Bone Targeting in Prostate Cancer for 10th Bham Uro-Onc Meeting

7/29/2019 Bone Targeting in Prostate Cancer for 10th Bham Uro-Onc Meeting

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Bone targeting in prostate cancer

Nicholas James

School of Cancer SciencesUniversity of Birmingham


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Introduction

Natural history

Skeletal related events

Bisphosphonates Denosumab

Ra223

TRAPEZE trial results


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Natural history for locally advanced

patients

PSA

Initial Diagnosis& Therapy ADT

Death

~2 yr

Bone Mets

~1.5 yr

HRPC(PSA relaps e under ADT)

SRE

Course of Disease

?


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Natural history for metastatic patients

PSA

Initial Diagnosis

& ADT

Death

~2 yr ~1.5 yr

SRE

?

Second line

hormone therapy

Chemotherapy

HRPC(PSA relapse un der ADT)


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Prognosis of metastatic prostate

cancer

640 newly-diagnosed men with M1 disease in

the trials control arm recruited to STAMPEDE

between Oct-2005 and Dec-2012

Median age 66, median PSA 111

Bone only mets 62%, soft tissue only 13%,

bone and soft tissue 25%


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Failure-free and overall survival for newly-

diagnosed M1 patients in the STAMPEDE trial

11.8 (10.8, 13.3) 41.5 (36.0, 45.4)

0.00

0.25

0.50

0.75

1.00

0 12 24 36 48 60Time from randomisation (Months)

682 197(258) 76(62) 36(18) 12(6) 2(1)FFS Event682 362(52) 192(61) 93(33) 31(18) 7(4)Death

Number at risk

Death FFS Event


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Survival by distribution of metastases

N %

Patient

Characteristic/

Grouping

2yr FFS

(95% CI)

Hazard

Ratio*

(95% CI)

2yr

Survival

(95% CI)

Hazard

Ratio*

(95% CI)

425 62Bone only

31 (25,

37)1.00 73 (67,

78)1.00

83 12 Soft Tissue 53 (39,66)

0.51(0.35,0.74)

87 (73,94)

0.35(0.18,0.67)

174 26 Bone & SoftTissue18 (11,27)

1.44(1.13,1.82)

57 (46,67)

1.55(1.11,2.16)


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Survival by distribution of metastases

8.2

(5.7,

11.3

)

11.6

(5.3,

32.9

)

26.9 (14.4, 38.3)0.00

0.25

0.50

0.75

1.00

174 38(81) 10(17) 6(3) 0(0) 0(0)Bone & soft tissue425 121(160) 47(36) 19(10) 6(5) 1(1)Bone only83 38(17) 19(9) 11(5) 6(1) 1(0)Soft tissue only

Number at risk

0 12 24 36 48 60Time from randomisation (Months)

Soft tissue only Bone only Bone & soft tissue


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Survival by PSA at diagnosis

N %PatientCharacteristic/

Grouping

2yr FFS

(95% CI)

HazardRatio*

(95% CI)

2yrSurvival

(95% CI)

HazardRatio*

(95% CI)

137 20 Lowest 43 (32,54) 1.0073 (61,82) 1.00

136 20 2 38 (27,48)

1.06(0.74,1.52)

69 (57,79)

0.80(0.48,1.32)

137 20 3 30 (19,40)

1.30(0.92,1.85)

71 (59,80)

0.97(0.60,1.56)

136 20 4 23 (14,33)

1.57(1.11,2.22)

75 (63,83)

0.94(0.58,1.51)

136 20 Highest 21 (12,30)

1.94(1.39,2.72)

66 (54,76)

1.27(0.80,2.02)


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Survival by age at diagnosis

N %

Patient

Characteristic

/ Grouping

2yr FFS

(95% CI)

Hazard

Ratio*

(95% CI)

2yr

Survival

(95% CI)

Hazard

Ratio*

(95% CI)

481 71 Under 70 29 (24,34) 1.0069 (62,74) 1.00

201 29 70 or over 36 (27,44)

0.87(0.69,1.10)

76 (67,83)

0.96(0.69,1.33)


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Survival by Performance Status

0.00

0.25

0.50

0.75

1.00

10 4 2 1 1 0WHO PS 2181 94 37 16 3 1WHO PS 1491 264 153 76 27 6WHO PS 0

Number at risk

0 12 24 36 48 60analysis time

WHO PS0 WHO PS1 WHO PS2


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PALLIATIVE ENDPOINTS

BONE EVENTS


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Bone metastases

Orthopaedic

SurgeryRadiation

to BonePathologic

FractureSpinal Cord

compression

SREs are clinically important endpoints

The burden of bone metastases

Pain

Disability

Hospitalizations Cost


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Systemic therapies for metastatic

disease Chemotherapy

Cabazitaxel, docetaxel

New generation hormone therapies Abiraterone

Enzalutamide

Bone targeting therapies

Radium 223

Denusomab

Zoledronic acid


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Bisphophonates


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Bisphosphonate therapy

33%

44%

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

All patients

P=.021

Zoledronic acid4 mgPlacebo

% with SRE at 15 monthsSaad F, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer

JNCI 2004 96 879-882.


