Survival with newly diagnosed metastatic prostate cancer in the “docetaxel era”: Data from >600 patients
in the control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019)
Noel W Clarke1, Nicholas D James2, Malcolm D Mason3, Daniel Abersold4, David P Dearnaley5, Johann S de Bono5, Christopher Parker5, Mahesh KB Parmar6,
Alastair WS Ritchie1, J Martin Russell7, Melissa R Spears6, George Thalmann4, Matthew R Sydes6 for the STAMPEDE investigators
Conclusion
Survival, and particularly FFS, remains relatively poor for men presenting with M1 disease
starting long-term ADT, despite potential access when castration-resistant (CRPC) to
docetaxel and other newer therapies. Better first-line therapy is required; STAMPEDE will
report many comparisons in the future. Different M1 patterns may vary prognostically.
Men with M1 disease will now spend most time in a state of CRPC, which has important
implications for clinicians and trialists.
Data Collection & Analysis
 Baseline characteristics were collected via randomisation and baseline
forms for details of patient demographics, metastatic site and diagnosis
date, any planned radiotherapy, nodal and tumour status and additional
treatments received.
 Outcome details were obtained from follow-up and progression forms.
 Data frozen: Apr-2013
 Kaplan-Meier estimates for assessing the survival curves were produced;
individuals not reporting an event were censored at the date of last
contact.
 Survival estimates are reported here according to the following groupings:
 Site of metastases (Bone only, Soft Tissue only, Bone & Soft Tissue)
 Nodal status at baseline (N0, N+, NX)
 Bone metastases and nodal status (Bone & N0, Bone & N+)
 Initial Gleason sum score category (2-6, 7, 8-10)
 Age group at randomisation (under 70, 70 or over)
 WHO performance status
 PSA nadir (< 4, ≥4)
 PSA at diagnosis (quintiles)
 Tumour status (≤T2, T3, T4, TX)
Survival outcomes reported are the intermediate and definitive primary
outcome measures for the trial: failure-free survival and overall survival, with
estimates of both median survival and survival at two years. Number of
deaths due to prostate cancer (PCa) compared to other causes, on those
whose death had been reviewed, were also tabulated.
Failure Free
Survival
Overall
Survival
Total number of
events
Biochemical Failure


296
Local progression


44
Lymph nodes progression


21
Distant metastases progn


120
PCa death


140
Other death


29
345
169
Total number of events
Patient Characteristics
 All newly diagnosed (within 6 months of randomisation) patients
with confirmed metastatic status randomised to control arm A of
the STAMPEDE trial between Oct-2005 and Mar-2013 were
included in this prospective cohort study.
 All patients received standard of care androgen deprivation
therapy (ADT) which consisted of orchidectomy, luteinising
hormone-releasing hormone (ant)agonists, or maximum androgen
blockade. Upon progression treatment given was at the discretion
of the consulting clinician.
 Details of the original trial can be found published elsewhere.
Figure 1: Selection criteria for newly-diagnosed M1 patients in the
control arm.
Key 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
N=3,984
Non-metastatic
N=459
Allocated to research arms
N=2,799
Metastatic
N=726
2yr Survival
(95% CI)
Hazard Ratio*
(95% CI)
682
100
All
Metastases Groupings
425
62
Bone only
83
12
Soft Tissue only
174
26
Bone & Soft Tissue
Nodal Status
220
32
N0
400
59
N+
62
9
NX
Bone Metastases & Nodal Status Grouping
165
44
Bone & N0
207
56
Bone & N+
Initial Gleason sum score category
9
2
2-6
104
21
7
391
77
8 - 10
Age Group
481
71
Under 70
201
29
70 or over
WHO performance status
491
72
0
181
27
1
10
1
2
PSA Nadir+
295
63
<4
173
37
≥4
PSA at diagnosis (quintiles)
137
20
Lowest
136
20
2
137
20
3
136
20
4
136
20
Highest
Tumour status
71
10
≤T2
388
57
T3
160
23
T4
62
9
TX
Metastatic site
31 (26, 35)
-
71 (66, 75)
-
599
88
Bone
+Analyses
32
14
208
46
5
2
31
7
Lung
Liver
Distant Nodes
Other
Patient Characteristic/
Grouping
Median age = 65y (IQR 60-70)
Median time from Pca diagnosis to randn = 2.2m (IQR 1.26-2.9)
Newly-diagnosed
N=692
Diagnosed more than
6 months prior randn
N=10
Included in
these analyses*
N=682
*Includes patients with high-risk newly diagnosed disease AND either TanyNanyM+ histologically confirmed
prostate adenocarcinoma OR multiple sclerotic bone metastases with PSA≥100ng/ml without histologically
confirmation of prostate adenocarcinoma
Further Reading



