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Lessons from STAMPEDE

Nicholas James
@Prof_Nick_James
#NJProstatecancer
1

Introduction

Systemic therapy for prostate cancer


STAMPEDE trial design
Data from the control arm
First results from the experimental arms

CRPC treatment 2005-2010

Clinical trial
Observation
2nd-line hormone Rx*

Docetaxel
Mitoxantrone
Clinical trial

Metastases

No metastases
Asymptomatic

Symptomatic

*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole

CRPC treatment 2011- 2013

Clinical trial
Observation
2nd-line hormone Rx*

Docetaxel
Clinical trial

Cabazitaxel
Or
Abiraterone
Or
Enzalutamide

Cabazitaxel
Or
Abiraterone
Or
Enzalutamide

Metastases

No metastases
Asymptomatic

Symptomatic

*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole


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.

CRPC treatment early 2013

Clinical trial
Observation
2nd-line hormone Rx*

Abiraterone
Docetaxel

Docetaxel
Or
Abiraterone
Or
Enzalutamide

Cabazitaxel
Or
Enzalutamide
Or
Abiraterone

Metastases

No metastases
Asymptomatic

Symptomatic

*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole


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.

CRPC treatment late 2014


Radium-223

Clinical trial
Observation
2nd-line hormone Rx*

Abiraterone
Docetaxel
Enzalutamide

Docetaxel
Or
Abiraterone
Or
Enzalutamide

Cabazitaxel
Or
Enzalutamide
Or
Abiraterone

Metastases

No metastases
Asymptomatic

Symptomatic

*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole

Trials showing survival advantage


in mCRPC
Trial

Disease state

Trial design

HR

Median survival (mo)

Tax 3271 (n=1006)

mCRPC with or without


symptoms

docetaxel/prednisone vs
mitoxantrone/prednisone

0.76

18.9 vs 16.5

IMPACT2 (n=512)

Few symptoms mCRPC

sipuleucel-T vs control

0.78

25.8 vs 21.7

TROPIC3 (n=755)

Post-docetaxel

cabazitaxel/prednisolone vs
mitoxantrone/prednisone

0.70

15.1 vs 12.7

COU-AA-3014 (n=1195)

Post-docetaxel

abiraterone/low-dose prednisolone vs
placebo/low-dose prednisolone

0.74

15.8 vs 11.2

AFFIRM5 (n=1199)

Post-docetaxel

enzalutamide vs placebo

0.63

18.4 vs 13.6

ALSYMPCA6 (n=921)

Post-docetaxel
(or unsuitable)

radium 223/BSC* vs placebo/BSC

0.70

14.9 vs 11.3

PREVAIL7 (n=1717)

Post-ADT in asymptomatic
or mildly symptomatic

enzalutamide vs placebo

0.71

32.4 vs 30.2

COU-AA-3028 (n=1088)

Post-ADT in asymptomatic
or mildly symptomatic

abiraterone/low-dose prednisolone vs
placebo/low-dose prednisolone

0.81

34.7 vs 30.3

*best standard care

1. Tannock IF et al. N Engl J Med 2004; 351:150212. 2. Kantoff PW et al. N Engl J Med 2010; 363:41122. 3. de Bono JS et al. Lancet
2010;376(9747):114754. 4. Fizazi K et al. Lancet Oncol 2012;13(10):98392. 5. Scher HI et al. N Engl J Med 2012;367(13):118797. 6.
Parker C et al. N Engl J Med 2013;369(3):21323. 7. Beer et al. N Engl J Med 2014;371(5):424-33. 8. Ryan C et al. Lancet Oncol
2015;16(2):15260.

STAMPEDE
Background:

Approximately 5000 men per year present with


newly diagnosed metastatic disease

Most patients become hormone refractory

Many therapies used in patients with metastatic


hormone refractory disease

STAMPEDE
Therapies used for hormone refractory patients include
stilboestrol
mitoxantrone
taxanes
anthracyclines
estramustine
steroids
strontium

STAMPEDE
New therapies under investigation include:

EGFR inhibitors (Iressa, Tarceva)


VEGF inhibitors
COX-2 inhibitors
Bisphosphonates

STAMPEDE

Can we use any of these first-line to improve outcomes?

On the basis of current evidence, which of these should


we bring forward to the first-line setting & why?

No good evidence to select just one (or two) above all


others

Can we assess as many as possible in an efficiently


designed randomised trial?

Proposed International Trial In


Metastatic Prostate Cancer
Stage 1
FFS

R
A
N
D
O
M
I
S
E

Stage 2
Survival

Hormones (H)

Continue

H+Chemotherapy

Continue?

Reject
H+EGFR inhibitor

at

Continue?

least
H+ VEGF inhibitor

2-3
new

Continue?

arms
H + COX-2 inhibitor

Continue?

