Clinical effectiveness of strontium-89 and zoledronic acid in patients with castraterefractory prostate cancer (CRPC) metastatic to bone receiving

docetaxel
(TRAPEZE)
Nick James On behalf of
Sarah Pirrie, Darren Barton, Janet Brown, Lucinda Billingham, Stuart Collins, Adam Daunton, Alison Birtle, Prabir Chakraborti, Daniel Ford, Syed Hussain, Helen Jones, Ann Pope, Emilio Porfiri, Martin Russell, Andrew Stanley, John Staffurth, Duncan McLaren, Chris Parker, James Wylie and the TRAPEZE trial investigators

Background
Bone metastases are a major cause of morbidity in castrate refractory prostate cancer (CRPC) Taxane based chemotherapy improves survival and quality of life 1 Zoledronic acid (ZA) reduces skeletal related events 2 but use remains controversial Older radio-isotopes such as Strontium-89 (Sr89) have palliative benefits 3 A study combining Sr89 with pre-taxane chemotherapy showed a survival advantage 4
1. 2. 3. 4. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. NEnglJ Med 2004;351:1502-12. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J NatlCancer Inst 2004;96:879-82. Dafermou A, Colamussi P, Giganti M, Cittanti C, Bestagno M, Piffanelli A. A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer. Eur J Nucl Med 2001;28:788-98. Tu SM, Millikan RE, Mengistu B, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet 2001;357:336-41.

Presented by: Nick James

Aims of study
Does upfront use of bone targeting agents with chemotherapy improve clinical outcomes? Is it cost effective to prevent bone complications or to treat them as they arise?

Presented by: Nick James

Aims of study
Does upfront use of bone targeting agents with chemotherapy improve clinical outcomes? Is it cost effective to prevent bone complications or to treat them as they arise?

Presented by: Nick James

Phase III Study treatments

A
B C D
Docetaxel 75mg/m2 every 3 weeks + prednisolone 10mg od
(cycles 1-10)

docetaxel + prednisolone + ZA 4mg iv

(cycles 1-10)

docetaxel + prednisolone
(cycles 1-6)

Sr89 150 MBq

(day 28 cycle 6)

+ 28

Days*

docetaxel + prednisolone
(cycles 7-10)

* At least 28 days

docetaxel + prednisolone + ZA
(cycles 1-6)

Sr89
(day 28 cycle 6)

+ 28 Days*

docetaxel + prednisolone + ZA
(cycles 7-10)

ARMS B & D : Post chemotherapy, ZA will be administered at 4-weekly intervals until protocol defined disease progression.
Presented by: Nick James

Phase III Study treatments

A B
Docetaxel 75mg/m2 every 3 weeks + prednisolone 10mg od
(cycles 1-10)

docetaxel + prednisolone + ZA 4mg iv

(cycles 1-10)

C
D

docetaxel + prednisolone
(cycles 1-6)

Sr89 150 MBq

(day 28 cycle 6)

+ 28

Days*

docetaxel + prednisolone
(cycles 7-10)

* At least 28 days

docetaxel + prednisolone + ZA
(cycles 1-6)

Sr89
(day 28 cycle 6)

+ 28 Days*

docetaxel + prednisolone + ZA
(cycles 7-10)

ARMS B & D : Post chemotherapy, ZA will be administered at 4-weekly intervals until protocol defined disease progression.
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Statistical Design
Zoledronic Acid No Yes

No

A C

B
D

Sr89 Yes

Primary outcome analysis Univariable log rank Multivariable Cox model Power = 80% Significance level 5%
Presented by: Nick James

Statistical Design
Zoledronic Acid No Yes

No

A C

B
D

Sr89 comparison A+B vs C+D

618 evaluable pts 750 pts needed to account for early progression

Sr89 Yes

Primary outcome analysis Univariable log rank Multivariable Cox model Power = 80% Significance level 5%
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Statistical Design
Zoledronic Acid No Yes

No

A C

B
D

Sr89 comparison A+B vs C+D

618 evaluable pts 750 pts needed to account for early progression Zoledronic acid comparison A+C vs B+D 618 evaluable pts

Sr89 Yes

Primary outcome analysis Univariable log rank Multivariable Cox model Power = 80% Significance level 5%
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Composite primary outcome

Bony clinical progression free survival the first occurrence of:
Clinical skeletal related event (SRE)
No blinded radiological assessment

Death from any cause Bone pain progression

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Key secondary outcomes

Skeletal related event free interval and total SREs Toxicity PSA progression free interval Pain progression free interval Overall survival time