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A Randomized Phase III Trial of Denosumab Versus

Zoledronic Acid in Patients With CRPC and Bone Metastases

Fizazi et al.J Clin Oncol2010; 28(suppl):951s (LBA4507).

Key inclusion criteria:

mCRPC and bone metastases No current/prior I.V.

bisphosphonate

Denosumab 120 mg s.c.

Placebo I.V.

q 4 weeks

R

A

N

D

O

M

I

Z

E

Zoledronic acid 4 mg I.V.

Placebo s.c.

q 4 weeks

(n = 1901)

1:1

Primary endpoint (noninferiority): Time to first on-study SRE

Secondary endpoints (superiority): Time to first on-study SRE and time to first and subsequent on-

study SRE

Calcium and vitamin D supplementation in both arms

Zoledronic acid dosing based on baseline creatinineclearance and subsequent dosing intervals based on

serum creatinine


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PercentofSubjectsWith

FirstSRE

Radiation

to BoneFracture

Surgery

to Bone

Spinal Cord

Compression

20.0

14.7

3.3

0.3

All subjects

0

5

10

15

20

25

30

Denosumab Versus Zoledronic Acid in CRPC Type

of SREs


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Denosumab Versus Zoledronic Acid in

CRPC Time to First On-Study SRE

Zoledronic Acid 951 733 544 407 299 207 140 93 64 47

Denosumab 950 758 582 472 361 259 168 115 70 39

Subjects at risk:

0

1.00

ProportionofSubjectsWithoutSRE

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

KM Estimate ofMedian Months

Denosumab

Zoledronic acid

20.7

17.1

HR 0.82 (95% CI: 0.71, 0.95)P= 0.0002 (Non-inferiority)

P= 0.008 (Superiority)

Study Month


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Denosumab Versus Zoledronic Acid in

CRPC Cumulative number of SREs

*Events occurring at least 21 days apart

Rate Ratio = 0.82 (95% CI: 0.71, 0.94)

Study Month

0.0

2.0

0 3 6 9 12 15 18 21 24 27

CumulativeMeanNumberofSREsper

Patient

30 33 36

0.2

0.6

1.0

1.4

1.8

0.4

0.8

1.2

1.6

DenosumabZoledronic acid 584

494

Events

P= 0.008


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Radio-isotopes


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Strontium-89

Pure -emitter, t1/2 50days

High uptake in

osteoblastic metastases

Remains in tumour sitesfor up to 100 days.

Pain relief in 80%, 10%pain free

Mean response duration 3to 6 months

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. European Journal of Nuclear Medicine 2001;28:788-98.


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Alpharadin

Radium 223 calcium mimetic agent

High uptake in bone metastases

Alpha-particle emitter

Phase III licencing trial completed


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Alpharadin uptake and elimination from body

Cleared rapidly, directly into gut (no apparent hepatobiliary excretion)

Spares kidney radiation dose low

Baseline Day 2 Day 699mTc-MDP 223RaImagingbasedon


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Alsympca trial


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Change in ALP and PSA

Nilson et al Lancet Oncology 2007. 8 587-94


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Alsympca trial SRE outcomes

Parker et al ESMO 2011.


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SRE frequency in trial of Ra223

vs placebo

28Radium-223 chloride (Alpharadin) impact on overall survival and skeletal-related events in patients with castration-resistant prostate

cancer with bone metastases: A phase III randomized trial (ALSYMPCA). Sartor et al AUA 2012

0

5

10

15

20

25

30

Pathologic Bone Fracture Spinal Cord Compression External beam RT Surgical intervention

Ra-223

Placebo


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Clinical effectiveness of strontium-89 and

zoledronic acid in patients with castrate-refractory 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


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Aims of study

Does upfront use of bone targeting agentswith chemotherapy improve clinical

outcomes?

Is it cost effective to prevent bonecomplications or to treat them as they arise?