Proposed International Trial in


Metastatic Prostate Cancer

Primary outcome measures

First stage: failure-free survival (inc. biochemical failure)


Second stage: overall survival

To

detect an absolute difference of 10% (50% to


60%) at 3 years

2200 patients needed for first stage


Assuming one arm goes through to second stage, 2750
patients needed overall (i.e. a further 550 patients)

Proposed International Trial in


Metastatic Prostate Cancer
Two-stage multi-arm design

Permits rapid comparison and testing of the main


treatment options that are currently available

Need to do this before any of these therapies


become widely used as first-line therapy without
adequate evaluation and before a new array of
treatments become available

Recruitment

Ideally at least 500 patients per year

If

first stage completed in 4.5 years


trial will give a reliable answer on survival after 5.5 years

recruitment is 350 patients per year

first stage completed in 5.5 years


trial will give a reliable answer in 7 years

Remember

Trial

- this gives an answer for four questions!

needs to be international

Trial Development Group

Prof M Parmar (Statistician, London)


Dr N.James (Oncologist, Birmingham)
Dr N.Clarke (Urologist, Manchester)
Dr DP.Dearnaley (Oncologist, Sutton)
Mr D.Hoe-Richardson (Patient Consumer Representative)
Prof D.Kirk (Urologist, Glasgow)
Dr S Meredith (Epidemiologist, London)
Miss S Naylor (Clinical Trials Manager, London)
Mr M Sydes (Statistician, London).

The setting up of STAMPEDE


First

files on my computer 2002


Grant application and funding 2002-3
First version of protocol 2004
Trial delayed by 12 months due to
concerns over celecoxib and
cardiovascular disease

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

T
r
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PhaseI
T3 T4 CT1T2T3T4
P
h
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1
PhaseI
CT3CT4
PhaseI

Advantages of MAMS trials


1. Fewer patients
2. Less overall time

Concurrent assessment of agents


Randomise from start
One seamless trial
One protocol Less bureaucracy

T
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PhaseI T2 T3 T4
C
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T
2
T
3
T
4
P
h
a
s
e
I
C
T
1
PhaseI
CT3CT4
PhaseI

Advantages of MAMS trials


3. Increased flexibility

Adapts to intermediate results


Focus on more promising arms

T
r
a
d
i
t
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o
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A
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PhaseI T2 T3 T4
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T
2
T
3
T
4
P
h
a
s
e
I
C
T
1
PhaseI
CT3CT4
PhaseI

Advantages of MAMS trials


4. Reduced costs

Limited resources for trials


Must use fairly and efficiently

T
r
a
d
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A
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T
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PhaseI T2 T3 T4
C
T
1
T
2
T
3
T
4
P
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a
s
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I
C
T
1
PhaseI
CT3CT4
PhaseI

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 outcome measures

Stage
Pilot

Activity

Outcome Measure

Primary

Secondary

Safety

Feasibility

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

t
n
ta
r
po
im

n
i
s
T
RC

5
1
<

ye

s
r
a

STAMPEDE time to first


patient activation

Why add arms to ongoing trial?


Reasonable

to update ongoing trial rather


than start up a new trial if:
1.
2.
3.
4.

Trial going to continue recruiting for some time


In same population
With same outcome measures
In same sites

Clear

advantages

Practically efficient
Financially efficient
Avoids competition

Future directions under


consideration
Metabolic

All patients

Radical

therapy for oligo-metastatic disease

Subset of M1

Molecular

pathway modification metformin

stratification

PARP inhibitor in M1 with DNA repair deficit

Immunotherapy
Radium-223

Control arm data

What is the prognosis for


newly diagnosed
advanced prostate
cancer?

Impact of node status and radiotherapy


on
failure-free survival in patients with
newlydiagnosed
Nicholas James , MR Spears,
NW Clarke,
MR Sydes, CC Parker,
non-metastatic
prostate
cancer:
DP Dearnaley,
JM Russell,
AWS Ritchie,
Thalmann,
JS De
Data
from >690
patients
in Gthe
control
Bono,
Attard,
C Amos, MK Parmar,
MasonPR08,
and the
arm
of Gthe
STAMPEDE
trialMD
(MRC
STAMPEDE Investigators
CRUK/06/019)
v

52

STAMPEDE

Recruits men from 4 groups starting long-term


ADT:
1.
2.
3.
4.

High-risk localised (T3/4, PSA >40 or Gleason 8-10)


Node-positive (N+) prostate cancer
Newly-diagnosed metastatic (M1)
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,
www.stampedetrial.
mandatoryorg
from Nov-2011
53

Aims
1.
2.