1.00
Overall Survival
Hazard Ratio*
(95% CI)
%
Continuous Variables
Relapsing
N=34
Failure-Free Survival
2yr FFS
(95% CI)
N
Population of Interest
Allocated to control arm
N=1,185
Figure 2: Failure-free and overall survival for newly-diagnosed M1
patients in the STAMPEDE trial.
Table 1: Patient characteristics at baseline and outcome survival times.
73 (67, 78)
87 (73, 94)
57 (46, 67)
1.00
0.35 (0.18, 0.67)
1.55 (1.11, 2.16)
33 (25, 41)
32 (26, 38)
20 (9, 33)
1.00
0.90 (0.71, 1.14)
1.08 (0.74, 1.56)
76 (67, 83)
68 (62, 74)
69 (53, 81)
1.00
1.12 (0.80, 1.58)
1.11 (0.65, 1.88)
33 (24, 41)
33 (23, 43)
1.00
0.86 (0.63, 1.16)
76 (66, 83)
70 (59, 78)
1.00
1.20 (0.79, 1.83)
38 (9, 68)
40 (28, 52)
31 (26, 37)
1.00
0.83 (0.33, 2.08)
1.09 (0.45, 2.66)
57 (8, 89)
81 (70, 89)
68 (62, 74)
1.00
0.78 (0.18, 3.31)
1.21 (0.30, 4.92)
29 (24, 34)
36 (27, 44)
1.00
0.87 (0.69, 1.10)
69 (62, 74)
76 (67, 83)
1.00
0.96 (0.69, 1.33)
1.00
33 (28, 39)
26 (19, 35)
NR
1.00
1.58 (1.25, 1.99)
3.24 (1.52, 6.88)
79 (74, 84)
52 (42, 62)
29 (4, 61)
1.00
2.40 (1.75, 3.30)
3.57 (1.56, 8.16)
0.75
1.00
1.42 (1.02, 1.97)
82 (76, 87)
60 (51, 68)
1.00
2.61 (1.87, 3.62)
43 (32, 54)
38 (27, 48)
30 (19, 40)
23 (14, 33)
21 (12, 30)
1.00
1.06 (0.74, 1.52)
1.30 (0.92, 1.85)
1.57 (1.11, 2.22)
1.94 (1.39, 2.72)
73 (61, 82)
69 (57, 79)
71 (59, 80)
75 (63, 83)
66 (54, 76)
1.00
0.80 (0.48, 1.32)
0.97 (0.60, 1.56)
0.94 (0.58, 1.51)
1.27 (0.80, 2.02)
51 (36, 64)
1.00
74 (57, 85)
31 (25, 37)
1.32 (0.89, 1.96)
73 (67, 79)
26 (17, 36)
1.93 (1.26, 2.95)
66 (54, 75)
20 (10, 34)
2.32 (1.42, 3.77)
64 (46, 77)
*Cox models adjusted for age at randomisation where relevant
1.00
1.20 (0.68, 2.11)
1.58 (0.86, 2.90)
1.86 (0.95, 3.62)
for PSA nadir were based on a landmark start time for patients of 6 months.
Two year survival is therefore survival at 18 months from the landmark.
Key
NR = not reached
WHO performance status is defined as
0: Normal activity without restriction;
1: Strenuous activity restricted, can do light work;
2: Up and about >50% of waking hours, capable of self-care
Parker CC, Sydes MR, Mason MD et al. Prostate radiotherapy for men with metastatic disease: A new comparison in the
STAMPEDE trial. Clinical Oncology 2013; 25 (5)
Sydes MR, Parmar MKB, Mason MD et al. Flexible trial design in practice – stopping arms for lack-of-benefit and adding
research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials 2012; 13 (168)
Sydes MR Parmar, MKB James, ND et al. Issues in applying multi-arm multi-stage (MAMS) methodology to a clinical trial in
prostate cancer: the MRC STAMPEDE trial. Trials 2009; 10 (39)
101 patients
37
29
21
18
Chemotherapy
11.8 (10.8, 13.3)
0.50
1.00
0.51 (0.35, 0.74)
1.44 (1.13, 1.82)
49 (41, 55)
31 (20, 44)
New HT
0.75
31 (25, 37)
53 (39, 66)
18 (11, 27)
Figure 4: Combinations of subsequent therapies ever received (including
numbers receiving that combination).
15
Radiotherapy
41.5 (36.0, 45.4)
15
Bisphosphonate
0.25
Abiraterone
0.00
0
Number at risk
Death 682
FFS Event 682
(52)
(258)
12
24
36
Time from randomisation (Months)
48
362
197
(61)
(62)
31
12
192
76
(33)
(18)
93
36
Death
(18)
(6)
60
(4)
(1)
7
2
FFS Event
0.50
0.00
0
Number at risk
Soft tissue only 83
Bone only 425
Bone & soft tissue 174
(17)
(160)
(81)
0.75
0.50
0.25
38
121
38
24
36
Time from randomisation (Months)
48
(9)
(36)
(17)
6
6
0
19
47
10
Soft tissue only
(5)
(10)
(3)
11
19
6
Bone only
(1)
(5)
(0)
Bone & soft tissue
60
Research Support
 Cancer Research UK provides grant funding
 MRC provides core funding support
 Pfizer provides drug and an educational grant
 Novartis provides drug and an educational grant
 Sanofi-Aventis provides drug and an educational grant
 Janssen provides drug and an educational grant
Email:
stampede@ctu.mrc.ac.uk
Trial website: www.stampede-trial.org
MRC CTU:
www.ctu.mrc.ac.uk
0.75
0.50
0.25
(0)
(1)
(0)
1
1
0
0.00
Randn
12
24
36
Time from randomisation (Months)
Number at risk
New HT682
255
99
47
Chemotherapy682
323
159
71
Radiotherapy682
331
164
79
Bisphosphonate 682
341
178
85
Abiraterone682
367
192
94