Presented by: Nick James


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Aims of study

Does upfront use of bone targeting agentswith chemotherapy improve clinical

outcomes?

Is it cost effective to prevent bonecomplications or to treat them as they arise?



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Phase III Study treatments


ARMS B & D : Post chemotherapy, ZA will be administered at 4-weekly intervals until protocol defined disease

progression.

A

Docetaxel 75mg/m2 every 3 weeks + prednisolone 10mg od

(cycles 1-10)

docetaxel +

prednisolone(cycles 1-6)

Sr89 150

MBq(day 28 cycle 6)

C + 28 Days*

docetaxel +


* At least 28 days

Bdocetaxel + prednisolone + ZA 4mg iv(cycles 1-10)

D

docetaxel +

prednisolone + ZA(cycles 7-10)

+ 28 Days*

docetaxel +

prednisolone +ZA(cycles 1-6)

Sr89(day 28 cycle 6)


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Phase III Study treatments


docetaxel +


Sr89 150

MBq(day 28 cycle 6)

A

B

C

D

+ 28 Days*

docetaxel +

prednisolone + ZA(cycles 7-10)

+ 28 Days*

ARMS B & D : Post chemotherapy, ZA will be administered at 4-weekly intervals until protocol defined disease

progression.

Docetaxel 75mg/m2 every 3 weeks + prednisolone 10mg od

(cycles 1-10)

docetaxel +

prednisolone +ZA(cycles 1-6)

docetaxel +


Sr89(day 28 cycle 6)

* At least 28 days

docetaxel + prednisolone + ZA 4mg iv(cycles 1-10)


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Statistical Design


A B

C D

Zoledronic Acid

Sr89

No

No Yes

Yes

Primary outcome analysis Univariable log rank

Multivariable Cox model

Power = 80%

Significance level 5%


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Statistical Design


A B

C D

Zoledronic Acid

Sr89

No

No Yes

Yes



Power = 80%


Sr89comparison A+B vs

C+D 618 evaluable pts

750 pts needed to account

for early progression


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Statistical Design


A B

C D

Zoledronic Acid

Sr89

No

No Yes

Yes



Power = 80%


Sr89comparison A+B vs

C+D 618 evaluable pts

750 pts needed to account

for early progression

Zoledronicacidcomparison

A+C vs B+D

618 evaluable pts


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Composite primary outcome

Bony clinical progression free survival thefirst 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 totalSREs

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 totalSREs

Toxicity

PSA progression free interval Pain progression free interval

Overall survival time


C t di


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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)

Number included :

ITT = 191

Per protocol = 131

Standard treatment :

Docetaxel + prednisolone

(n = 191)

Standard treatment + Sr89

(n = 190)

Allocation

Analysis

Randomized

(n = 757)

Enrollment

Standard treatment +

Zoledronic acid

(n = 188)

Standard treatment +

Zoledronic acid + Sr89

(n = 188)

Number included :

ITT = 188Per protocol = 135

Number included :

ITT = 190

Per protocol = 134

Number included :

ITT = 188Per 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

ZA comparison

No ZA ZA

Age median (IQR) 68 (64, 73) 68 (63, 73) 68 (63, 73) 68 (64, 73)

PSA median (IQR) 143

(54, 354)

147

(48, 371)

147

(51, 347)

142

(51, 377)

ECOG n(%) 0 153 152 153 152

1 195 194 195 1942 31 32 33 30

Prior RT (%) 156 (42) 179 (48) 169 (45) 166 (45)

Pain median (IQR) 1.6 (0.9, 2) 1.4 (0.7, 2) 1.4 (1, 2) 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 S r i al


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Clinical Progression Free Survival:

Zoledronic acid comparison



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Sr89 comparison




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Sr89 comparison




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Sr89 comparison




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Sr89 comparison



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SECONDARY OUTCOMES

Presented by:


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SRE Free Interval: ZA comparison



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SRE Free Interval: Sr89 comparison



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Total Skeletal Related Events by


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type


Sr89 comparison

No Sr89 Sr89

ZA comparison

No ZA ZA

N (%) N (%) N (%) N(%)