Describe prognosis for men with newlydiagnosed high-risk M0 disease


Describe impact of planned radical RT on
time to progression

split by nodal status

54

Results Aim 1
Prognosis

of
newly-diagnosed
high-risk M0
disease
Cohort selection:

Randomised by 01May-2014
N=5,573

Allocated to
research arms
N=3,715

Allocated to
control arm
N=1858

Metastat
ic
N=1090

Nonmetastatic
N=788

Diagnosed more
than 6m
prerandomisation
N=67

Diagnosed
within 6m
prerandomisation
N=721
55

Survival & FFS outcomes M0 cohort


Proportion event-free

1.00

0.75
63.3 (IQR 26.4-NR)

0.50

0.25

0.00
0

12

24

36

48

60

72

84

Time from randomisation (Months)


N(risk)
FFS Event
Death

721
721

(74)
(7)

345
392

(32)
(10)

219
273

(18)
(6)

128 (14)
173 (6)

FFS Event

69
108

(6)
(9)

35
46

(3)
(2)

Death

56

18
24

(2)
(0)

3
8

Results Aim 2
Impact
Split

of planned RT on time to progression

by nodal status:

N0
N+

randomised prior to 15-Nov-2011


randomised at least 1 year prior to data freeze

57

Nodal subgroups
Diagnosed
within 6m
prerandomisation
N=721

Data

frozen
01-May-2014

N0
N=43
3
Randomised
<15/11/2011
N=180
RT
plann
ed
N=12
1
FFS
Events
N=21

Nodal stage
unknown
N=1

N+
N=28
7
Randomised
>1yr ago
N=178

RT not
plann
ed
N=59

RT
plann
ed
N=98

RT not
plann
ed
N=80

FFS
Events
N=30

FFS
Events
N=27

FFS
Events
N=40
58

FFS by RT status: Node-negative cohort


N0 Planned radical RT status
1.00

HR 0.33
(95% CI 0.18-0.61)
87% (95% CI 79-92)

0.75
62% (95% CI 48-73)
0.50

0.25

0.00
0

12

24

36
48
60
Time from randomisation (months)

72

84

N(risk)
-RT
+RT

59
121

(11)
(5)

48
112

(8)
(3)

39
101

(3)
(6)

29
61

-RT

(4)
(5)

13
37

(3)
(2)

4
19

+RT

Note landmark analysis of patients FFS event-free at 6m = same

59

(1)
(0)

2
8

(0)
(0)

2
0

FFS by RT status: Node-positive cohort


N+ Planned radical RT status

HR 0.51
(95% CI 0.31-0.84)

1.00

0.75

71% (95% CI 58-81)

0.50

47% (95% CI 33-59)

0.25

0.00
0

12

24

36
48
60
Time from randomisation (months)

72

84

N(risk)
-RT
+RT

80
98

(18)
(14)

54
75

(13)
(4)

29
42

(4)
(4)

15
23

-RT

(3)
(2)

9
10

(0)
(1)

5
7

(0)
(2)

+RT

60

Note landmark analysis of patients FFS event-free at 6m = same

4
4

(2)
(0)

1
0

Conclusions
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 nodepositive prostate cancer

How best to administer?

ND James et al Proc ASTRO 2014.

61

STAMPEDE
Recruits

men from 4 groups starting longterm ADT:


1.
2.
3.
4.

High-risk localised (T3/4, PSA >40 or Gleason 810)


Node-positive (N+) prostate cancer
Newly-diagnosed metastatic (M1)
High risk recurrence post surgery or RT

www.stampedetrial.
org

62

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
Randomised by 07Jan-2014
N=5,272

Allocated to control arm


N=1,716

Allocated to research
arms
N=3,556

NonMetastati
metastatic
c
N=740
N=976

Rapidly
relapsing
Newly
after previous
diagnosed
treatment
N=929
N=47

Included in

these

analyses
N=917

Diagnosed more
than
6 months prior
to randomisation
N=12

Stampede M1 control arm outcomes


Proportion event-free

1.00

0.75
11.2 IQR 5.1, 28.8)

0.50

42.1 (IQR 22.7, 90.7)

0.25

0.00
0

12

24

36

48

60

Time from randomisation (Months)

Number at risk
FFS Event 917 (369) 272 (93)
Death 917 (61) 523 (90)

107 (28) 50
(8)
283 (43) 148 (30)
FFS Event

ND James et al Eur Urol 2014

25
71

Death

(3)
(9)

8
20

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 6569 vs 70 or more

Docetaxel and/or zoledronic


acid for hormone-nave
prostate cancer:
First survival results from
STAMPEDE
Nicholas James
University of Warwick and Queen Elizabeth Hospital Birmingham
on behalf of
Matthew Sydes, Malcolm Mason, Noel Clarke, David Dearnaley, Melissa Spears,
Robin Millman,
Chris Parker, Alastair Ritchie, J. Martin Russell, John Staffurth, Robert Jones, Shaun
Tolan,
John Wagstaff, Andrew Protheroe, Rajaguru Srinivasan, Alison Birtle, Joe O'Sullivan,
Richard Cathomas, Mahesh Parmar and the STAMPEDE Investigators

Docetaxel & ZA
comparisons: patients

Accrual
Comparison
Open:
Oct-2005
Closed: Mar-2013
Accrual: 2962
Number
1184
593
592
593

of patients
A Standard-of-care (SOC)
B SOC + zoledronic acid
C
SOC + docetaxel
E
SOC + zoledronic acid + docetaxel

