve patients and the oncology community by
keeping to its original analysis plan and generating mature, robust
and reliable data.
On track for analysis Q2 2015
No current case for change in M0
GETUG 15 and CHAARTED results should be discussed with
relevant patients
Conclusions
Treatment options are rapidly changing across the
whole spectrum
Much of current sequencing driven by timing
rather than science
137