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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

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[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

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G

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J

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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

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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

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[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

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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

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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

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

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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

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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

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RT in high-risk M0 prostate cancer

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• 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

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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

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Nodal subgroups• Data frozen

01-May-2014

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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

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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

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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

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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

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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

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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

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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

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Thanks to all investigators + site staff, IDMC, and TSC