stampede m0 astro presentation sept 2014
DESCRIPTION
Outcomes of control arm non-metastatic patients in STAMPEDE trial in advanced prostate cancerTRANSCRIPT
1
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 on behalf of: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
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 cancer3. 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
2www.stampedetrial.org
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 cancer3. 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
3www.stampedetrial.org
4
[A]+zoledronic acid
[A]+docetaxel
[A]+celecoxib
[A]+ZA+docetaxel
[A]+ZA+celecoxib
[A]+(abi) *
ADT ( +/-RT) [CTRL]
[A]+M1|RT {M1}
[A]+(enza+abi)**
* Abiraterone** Enzalutamide + abiraterone
Accrual - past
Accrual - f uture
Follow-up
A
B
C
D
E
F
G
H
J
A
B
C
D
E
F
G
H
J
Trial
arm
2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2 2 0 1 3 2 0 1 4 2 0 1 5 2 0 1 6 2 0 1 7 2 0 1 8 2 0 1 9 2 0 2 0 2 0 2 1 2 0 2 2
2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2 2 0 1 3 2 0 1 4 2 0 1 5 2 0 1 6 2 0 1 7 2 0 1 8 2 0 1 9 2 0 2 0 2 0 2 1 2 0 2 2
Ju l-2 0 1 4 : Th ird new comparison
STAMPEDE: Enzalutamide + abiraterone comparison activated
[A]+zoledronic acid
[A]+docetaxel
[A]+celecoxib
[A]+ZA+docetaxel
[A]+ZA+celecoxib
[A]+(abi) *
ADT ( +/-RT) [CTRL]
[A]+M1|RT {M1}
[A]+(enza+abi)**
* Abiraterone** Enzalutamide + abiraterone
Accrual - past
Accrual - f uture
Follow-up
A
B
C
D
E
F
G
H
J
A
B
C
D
E
F
G
H
J
Trial
arm
2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2 2 0 1 3 2 0 1 4 2 0 1 5 2 0 1 6 2 0 1 7 2 0 1 8 2 0 1 9 2 0 2 0 2 0 2 1 2 0 2 2
2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2 2 0 1 3 2 0 1 4 2 0 1 5 2 0 1 6 2 0 1 7 2 0 1 8 2 0 1 9 2 0 2 0 2 0 2 1 2 0 2 2
Ju l-2 0 1 4 : Th ird new comparison
STAMPEDE: Enzalutamide + abiraterone comparison activated
8 importa
nt RCTs
in <15 years
5
6
[A]+zoledronic acid
[A]+docetaxel
[A]+celecoxib
[A]+ZA+docetaxel
[A]+ZA+celecoxib
[A]+(abi) *
ADT ( +/-RT) [CTRL]
[A]+M1|RT {M1}
[A]+(enza+abi)**
* Abiraterone** Enzalutamide + abiraterone
Accrual - past
Accrual - f uture
Follow-up
A
B
C
D
E
F
G
H
J
A
B
C
D
E
F
G
H
J
Trial
arm
2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2 2 0 1 3 2 0 1 4 2 0 1 5 2 0 1 6 2 0 1 7 2 0 1 8 2 0 1 9 2 0 2 0 2 0 2 1 2 0 2 2
2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2 2 0 1 3 2 0 1 4 2 0 1 5 2 0 1 6 2 0 1 7 2 0 1 8 2 0 1 9 2 0 2 0 2 0 2 1 2 0 2 2
Ju l-2 0 1 4 : Th ird new comparison
STAMPEDE: Enzalutamide + abiraterone comparison activated
Aims1. Describe prognosis for men with newly-diagnosed
high-risk M0 disease2. Describe impact of planned radical RT on time to
progression• split by nodal status
7
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
8
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
9
Results – Aim 1• Prognosis of newly-diagnosed high-risk M0 disease• Cohort selection:
10
Allocated to control armN=1858
Allocated to research armsN=3,715
Non-metastaticN=788
MetastaticN=1090
Randomised by 01-May-2014N=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) 43 (IQR 18-88)
Node-positive 40% (n=287/721)
Gleason summary score 8-10 74% (n=535/721)
WHO Performance Status 1-2 15% (n=110/721)
Planned for RT 75% (n=539/721)
Median follow-up (months) 17 (IQR 6-36)
FFS events 149
Deaths 40
M0 cohort demographics
11
63.3 (IQR 26.4-NR)
0.00
0.25
0.50
0.75
1.00
Pro
portio
n e
vent-free
721 392(7) 273(10) 173(6) 108(6) 46(9) 24(2) 8(0)Death721 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 84Time from randomisation (Months)
FFS Event Death
Survival & FFS outcomes – M0 cohort
12
RT in high-risk M0 prostate cancer
13
• 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
RT recommended schedules
14
Trial patient intended for standard (M0) RT on arms ABCDEFG
N0 N+
Prostate: 74Gy/37f Pelvis: 46Gy/23f to 50Gy/25fOr equivalent schedule
Prostate: 74Gy/37fOr equivalent schedule
Whole pelvis + prostate boost
RT to prostate only +/- seminal vesicles
Prostate: 74Gy/37f Pelvis: ~55Gy/37fOr equivalent schedule
Clinical choice
Clinical choice
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
15
Nodal subgroups• Data frozen
01-May-2014
16
FFS EventsN=21
FFS EventsN=30
FFS EventsN=27
FFS EventsN=40
RT not planned
N=59
RT plannedN=121
RT not planned
N=80
RT planned
N=98
Randomised >1yr agoN=178
Randomised <15/11/2011N=180
Nodal stage unknownN=1
N+N=287
N0N=433
Diagnosed within 6m pre-randomisation
N=721
Nodal subgroup demographics
17
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)
Median PSA pre-ADT (ng/mL) 26 (IQR 58-104) 35 (IQR 15-76)
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)
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
18
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)+RT59 48(11) 39(8) 29(3) 13(4) 4(3) 2(1) 2(0)-RT
N(risk)
0 12 24 36 48 60 72 84Time 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)+RT59 48(11) 39(8) 29(3) 13(4) 4(3) 2(1) 2(0)-RT
N(risk)
0 12 24 36 48 60 72 84Time from randomisation (months)
-RT +RT
N0 Planned radical RT status
FFS by RT status: Node-negative cohort
19
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)+RT80 54(18) 29(13) 15(4) 9(3) 5(0) 4(0) 1(2)-RT
N(risk)
0 12 24 36 48 60 72 84Time from randomisation (months)
-RT +RT
N+ Planned radical RT status
FFS by RT status: Node-positive cohort
20
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)+RT80 54(18) 29(13) 15(4) 9(3) 5(0) 4(0) 1(2)-RT
N(risk)
0 12 24 36 48 60 72 84Time from randomisation (months)
-RT +RT
N+ Planned radical RT status
FFS by RT status: Node-positive cohort
21
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 overall 63.3m
• 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
Conclusions
23
Acknowledgements• Funding:
• Cancer Research UK (CRUK/016/09)• Novartis; free drug & educational grant• Sanofi-Aventis; discounted drug & educational grant • Pfizer; free drug & educational grant• Janssen; free drug & educational grant• Astellas; free drug & educational grant• Medical Research Council; core funding
• All clinicians and hospital staff who have supported, and continue to support, the trial
• All patients, who have joined the trial, and their families• Slides available via @Prof_Nick_James
24
Thanks to all investigators + site staff, IDMC, and TSC