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Key secondary outcomes

Skeletal related event free interval and total SREs Toxicity PSA progression free interval Pain progression free interval Overall survival time

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Consort diagram
Assessed for eligibility (n = 1016)
Excluded (n=260) Not meeting inclusion criteria (n=164) Declined to participate (n=68) Other reasons (n=28)

Enrollment
Randomized (n = 757)

Allocation
Standard treatment : Docetaxel + prednisolone (n = 191) Standard treatment + Zoledronic acid (n = 188) Standard treatment + Sr89 (n = 190) Standard treatment + Zoledronic acid + Sr89 (n = 188)

Analysis
Number included : ITT = 191 Per protocol = 131 Number included : ITT = 188 Per protocol = 135 Number included : ITT = 190 Per protocol = 134 Number included : ITT = 188 Per protocol = 138

Definitions :

ITT = Intention to treat (ie. all patients) Per protocol = Any patient who did not reach CPFS within 21 days following the 6th administration of docetaxel.

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Patient Demographics
Sr89 comparison No Sr89 Sr89
Age median (IQR) PSA median (IQR) ECOG n(%) 0 1 2 Prior RT (%) Pain median (IQR)

ZA comparison No ZA ZA

68 (64, 73) 143 (54, 354) 153 195 31 156 (42) 1.6 (0.9, 2)

68 (63, 73) 147 (48, 371) 152 194 32 179 (48) 1.4 (0.7, 2)

68 (63, 73) 147 (51, 347) 153 195 33 169 (45) 1.4 (1, 2)

68 (64, 73) 142 (51, 377) 152 194 30 166 (45) 1.5 (0.7, 2)

Analgesic score median (IQR)

11 (0.9, 28)

9 (1, 23)

10.2 (1, 28)

10 (0.4, 28)

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PRIMARY OUTCOMES

Presented by:

Clinical Progression Free Survival: Zoledronic acid comparison

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Clinical Progression Free Survival: Zoledronic acid comparison

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Clinical Progression Free Survival: Zoledronic acid comparison

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Clinical Progression Free Survival: Sr89 comparison

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Clinical Progression Free Survival: Sr89 comparison

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Clinical Progression Free Survival: Sr89 comparison

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Clinical Progression Free Survival: Sr89 comparison

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SECONDARY OUTCOMES

Presented by:

SRE Free Interval: ZA comparison

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SRE Free Interval: ZA comparison

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SRE Free Interval: ZA comparison

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SRE Free Interval: Sr89 comparison

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SRE Free Interval: Sr89 comparison

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SRE Free Interval: Sr89 comparison

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Total Skeletal Related Events by type

Sr89 comparison No Sr89 Sr89
N (%) Symptomatic pathological fractures Spinal cord or nerve root compression Cancer related surgery to bone Radiation therapy to bone Change in antineoplastic therapy to treat bone pain Hypercalcaemia Other Total N (%)

ZA comparison No ZA ZA
N (%)

N(%)

16 39 10 317 16 0 1 399

18 45 13 258 12 2 1 349

23 52 18 337 17 2 0 449

11 32 5 238 11 0 2 299

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Total Skeletal Related Events by type

Sr89 comparison No Sr89 Sr89
N (%) Symptomatic pathological fractures Spinal cord or nerve root compression Cancer related surgery to bone Radiation therapy to bone Change in antineoplastic therapy to treat bone pain Hypercalcaemia Other Total N (%)

ZA comparison No ZA ZA
N (%)

N(%)

16 39 10 317 16 0 1 399

18 45 13 258 12 2 1 349

23 52 18 337 17 2 0 449

11 32 5 238 11 0 2 299

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Total Skeletal Related Events by type

Sr89 comparison No Sr89 Sr89
N (%) Symptomatic pathological fractures Spinal cord or nerve root compression Cancer related surgery to bone Radiation therapy to bone Change in antineoplastic therapy to treat bone pain Hypercalcaemia Other Total N (%)

ZA comparison No ZA ZA
N (%)

N(%)

16 39 10 317 16 0 1 399

18 45 13 258 12 2 1 349

23 52 18 337 17 2 0 449

11 32 5 238 11 0 2 299

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Skeletal Related Events per patient

Sr89 comparison No Sr89 Sr89
N(%) 0 1 2 3 4 5 or more Number of patients with at least one SRE 196 (52) 92 (25) 32 (8) 28 (7) 11 (3) 19 (5) 182 (48) N(%) 201 (53) 96 (25) 38 (10) 20 (5) 11 (3) 12 (4) 177 (47)

