Survival with newly diagnosed metastatic prostate cancer in the docetaxel era: Data from >770 patients in the

control arm of the STAMPEDE trial

Nicholas James Professor of Clinical Oncology Queen Elizabeth Hospital and University of Warwick

Cancer research spending

Half of all drugs in trials are cancer drugs Global cancer drug market risen from $48bn (2008) to $75bn (est 2012) 25 drugs with sales >1bn pa Annual research spend:
pharmaceutical industry $6-8 bn NCI $3.6 bn EU public bodies Eur 1.4 bn

If we are to afford new drugs, we must make trials cheaper and quicker

Research environment
New treatments usually not better than current
About 30 to 40% are positive Both academia and industry

Trials require huge time, effort and cost

Must be a better way to select treatments for efficacy assessments

MAMS Trial Design

Multi-Stage: Are there reasons why we should continue investigating a treatment?
Require sufficiently encouraging activity to continue assessment

Focus away from insufficiently active regimens

Focus limited resources on regimens that may benefit patients

Add new treatments of interest

STAMPEDE Celecoxib -- ECCO 2011 [LBA20] N Clarke

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
Multi-arm, Multi-stage

Traditional Approach T1 Phase II T2 T3 T4

C Phase II

T1

T2 T3 T4

C T1 Phase III C T3 C T4 Phase III

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Clinical Setting
Men with metastatic or high-risk non-metastatic prostate cancer Long-term hormone therapy (HT) alone is the standard of care Investigating whether early use of additional therapies can improve overall survival Many interesting agents demand assessment
No clear reason to choose one particular regimen Do not want to choose arbitrarily Want to assess all interesting agents

Focussed on three distinct initial treatments

STAMPEDE Celecoxib -- ECCO 2011 [LBA20] N Clarke

STAMPEDE outcome measures

Outcome Measure Stage Primary Secondary

Pilot
Activity I-III (phase II)

Safety
Failure-free survival

Feasibility
Overall survival Toxicity / safety Skeletal events

Efficacy IV (Phase III)

Overall survival

Failure-free survival Toxicity / safety Skeletal events Quality of life

STAMPEDE practicalities Heidelberg 2012 MR Sydes

STAMPEDE trial
Launched 2005 Initial feasibility stage:
Would patients accept randomisation between 6 treatment arms? Would clinicians put the time into the study to make it work? Would the chosen treatments be safe?

STAMPEDE original design

A Deprivation
Therapy Androgen Control arm
Treatment detail Androgen Deprivation Therapy :: Standard hormones :: Given for >3 year

Man with high-risk prostate cancer starting long-term hormone therapy

RANDOMISATION

B ADT + Zoledronic Acid C ADT + Docetaxel D ADT + Celecoxib E ADT + ZA + Doc F ADT + ZA + Cel

Zoledronic Acid :: 3rd generation bisphosphonat :: IV for 2 years every 3 to 4 we

Docetaxel :: Taxane chemotherapy :: IV for 6 cycles over 18 weeks Celecoxib :: Cox-2 inhibitor :: Oral MRC for 1 PR08 year

CRUK/06/019 ISRCTN78818544

NCT00268476

2005 A B C D E F

2006

2007

2008

2009

Accrual: start
2010 2011 2012 2013

2014

2015

2016

2017

ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

Past accrual Possible future accrual

Slides for Kim Chi and NCIC CTG: Oct-2011

Follow-up

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

Accrual: end of Pilot Phase

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

Feasibility and safety confirmed

Past accrual Possible future accrual Follow-up

STOPPING ARMS WITH INSUFFICIENT ACTIVITY

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

Accrual: end of Activity Stage I

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

Past accrual Possible future accrual

All arms complete round 2 of their high jump!