Accrual
Comparison
Open:
Oct-2005
Closed: Mar-2013
Accrual: 2962
Number
1184
593
592
593

of patients
A Standard-of-care (SOC)
B SOC + zoledronic acid
C
SOC + docetaxel
E
SOC + zoledronic acid + docetaxel

Patient characteristics
1%

WHO PS 2

[s]

21%

WHO PS 1

[s]

65yr

Median age

[s]

61%

Metastatic

[s]

15%

N+M0

24%

N0M0

98%

LHRH analogues

[s]

29%

Planned for RT

[s]

6%

Previous local therapy

(min 40, max 84)


(85% Bony mets)

(72% of N0M0 pts)

Balanced by arm
[s] Stratification factors + hospital +
NSAID/aspirin

Zoledronic acid: Survival


SOC
405 deaths
SOC+ZA 197 deaths
HR (95%CI)
(0.79, 1.11)
P-value
0.44

0.93

Non-PH p-value

Median OS (95% CI)


SOC
67m (60, 91m)
SOC+ZA
80m (70, NR)

Restricted mean OS
time
SOC
58.5m
SOC+Doc
59.5m
Diff (95%CI)1.0m (-1.4,
3.4m)

Docetaxel: Failure-free survival


SOC
750 FFS
events
SOC+Doc371 FFS
events
HR (95%CI)
0.62
(0.54, 0.70)
P-value Non-PH p-value
<0.0000000001*

Median FFS (95% CI)


SOC
21m (18, 24m)
SOC+Doc 37m (33, 42m)

Restricted mean FFS


time
SOC
35.3m
SOC+Doc
44.4m
Diff (95%CI)9.1m (6.3,
11.9m)
*exact p-value
0.0000000000002014

Docetaxel: Survival
SOC
405 deaths
SOC+Doc165 deaths
HR (95%CI)
0.76
(0.63, 0.91)
P-value
0.003
Non-PH p-value

Median OS (95% CI)


SOC
67m (60, 91m)
SOC+Doc 77m (70, NR)

Restricted mean OS
time
SOC
58.8m
SOC+Doc
63.4m
Diff (95%CI)4.6m (1.8,
7.3m)

Zoledronic acid + docetaxel: Survival


SOC
405 deaths
SOC+ZA+Doc 181
deaths
HR (95%CI)
0.81
(0.68, 0.97)
P-value
0.02
Non-PH p-value 0.40

Median OS (95% CI)


SOC
67m (60, 91m)
SOC+ZA+Doc
72m
(63, 90m)

Restricted mean OS
time
SOC
58.4m
SOC+Doc
61.5m
Diff (95%CI)3.4m (0.5,
6.2m)

Consistency of treatment effect


Subgroups included:

Metastatic status (M0, M1)


Nodal status (N0, N+, NX)
Gleason sum score (7, 8+, unknown)
PSA pre-hormone therapy (0-20ng/ml, 20-40, 40-100, 100+)
Age at randomisation (under 70, 70 or over)
WHO PS (0, 1-2)
NSAID/Aspirin use (no use, uses either)

No good evidence of heterogeneity

Treatment effect by metastatic status: FFS


Pre-planned analysis

+ZA

+Doc

+ZA+Doc

Treatment effect by metastatic status: Overall survival


Pre-planned analysis

+ZA

+Doc

+ZA+Doc

Docetaxel: Survival M1 Patients


SOC
343 deaths
SOC+Doc134 deaths
HR (95%CI)
0.73
(0.59, 0.89)
P-value
0.002
Non-PH p-value

Median OS (95% CI)


SOC
43m (24, 88m)
SOC+Doc 65m (27, NR)

Restricted mean OS
time
SOC
49.3m
SOC+Doc
56.1m
Diff (95%CI)6.8m (2.8,
11.0m)

Docetaxel treatment
Target Dose: 75mg/m2, every 3 weeks for 6 cycles (+prednisolone 10mg od)
Doc
Report receiving 6 cycles
76%
Report receiving 5 cycles 80%

ZA+Doc
69%
74%

Grade 3+ adverse events ever reported


A
SOC

B
SOC+ZA

C
SOC+Doc

1184

593

592

E
SOC+ZA+
Doc
593

1174

587

579

564

363 (3)

185 (1)

291 (3)

294 (7)

31%

31%

51%

52%

12%

12%

10%

12%

1%

2%

12%

12%

1%

1%

12%

11%

General disorder

4%

5%

8%

11%

Musculo-skeletal

5%

5%

6%

8%

Gastrointestinal disorder

3%

3%

7%

7%

Renal

5%

4%

4%

6%

Patients randomised
Patients with adverse event
data
Grade 3-5 AE (G5)

Endocrine disorder
Blood and lymphatic (febrile
neutropenia)
Blood/bone marrow
(neutrophils)

Grade 3+ adverse events ever reported


A
SOC

B
SOC+ZA

C
SOC+Doc

1184

593

592

E
SOC+ZA+
Doc
593

1174

587

579

564

363 (3)

185 (1)

291 (3)

294 (7)