Symptomatic pathological

fractures16 18 23 11

Spinal cord or nerve root

compression39 45 52 32

Cancer related surgery to

bone10 13 18 5

Radiation therapy to bone 317 258 337 238

Change in antineoplastic

therapy to treat bone pain16 12 17 11

Hypercalcaemia 0 2 2 0

Other 1 1 0 2

Total 399 349 449 299



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type


Sr89 comparison

No Sr89 Sr89

ZA comparison

No ZA ZA

N (%) N (%) N (%) N(%)






bone10 13 18 5





Other 1 1 0 2

Total 399 349 449 299



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type


Sr89 comparison

No Sr89 Sr89

ZA comparison

No ZA ZA

N (%) N (%) N (%) N(%)






bone10 13 18 5





Other 1 1 0 2

Total 399 349 449 299

Skeletal Related Events per


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patient


Sr89 comparisonNo Sr89 Sr89

ZA comparisonNo ZA ZA

N(%) N(%) N(%) N(%)

0 196 (52) 201 (53) 185 (49) 213 (56)

1 92 (25) 96 (25) 91 (24) 97 (26)

2 32 (8) 38 (10) 33 (9) 37 (10)

3 28 (7) 20 (5) 38 (10) 10 (3)

4 11 (3) 11 (3) 13 (3) 9 (2)

5 or more 19 (5) 12 (4) 21 (5) 10 (3)

Number of patients withat least one SRE 182 (48) 177 (47) 196 (51) 163 (44)



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patient


Sr89 comparisonNo Sr89 Sr89

ZA comparisonNo ZA ZA

N(%) N(%) N(%) N(%)

0 196 (52) 201 (53) 185 (49) 213 (56)

1 92 (25) 96 (25) 91 (24) 97 (26)

2 32 (8) 38 (10) 33 (9) 37 (10)

3 28 (7) 20 (5) 38 (10) 10 (3)

4 11 (3) 11 (3) 13 (3) 9 (2)

5 or more 19 (5) 12 (4) 21 (5) 10 (3)

Number of patients withat least one SRE 182 (48) 177 (47) 196 (51) 163 (44)


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Overall survival: ZA Comparison



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Overall survival: Sr89 Comparison



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Conclusions


Sr89 but not ZA significantly increased bonyclinical progression free survival

ZA did however significantly increase SRE

free interval and decrease total SREnumbers, mostly post-progression

No significant differences in toxicity between

arms

No impact on overall survival

Acknowledgements


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Acknowledgements


Investigator/Site Investigator/Site

Nick James/Emilio Porfiri

Queen Elizabeth Hospital, Birmingham

Janet Brown

St James University Hospital, Leeds

Duncan McLaren

Western General Hospital, Edinburgh

Anna Tran/Richard Cowan

Royal Albert Edward Infirmary, Wigan

James Wylie

The Christie Hospital, Manchester

Catherine Heath

Southampton General Hospital

Chris Parker

Royal Marsden Hospital, Sutton

Serena Hillman

Weston General Hospital, Weston-s-Mare

Rob Jones/Martin Russell

Beatson West of Scotland Cancer Centre

Robert Crellin

Dorset County Hospital, Dorchester

Graham MacDonald

Aberdeen Royal Infirmary

Norma Sidek/Martin Russell

Forth Valley Royal Hospital, Larbert

David Dodds

Wishaw General Hospital

Katharine Piggot

Royal Free Hospital, London

Audrey Cook/Roger Owen

Cheltenham General &

Gloucester Royal Hospitals

Susannah Brock

The Royal Bournemouth &

Poole Hospitals

Hilary Glen/Jay Ansari/Rana Mahmood

Ayr & Crosshouse Hospitals, Ayr

Ursula Hofmann

Calderdale & Huddersfield Royal Hospitals

Christopher Scrase

Ipswich Hospital

Simon Brown

Bradford Royal Infirmary

Joanna Gale

Queen Alexandra Hospital, Portsmouth

Prabir Chakraborti

Royal Derby Hospital

John Staffurth

Velindre Hospital, Cardiff

Alison Birtle

Preston Royal Hospital

Sharon Beesley

Maidstone Hospital, Kent

Trial Management Staff Other contributors


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Trial Coordinators

Ann Pope and Darren Barton

Trial Statisticians

Sarah Pirrie and Stuart Collins

Trial Administrator

Gavin Nixon

Data Managers

Alyssia Cooke

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

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

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

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

Sponsor : The University of Birmingham, UK


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Future CRPC treatment

Clinical trial

Observation

2nd-line hormone Rx*

No metastases

Abiraterone

Docetaxel

Symptomatic

Docetaxel

Radium 223

Cabazitaxel

Docetaxel

Abiraterone

Enzalutamide

Metastases

Asymptomatic

Bone Targeting in Prostate Cancer for 10th Bham Uro-Onc Meeting

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