Follow-up

Slides for Kim Chi and NCIC CTG: Oct-2011

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

Accrual: end of Activity Stage II

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

Celecoxib fails round 3 of its contest

Past accrual Possible future accrual

Slides for Kim Chi and NCIC CTG: Oct-2011

Follow-up

ADDING NEW AGENTS

Flexibility and extension

Design adapts to include further agents
Can add new research arms during trial

Might see as a new trial within STAMPEDE protocol Must be scientifically compelling case for inclusion
Proposed through Trial Management Group Survey of participants Peer review through original funder (Cancer Research UK)

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Advantages?
1. Can start recruiting quicker than a new trial
Updated 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 STAMPEDE practicalities
Heidelberg 2012 MR Sydes

STAMPEDE trial design

A

Composition of arms Abiraterone added Nov 2011

R A N D O M I S E
E C B

Hormone Androgen suppression Therapy (AS) (HT)

Control

Con trol a r m

HT + zoledronic acid

HT + docetaxel

HT + zoledronic acid + docetaxel

HT + G abiraterone

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

Accrual: from Nov-2011

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

ADT + abiraterone

Past accrual Possible future accrual

Slides for Kim Chi and NCIC CTG: Oct-2011

Follow-up

Local approvals of new comparison

Timely R&D approval for new protocol 1.0
Ready on activation Suspended until ready

0.8

New arm switched on for whole trial on set date Sites given ~4 wk notice to gain local approvals 80 sites ready to recruit on activation day!
Activation day

0.6

0.4

0.2

Accrual nearly seamless

0.0 0
Sites needing approval

4 5 6 7 8 9 10 11 12 13 14 15 Time (weeks) from notifying sites

104 (6) 98 (21) 77 (19) 58 (11) 47 (26) 21 (8) 13 (0) 13 (1) 12 (1) 11 (4) 7 (0) 7 (0) 7 (0) 7 (1) 6 (3) 3

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Aug 13

O ct 05 Jan 06

J ul 06

Jan 07

J ul 07

Jan 08

J ul 08

Jan 09

J ul 09

Jan 10

J ul 10

Jan 11

J ul 11

Jan 12

J ul 12

Jan 13

Z:\Prostate\Stampede\Data\Accrual\rand_planned.wmf

Accrual to new arms

D ate of randomisation

Accrual to abiraterone comparison

1500

Patients in abir ater one compar ison

1200

900

600

Closure of original arms

O ct 13

Apr 13

300

0
J an 12 J ul 12 J an 13 J ul 13 J an 14 J ul 14 J an 15

D ate of r andomisation

Z:\Prostate\Stampede\Data\Accrual\abi_comparison_accrual.wmf

J ul 13

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H
Past accrual Possible future accrual

Accrual: from autumn 2012

ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

Docetaxel and Zoledronic Acid pass their final high jump round

ADT + abiraterone ADT + RT

Follow-up

Slides for Kim Chi and NCIC CTG: Oct-2011

ADDING FURTHER NEW AGENTS

Adding a randomisation to a subgroup

Prostate radiotherapy standard of care in locally advanced cases Of unproven benefit but of interest in M1 cases
Patients eligible for STAMPEDE NEWLY DIAGNOSED M1 PATIENTS1 RANDOMISATION A G H ADT ADT + abiraterone ADT + RT to prostate A G ALL OTHER PATIENTS2 RANDOMISATION ADT ADT + abiraterone

Future arms
Abiraterone + Enzalutamide
Set to open Spring 2014

Radium-223 Metformin

WHATS THE CONTROL ARM?

Analysis: ZA comparison
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only
In analysis Not in analysis

ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

ADT + abiraterone ADT + RT

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Fully powered: accrued through AS4

Analysis: Docetaxel comparison

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only
In analysis Not in analysis

ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

ADT + abiraterone ADT + RT

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Fully powered: accrued through AS4

Analysis: Doc + ZA comparison

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only
In analysis Not in analysis

ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

ADT + abiraterone ADT + RT

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Fully powered: accrued through AS4

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only
In analysis Not in analysis

Analysis: Celecoxib comparisons

ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

ADT + abiraterone ADT + RT

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Less power: stopped accrual in AS2

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only
In analysis Not in analysis

Analysis: Abiraterone comparison

ADT-alone

ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

ADT + abiraterone ADT + RT

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Recruitment in Efficacy Phase 2