31%

31%

51%

52%

12%

12%

10%

12%

1%

2%

12%

12%

1%

1%

12%

11%

General disorder

4%

5%

8%

11%

Musculo-skeletal

5%

5%

6%

8%

Gastrointestinal disorder

3%

3%

7%

7%

Renal

5%

4%

4%

6%

Patients randomised
Patients with adverse event
data
Grade 3-5 AE (G5)

Endocrine disorder
Blood and lymphatic (febrile
neutropenia)
Blood/bone marrow
(neutrophils)

Grade 3+ adverse events at 1 year


Treatment
SOC
SOC+ZA
SOC+Doc
SOC+ZA+Doc

Incidence
71/732
40/377
44/437
51/450

Rate
9.7%
10.6%
10.1%
11.3%

95%CI
(7.6% to
(7.5% to
(7.2% to
(8.4% to

11.8%)
13.7%)
12.9%)
14.3%)

Early peak in toxicity during chemotherapy seems to settle by 1 year

Time to first treatment for failure-free survival event

*treatment for
progression
given at the
investigators

Time to first life-prolonging therapy for progression

Use of life-prolonging therapy for progression

A
SOC

B
SOC+
ZA

C
SOC+
Doc

E
SOC+ZA+
Doc

Pts with FFS


event (n)

750

371

311

314

Life-prolonging
therapy
reported ever

372
50%

168
45%

135
43%

130
41%

Docetaxel

41%

36%

14%

15%

Abiraterone

23%

19%

28%

27%

Enzalutamide

7%

4%

7%

7%

Cabazitaxel

3%

3%

6%

9%

Radium-223

0%

0%

1%

1%

Use of life-prolonging therapy for progression

A
SOC

B
SOC+
ZA

C
SOC+
Doc

E
SOC+ZA+
Doc

Pts with FFS


event (n)

750

371

311

314

Life-prolonging
therapy
reported ever

372
50%

168
45%

135
43%

130
41%

Docetaxel

41%

36%

14%

15%

Abiraterone

23%

19%

28%

27%

Enzalutamide

7%

4%

7%

7%

Cabazitaxel

3%

3%

6%

9%

Radium-223

0%

0%

1%

1%

Conclusions
Docetaxel improves survival for hormone-naive prostate cancer
Zoledronic acid does not improve survival
Adding both improves survival but offers no obvious benefit
over adding just docetaxel

Multi-arm, multi-stage trials are practicable and efficient


Docetaxel should be:
Considered for routine practice in suitable men with
newly-diagnosed metastatic disease
Considered for selected men with high-risk non-metastatic disease
in view of substantial prolongation of failure-free survival

Conclusions
Docetaxel improves survival for hormone-naive prostate cancer
Zoledronic acid does not improve survival
Adding both improves survival but offers no obvious benefit
over adding just docetaxel

Multi-arm, multi-stage trials are practicable and efficient


Docetaxel should be:
Considered for routine practice in suitable men with
newly-diagnosed metastatic disease
Considered for selected men with high-risk non-metastatic disease
in view of substantial prolongation of failure-free survival

Conclusions
Docetaxel improves survival for hormone-naive prostate cancer
Zoledronic acid does not improve survival
Adding both improves survival but offers no obvious benefit
over adding just docetaxel

Multi-arm, multi-stage trials are practicable and efficient


Docetaxel should be:
Considered for routine practice in suitable men with
newly-diagnosed metastatic disease
Considered for selected men with high-risk non-metastatic disease
in view of substantial prolongation of failure-free survival

Conclusions
Docetaxel improves survival for hormone-naive prostate cancer
Zoledronic acid does not improve survival
Adding both improves survival but offers no obvious benefit
over adding just docetaxel

Multi-arm, multi-stage trials are practicable and efficient


Docetaxel should be:
Considered for routine practice in suitable men with
newly-diagnosed metastatic disease
Considered for selected men with high-risk non-metastatic disease
in view of substantial prolongation of failure-free survival

Conclusions
Docetaxel improves survival for hormone-naive prostate cancer
Zoledronic acid does not improve survival
Adding both improves survival but offers no obvious benefit
over adding just docetaxel

Multi-arm, multi-stage trials are practicable and efficient


Docetaxel should be:
Considered for routine practice in suitable men with
newly-diagnosed metastatic disease
Considered for selected men with high-risk non-metastatic disease
in view of substantial prolongation of failure-free survival

Chemotherapy trials in hormone


nave prostate cancer (HNPC)
GETUG-15
Gravis et al, Lancet Oncol 2013. 14: 149-158 updated J
Clin Oncol 33, 2015 (suppl 7; abstr 140)

CHAARTED
Sweeney et al, N Engl J Med 2015; 373:737-746August
20, 2015 DOI: 10.1056/NEJMoa1503747

STAMPEDE
James et al, J Clin Oncol 33, 2015 (suppl; abstr 5001)

GETUG-15
Median OS:
ADT alone: 54.2 [44.2- NR]
ADT + D: 58.9 [50.8- 69.1]
HR: 1.01 [0.7-1.4]
p=0.95