ZA comparison No ZA ZA
N(%) 185 (49) 91 (24) 33 (9) 38 (10) 13 (3) 21 (5) 196 (51) N(%) 213 (56) 97 (26) 37 (10) 10 (3) 9 (2) 10 (3) 163 (44)

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Skeletal Related Events per patient

Sr89 comparison No Sr89 Sr89
N(%) 0 1 2 3 4 5 or more Number of patients with at least one SRE 196 (52) 92 (25) 32 (8) 28 (7) 11 (3) 19 (5) 182 (48) N(%) 201 (53) 96 (25) 38 (10) 20 (5) 11 (3) 12 (4) 177 (47)

ZA comparison No ZA ZA
N(%) 185 (49) 91 (24) 33 (9) 38 (10) 13 (3) 21 (5) 196 (51) N(%) 213 (56) 97 (26) 37 (10) 10 (3) 9 (2) 10 (3) 163 (44)

Presented by: Nick James

Overall survival: ZA Comparison

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Overall survival: Sr89 Comparison

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Conclusions
Sr89 but not ZA significantly increased bony clinical progression free survival ZA did however significantly increase SRE free interval and decrease total SRE numbers, mostly post-progression No significant differences in toxicity between arms No impact on overall survival
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Acknowledgements
Investigator/Site
Nick James/Emilio Porfiri Queen Elizabeth Hospital, Birmingham Duncan McLaren Western General Hospital, Edinburgh James Wylie The Christie Hospital, Manchester Chris Parker Royal Marsden Hospital, Sutton Rob Jones/Martin Russell Beatson West of Scotland Cancer Centre Graham MacDonald Aberdeen Royal Infirmary

Investigator/Site
Janet Brown St James University Hospital, Leeds Anna Tran/Richard Cowan Royal Albert Edward Infirmary, Wigan Catherine Heath Southampton General Hospital Serena Hillman Weston General Hospital, Weston-s-Mare Robert Crellin Dorset County Hospital, Dorchester Norma Sidek/Martin Russell Forth Valley Royal Hospital, Larbert

David Dodds Wishaw General Hospital

Audrey Cook/Roger Owen Cheltenham General & Gloucester Royal Hospitals Hilary Glen/Jay Ansari/Rana Mahmood Ayr & Crosshouse Hospitals, Ayr Christopher Scrase Ipswich Hospital Joanna Gale Queen Alexandra Hospital, Portsmouth John Staffurth Velindre Hospital, Cardiff Sharon Beesley Maidstone Hospital, Kent

Katharine Piggot Royal Free Hospital, London

Susannah Brock The Royal Bournemouth & Poole Hospitals Ursula Hofmann Calderdale & Huddersfield Royal Hospitals Simon Brown Bradford Royal Infirmary Prabir Chakraborti Royal Derby Hospital Alison Birtle Preston Royal Hospital

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Trial Management Staff

Trial Coordinators Ann Pope and Darren Barton Trial Statisticians Sarah Pirrie and Stuart Collins Trial Administrator Gavin Nixon Data Managers Alyssia Cooke

Other contributors
Trial Management Team Leader Jenny Barnwell, CRCTU, University of Birmingham (UoB) Health Economic Analysis Lazaros Andronis and Ilias Goranitis, UoB Skeletal Related Event sub-study audit Adam Daunton and David Liu, UoB Medical School Analysis of proteomic samples for biomarkers Kaisheng Wen and Vivek Wadwha, UoB Cancer Sciences

Data Monitoring Committee

Mario Eisenberger (Chair) Professor of Oncology & Urology, USA
Fred Saad Professor of Surgery & Urology, Canada Matthew Sydes Senior Scientist and Biostatistician, London

Funders
NIHR HTA, UK This project was funded by the National Institute for Health Research Health Technology Assessment programme (NIHR HTA, UK) (project number 06/303/205) and will be published in full in the Health Technology Assessment journal in 2014. Further information available at : http://www.hta.ac.uk/1605 Department of Health disclaimer : This report presents independent research commissioned by the NIHR. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, MRC, CCF, NETSCC, the HTC or the Department of Health.

Sanofi Aventis: Educational grant, support for drug costs Novartis: Educational grant, support for drug costs GE Healthcare: support for drug costs

Trial Steering Committee

Richard Gray Professor of Medical Statistics, Oxford John Anderson Consultant Urologist, Sheffield Noel Clark Honorary Professor in Urological Cancer/Consultant Urologist, Manchester Robert Coleman Professor of Medical Oncology, Sheffield

Sponsor : The University of Birmingham, UK

Presented by: Nick James