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only
In analysis Not in analysis

Analysis: M1/RT comparison

ADT-alone (M1-only)

ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

ADT + abiraterone ADT + RT (M1-only)

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Recruitment in Feasibility Phase

Prognosis of metastatic prostate cancer

776 newly-diagnosed men with M1 disease in the trials control arm recruited to STAMPEDE between Oct-2005 and July 2013 Median age 66, median PSA 111 Bone only mets 62%, soft tissue only 12%, bone and soft tissue 26% Age, PSA at diagnosis, Gleason score not prognostic

Survival by distribution of metastases

Failure-free survival 1.00 1.00 Overall survival

0.75
Proportion event-free

0.75

0.50

0.50

0.25

0.25

0.00 0 Number at risk

Bone only 482 Soft tissue only 95 Bone & soft tissue 199 147 49 46 57 22 13 28 12 6 9 7 4

0.00 12 24 36 48 Number at risk

Bone only 482 Soft tissue only 95 Bone & soft tissue 199 285 63 109 151 34 47 79 22 23 29 15 7

12

24

36

48

Time from randomisation (Months)

Time from randomisation (Months)

Bone only

S oft tissue only

Bone & soft tissue

Survival by PSA at diagnosis

N % Patient Hazard 2yr Hazard 2yr FFS Characteristic/ Ratio* Survival Ratio* (95% CI) Grouping (95% CI) (95% CI) (95% CI)

137 136 137 136 136

20 Lowest 20 2 20 3 20 4 20 Highest

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)

Survival by age at diagnosis

N %
Patient Hazard 2yr Hazard 2yr FFS Characteristic Ratio* Survival Ratio* (95% CI) / Grouping (95% CI) (95% CI) (95% CI) 29 (24, 34) 36 (27, 44) 69 (62, 74) 76 (67, 83)

481 201

71 29

Under 70 70 or over

1.00 0.87 (0.69, 1.10)

1.00 0.96 (0.69, 1.33)

Survival by Performance Status

Failure-free survival 1.00 1.00 Overall survival 0.75 0.75

0.50

0.50

0.25

0.25

0.00 0 Number at risk

W HO PS 0 564 W HO PS 1&2 212 195 47 75 17 39 7 18 2

0.00 12 24 36 48 Number at risk

W HO PS 0 564 W HO PS 1&2 212 338 119 181 51 100 24 42 9

12

24

36

48

Time from randomisation (Months)

Time from randomisation (Months)

W HO PS 0

W HO PS 1&2

Survival by PSA nadir < / > 4

Failure free survival 1.00 1.00 Overall survival

0.75

0.75

0.50

0.50

0.25

0.25

0.00 0 Number at risk 12 24 36 48

0.00 0 Number at risk 12 24 36 48

Time from randomisation (Months) <4 317 4+ 89 116 27 57 9 33 2 12 0

Time from randomisation (Months) <4 363 4+ 201 233 112 124 45 73 16 24 3

<4

4+

Subsequent therapies post relapse

1.00 0.75 0.50 0.25 0.00 0 Number at risk Chemotherapy Radiotherapy Bisphosphonate Abiraterone 427 427 427 427
Chemotherapy

12 24 Time from FFS event (Months) 131 160 173 204

Radiotherapy

36 10 16 18 22
Abiraterone

44 59 63 72
Bisphosphonate

Failure-free and overall survival for newlydiagnosed M1 patients in the STAMPEDE trial

Conclusions
Metastatic patients are castration resistant for the majority of the disease course Performance status, PSA nadir and metastatic site are highly prognostic Age, PSA and Gleason score at diagnosis were not prognostic Overall survival is longer than in older series

Study authors
James, Nicholas David Clarke, Noel W Mason, Malcolm David Dearnaley, David Paul De Bono, Johann Parker, Christopher Parmar, Mahesh Ritchie, Alastair SW Russell, J. Martin Spears, Melissa R Thalmann, George Sydes, Matthew Robert On behalf of the STAMPEDE Investigators