Gravis et al, Lancet Oncol 2013. 14: 149-158

CHAARTED

Sweeney et al, N Engl J Med 2015; 373:737-746

Forest plot of overall survival for the 3


studies
*

* weight by
inverse
variance

Slide courtesy of Dr Ian Tannock and Dr Eitan Amir, PMH Toronto


15-09-11

ASCO

Role of chemotherapy for localized


high-risk PC (M0) after radiation
therapy

GETUG-12 (Fizazi et al; Lancet Oncol, 2015)


ADT +/- 4 cycles docetaxel/estramustine (N=413)
RFS: 199 events: HR=0.71 (0.54-0.94)
OS: 91 deaths: too early
STAMPEDE (Not all M0 men had RT)
ADT +/- 6 cycles docetaxel/prednisone (N=689)
RFS: 229 events; HR=0.57 (0.42-0.76)
OS: 93 deaths; HR=1.01 but too early
RTOG 0521
ADT +/- 6 cycles docetaxel/prednisone (N=563)
RFS: 221 events: HR=0.76 (0.58-0.99)
OS: 102 deaths: HR=0.70 (0.51-0.98)

Relapse free survival


GETURG-12

Disease free survival


RTOG 0521

Sandler et al Proc ASCO 2015

Overall survival RTOG


0521

Sandler et al Proc ASCO 2015

A closer look at RTOG


5201

Slide courtesy of Dr Ian Tannock, PMH Toronto

Forest plot of failure free survival for the 3


studies
*

Slide courtesy of Dr Ian Tannock and Dr Eitan Amir, PMH Toronto


15-09-11

ASCO

Conclusions
Docetaxel improves survival for hormone-nave prostate cancer

Docetaxel should be considered for routine practice in suitable


men with newly-diagnosed metastatic disease

For men with M0 disease, consideration should be given to


using docetaxel as part of multi-modality therapy where risk of
prostate cancer death is high

Further data and follow up needed for M0 disease

STAMPEDE investigators
UNITED KINGDOM

Aberystwyth, Bronglais General Hospital (4; S Durrani)


Ashford, William Harvey Hospital (0; C Thomas, N Mithal)
Aylesbury, High Wycombe & Stoke Mandeville Hospital (1; A Sabharwal, P Camilleri, C Alcock, J Brady, A Protheroe)
Ayr, Ayr Hospital (14; H Glen, J Ansari, R Mahmood)
Barnet, Barnet General Hospital (14; U McGovern, A Eichholz)
Barnstaple, North Devon District Hospital (25; D Sheehan)
Basingstoke, Basingstoke and North Hampshire Hospital (12; R Shaffer, T Guerrero-Urbano)
Bath, Royal United Hospital (22; O Frim, M Beresford, H Newman, P Kehagioglou)
Bebington, Clatterbridge Centre for Oncology (64; S Tolan, J Littler, I Syndikus, A Ibrahim, A Montazeri)
Belfast, Belfast City Hospital (118; J O'Sullivan, D Mitchell, P Lin, D Stewart, S Jain)
Birmingham, Birmingham Heartlands Hospital (32; A Zarkar)
Birmingham, City Hospital (24; D Ford)
Birmingham, Queen Elizabeth Hospital (Birmingham) (141; N James, E Porfiri, D Ford)
Blackburn, Royal Blackburn Hospital (62; O Parikh)
Bolton, Royal Bolton Hospital (23; T Elliott, M Pantelides)
Boston, Pilgrim Hospital (; T Sreenivasan, M Panades)
Bournemouth, Royal Bournemouth Hospital (83; S Brock, J Davies)
Bradford, Bradford Royal Infirmary (24; S Brown)
Brighton, Royal Sussex County Hospital (63; A Robinson, G Plataniotis, D Bloomfield, M Wilkins)
Bristol, Bristol Haematology & Oncology Centre (60; A Bahl, M Beresford, S Hilman, P Wilson, C Herbert)
Burnley, Burnley General Hospital (8; N Charnley, O Parikh)
Burton-on-Trent, Queens Hospital Burton (37; S Chetiyawardana, D Muthukumar, P Pattu, M Smith-Howell, P Chakraborti)
Bury St Edmunds, West Suffolk Hospital (16; C Woodward, Y Rimmer)
Cambridge, Addenbrooke's Hospital (5; D Mazhar)
Canterbury, Kent and Canterbury Hospital (36; C Thomas, N Mithal, R Raman, A Edwards)
Cardiff, Velindre Hospital (5; M Mason, J Barber, J Lester, J Staffurth, J Tanguay, N Palaniappan, S Kumar, M Button, D Mort)
Carlisle, Cumberland Infirmary (7; A Kumar, N Sidek)
Chelmsford, Broomfield Hospital (30; A Hamid, U Panwar, P Leone)