New HT
Contacts & Information
1.00
0.00
26.9 (14.4, 38.3)
12
Figure 5: Time to subsequent therapy received from a) randomisation &
b) FFS event
1.00
Figure 3: Failure-free survival split by metastatic site.
0.25
Example – of all patients who report an FFS event 37 report only ever receiving both new hormone therapy and chemotherapy at
any time following their failure-free survival event.
N.B. Numbers are not given for combinations with less than 10 patients; 46 patients do not report receiving any therapies post-failurefree survival event.
The majority of patients reporting being on chemotherapy are on docetaxel, and the majority of patients reporting subsequent
bisphosphonate are on zoledronic acid.
Proportion starting treatment
Results
3,984 men were recruited to STAMPEDE Oct-2005 to Mar-2013, including a control arm
cohort of 682 M1 men with newly-diagnosed disease. This cohort has median age at
randomisation 65yr (quartiles 60-70), median PSA 108 (quartiles 35-379) IU/l; metastases
to bone only (B) 425 (62%), soft tissue only (ST) 83 (12%) or bone and soft tissue (B+ST)
174 (26%). ST was mainly lymph nodes. Median time from diagnosis to randomisation is
68 days (max 180 days). Median duration of ADT prior to randomisation is 47 days (max
105 days). There were 169 deaths, of which 140 were from PCa. Median OS from
randomisation is 42 months, with 2-yr OS 71% (95%CI 66, 75) in this cohort; B 73%
(95%CI 67, 78), ST 87% (95%CI 73, 94), B+ST 57% (95%CI 46, 67). Median FFS is 12
months, driven by rising PSA; 2-yr FFS 31% (95%CI 26, 35). Median time from FFS event to
death was 20 months. Additional data on relapse therapies presented.
 What is the prognosis for patients with newly diagnosed
metastatic disease and does this appear to have changed over
time?
 Should sites scan for nodes in those patients with distant
metastases?
 What treatments are patients receiving following progression?
Subsequent Therapies Received
Proportion starting treatment
Methods
Newly diagnosed men with M1 disease in the trial’s control arm (standard of care: ADT
alone for at least 2yr), diagnosed up to 6 months prior to randomisation, were identified
from trial records in Apr-2013. We report overall survival (OS) and failure-free survival
(FFS) from randomisation by primary disease characteristics.
Outcomes
Patient Characteristics & Prognosis
11.6 (5.3, 32.9)
Background
STAMPEDE (www.stampedetrial.org) recruits men with newly diagnosed or rapidly
relapsing prostate cancer (PCa) that is metastatic (M1) or high-risk locally advanced, all
commencing long-term androgen deprivation therapy (ADT) for the first time. This is now
the largest therapeutic RCT in PCa. We report survival outcomes for newly diagnosed M1
control arm men in order to inform future trials in this setting.
Aim
Proportion event-free
(data updated since abstract submitted to ASCO)
Proportion event-free
Abstract
of Urology, The Christie NHS Foundation Trust, Manchester, UK; 2School of Cancer Sciences, University of Birmingham, UK; 3Cardiff University, UK; 4Dept of Urology, University of Bern, Switzerland;
5Institute of Cancer Research/Royal Marsden Hosp, Sutton, UK; 6MRC Clinical Trials Unit, London, UK; 7Beatson West of Scotland Cancer Centre, Glasgow, UK
8.2 (5.7, 11.3)
1Dept
Chemotherapy
0
Number at risk
New HT345
Chemotherapy345
Radiotherapy345
Bisphosphonate 345
Abiraterone345
Radiotherapy
12
24
36
Time from FFS event (Months)
46
112
129
137
167
Bisphosphonate
14
35
45
48
59
1
3
8
9
13
Abiraterone
Conclusions
 Failure-free survival is shorter than anticipated from pre-trial projections
but overall survival is longer.
 Approximately 70% of time from diagnosis with metastatic disease is spent
after a failure-free survival event.
 Patients with lymph node-only disease have significantly better outcomes
than bone-only disease.
 Patients with bone and lymph node disease have significantly worse
outcomes than bone-only disease.
 There is no clear pattern in the choice of therapy for the first on-trial
failure-free survival event.