Page 1/5

STAMPEDE investigators
UNITED KINGDOM

Page 2/5
Cheltenham, Cheltenham General Hospital (10; J Bowen, P Jenkins)
Chester, Countess of Chester Hospital (66; A Ibrahim)
Colchester, Essex County Hospital (7; B Sizer, M Kumar)
Coventry, University Hospital Coventry and Warwickshire (24; A Stockdale, J Worlding)
Crewe, Leighton Hospital (41; J Wylie)
Darlington, Darlington Memorial Hospital (27; J Hardman, C Peedell, M Kagzi, T Mukhopadhyay)
Derby, London Road Community Hospital (16; P Chakraborti, D Muthukumar)
Derby, Royal Derby Hospital (71; P Chakraborti, D Muthukumar, P Pattu)
Doncaster, Doncaster Royal Infirmary (0; M Alzouebi, C Ferguson, M Alzouebi)
Dorchester, Dorset County Hospital (21; P Crellin, S Andrews)
Dudley, Russells Hall Hospital (46; P Ramachandra, P Keng-Koh)
Durham, University Hospital of North Durham (17; R McMenemin)
Eastbourne, Eastbourne District General Hospital (52; F McKinna)
Edinburgh, Western General Hospital (105; D McLaren)
Edmonton, North Middlesex Hospital (15; J Newby, A Thompson, S Karp, F Neave)
Exeter, Royal Devon and Exeter Hospital (102; D Sheehan, R Srinivasan, V Ford)
Gillingham, Medway Maritime Hospital (18; H Taylor)
Glasgow, Beatson W.Scotland Cancer Centre (41; R Jones, M Russell, J Wallace, J Graham, R Mahmood, C Lamb, A Al-hasso, B Venugopal)
Guildford, Royal Surrey County Hospital (30; R Laing, J Money-Kyrle, S Khaksar, K Wood, T Guerrero-Urbano)
Harlow, Princess Alexandra Hospital (Harlow) (10; N Gupta, L Melcher)
Hereford, Hereford County Hospital (9; W Grant, A Cook)
High Wycombe, Wycombe Hospital (15; A Sabharwal, A Protheroe, P Camilleri, T Pwint, G Andrade)
Huddersfield, Huddersfield Royal Infirmary (76; U Hofmann)
Hull - Cottingham, Castle Hill Hospital (2; M Simms, J Hetherington)
Inverness, Raigmore Hospital (68; N McPhail, K Kelly, A Sadozye, C Macgregor)
Ipswich, Ipswich Hospital (0; R Brierly, R Venkitaraman, C Scrase, G Banerjee)
Keighley, Airedale General Hospital (37; S Brown, M Crawford, C Sentamans)
Kidderminster, Kidderminster General Hospital (19; M Churn, L Capaldi)

STAMPEDE investigators
UNITED KINGDOM

Page 3/5
Larbert, Forth Valley Royal Hospital (22; N Sidek)
Leeds, St James University Hospital (Leeds) (26; W Cross, S Prescott, D Bottomley, S Jain, C Loughrey, A Paul, A Henry, P Whelan)
Lincoln, Lincoln County Hospital (15; T Sreenivasan, D Ballesteros-Quintail, M Panades, K Baria)
Liverpool, Royal Liverpool University Hospital (37; Z Malik, C Eswar, P Robson)
Liverpool, Triemlispital (1; D Siciliano)
Liverpool, University Hospital Aintree (16; P Robson)
London, Charing Cross Hospital (26; A Falconer)
London, Guy's Hospital (104; S Chowdhury, P Harper, S Morris, R Popert, R Beaney)
London, Hammersmith Hospital (0; A Falconer, S Mangar)
London, Queen Elizabeth Hospital (Woolwich) (18; S Hughes)
London, Royal Free Hospital (15; M Vilarino-Varela, K Pigott)
London, Royal Marsden Hospital (9; V Khoo)
London, St Bartholomews Hospital (3; K Tipples, P Wells)
London, St George's Hospital (29; L Pickering)
London, St Mary's Hospital (0; A Falconer, S Stewart)
London, University College Hospital (21; U McGovern, S Harland, H Payne)
Maidstone, Maidstone Hospital (84; S Beesley, A Clarke, H Taylor)
Manchester, Christie Hospital (1; N Clarke, T Elliott, J Wylie, J Livsey, J Logue, R Cowan)
Manchester, Withington Hospital (7; V Sangar)
Margate, Queen Elizabeth The Queen Mother Hospital (1; C Thomas, R Raman, N Mithal)
Middlesbrough, James Cook University Hospital (31; C Peedell, J Hardman, H Van, D Shakespeare, D Chadwick)
Newcastle-upon-Tyne, Freeman Hospital (21; A Azzabi, R McMenemin, J Frew)
Northwood, Mount Vernon Hospital (19; P Hoskin, R Alonzi, P Ostler, N Anyamene, R Hughes, J Dickson, C Westbury)
Nottingham, Nottingham University Hospitals, City Campus (59; S Sundar, J Mills, E Chadwick)
Nuneaton, George Eliot Hospital (9; A Chan)
Oldham, Royal Oldham Hospital (17; J Livsey, A Choudhury)
Oxford, Churchill Hospital (96; A Protheroe, D Cole)
Poole, Poole Hospital (0; S Brock, J Davies)

STAMPEDE investigators
UNITED KINGDOM

Portsmouth, Queen Alexandra Hospital (141; J Gale)


Preston, Royal Preston Hospital (92; A Birtle, O Parikh, M Wise)
Reading, Royal Berkshire Hospital (24; P Rogers, H O'Donnell, R Brown)
Redditch, Alexandra Hospital (13; J Hamilton)
Romford, Queen's Hospital (Romford) (74; S Gibbs, R Subramaniam)
Salford, Salford Royal Hospital (48; N Clarke, M Lau, T Elliott)
Scarborough, Scarborough General Hospital (59; M Hingorani)
Sheffield, Weston Park Hospital (67; C Ferguson, P Kirkbride, M Alzouebi, T Das)
Shrewsbury, Royal Shrewsbury Hospital (116; N Srihari, R Prashant)
South Shields, South Tyneside District Hospital (5; A Azzabi)
Southampton, Southampton General Hospital (48; C Heath, S Crabb, M Wheater)
Southport, Southport and Formby District General Hospital (29; N Bhalla, C Eswar, A Sivapalasuntharam)
St Leonards-on-Sea, Conquest Hospital (5; F McKinna, K Lees, S Beesley)
Stevenage, Lister Hospital (27; R Hughes)
Stockport, Stepping Hill Hospital (90; J Logue, A Adeyoju)
Stockton-on-Tees, University Hospital of North Tees (10; D Shakespeare)
Stoke-on-Trent, Royal Stoke Hospital (56; F Adab, R Bhana)
Sunderland, Sunderland Royal Hospital (22; A Azzabi, I Pedley)
Sutton, Royal Marsden Hospital (Sutton) (104; D Dearnaley, C Parker, R Huddart, V Khoo)
Sutton Coldfield, Good Hope Hospital (15; D Ford)
Sutton-in-Ashfield, King's Mill Hospital (35; D Saunders, G Walker)
Swansea, Singleton Hospital (122; J Wagstaff, G Bertelli, D Pudney, M Phan)
Swindon, Great Western Hospital (40; D Cole, E Hill)
Taunton, Musgrove Park Hospital (18; E Gray, J Graham, M Varughese, M Keni, G Plataniotis)
Torquay, Torbay District General Hospital (81; A Lydon, R Srinivasan)
Warrington, Warrington Hospital (56; I Syndikus, S Tolan)
Warwick, Warwick Hospital (14; A Stockdale)

Page 4/5

STAMPEDE investigators
UNITED KINGDOM

Westcliff on Sea, Southend University Hospital (51; D Tsang, I Ahmed, O Chan, N Sarwar)
Weston Super Mare, Weston General Hospital (12; S Hilman)
Whitehaven, West Cumberland Hospital (1; J Nicoll)
Wigan, Royal Albert Edward Infirmary (22; A Tran, R Cowan)
Wolverhampton, New Cross Hospital, Wolverhampton (19; I Sayers)
Worcester, Worcestershire Royal Hospital (19; L Capaldi, J Bowen)
Worthing, Worthing Hospital (59; A Nikapota, D Bloomfield, F Castell)
Yeovil, Yeovil District Hospital (3; E Gray, G Sparrow)

SWITZERLAND

Aarau, Hirslanden Medical Centre (3; R Popescu)


Basel, Universittsspital Basel (2; C Reutsch, B Seifest)
Berne, Inselspital (2; G Thalmann, B Roth)
Chur, Kantonsspital Graubnden (8; R Strebel, R Cathomas)
Lausanne, Centre Hospitalier Universitaire Vaudois (2; D Berthold, P Jichlinski, F Herrera)
St Gallen, Kantonsspital St Gallen (5; D Engeler, S Prensser)

Page 5/5

Acknowledgements
MRC Clinical Trials Unit at UCL
Current M Sydes, M Spears, M Parmar, C Amos, F Schiavone, A Brown, O Prendiville, C Au, P Vaughan, Z Khan, N
Begum,
D Hague, Z Islam,
Ex
S Naylor, N Kelk, J Nuttall, J Latham, K Sanders, C Green, T Fairfield, G Jovic, H Gardner, K Ward, S Peres, E
Ades
Patient representations on Trial Management Group
Current R Millman, D Matheson
Ex
D Hoe-Richardson, J Stansfeld, J Dwyer
Independent Data Monitoring Committee (IDMC)
Current John Yarnold (chair), Doug Altman, Reg Hall, Bertrand Tombal
Ex
Chris Williams (ex-chair)
Trial Steering Committee (TSC)
Current Jonathan Ledermann (chair), David Kirk, Jim Paul, Jan-Erik Damber
Ex
John Fitzpatrick
Industry partners
Sanofi-Aventis
Novartis
Pfizer
Astellas
Janssen

Acknowledgements

And the 7000 men who have joined the trial to date

www.stampedetrial.org