asco slides trapeze results jun2013 v22

Clinical effectiveness of strontium-89 and zoledronic acid in patients with castrate-refractory prostate cancer (CRPC) metastatic to bone receiving docetaxel (TRAPEZE)Nick JamesOn behalf ofSarah 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

Presented by:

BackgroundBone metastases are a major cause of morbidity in castrate refractory prostate cancer (CRPC)Taxane based chemotherapy improves survival and quality of life 1Zoledronic acid (ZA) reduces skeletal related events 2 but use remains controversialOlder radio-isotopes such as Strontium-89 (Sr89) have palliative benefits 3A study combining Sr89 with pre-taxane chemotherapy showed a survival advantage 4

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


Phase III Study treatmentsPresented by: Nick Jamesdocetaxel +prednisolone(cycles 1-6)Sr89 150 MBq(day 28 cycle 6)+ 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 +prednisolone + ZA(cycles 1-6)docetaxel +prednisolone(cycles 7-10)Sr89(day 28 cycle 6)* At least 28 days


Statistical DesignPresented by: Nick JamesZoledronic AcidSr89NoNoYesYesPrimary outcome analysisUnivariable log rankMultivariable Cox modelPower = 80%Significance level 5%


Statistical DesignPresented by: Nick JamesZoledronic AcidSr89NoNoYesYesPrimary outcome analysisUnivariable log rankMultivariable Cox modelPower = 80%Significance level 5% Sr89 comparison A+B vs C+D618 evaluable pts750 pts needed to account for early progression


Statistical DesignPresented by: Nick JamesZoledronic AcidSr89NoNoYesYesPrimary outcome analysisUnivariable log rankMultivariable Cox modelPower = 80%Significance level 5% Sr89 comparison A+B vs C+D618 evaluable pts750 pts needed to account for early progression

Zoledronic acid comparison A+C vs B+D618 evaluable pts


Composite primary outcomeBony clinical progression free survival the first occurrence of:Clinical skeletal related event (SRE)No blinded radiological assessmentDeath from any causeBone pain progressionPresented by: Nick James


Key secondary outcomesSkeletal related event free interval and total SREsToxicityPSA progression free intervalPain progression free intervalOverall survival time



Consort diagramPresented by: Nick JamesDefinitions : 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.


Patient DemographicsPresented by: Nick James

Sr89 comparison No Sr89 Sr89ZA comparison No ZA ZAAge 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(%) 01531521531521195194195194231323330Prior 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)


Primary outcomesPresented by:

Presented by:

Presented by: Nick JamesClinical Progression Free Survival:Zoledronic acid comparison


Clinical Progression Free Survival:Zoledronic acid comparisonPresented by: Nick James


Clinical Progression Free Survival: Sr89 comparisonPresented by: Nick James


Secondary outcomesPresented by:

Presented by:

SRE Free Interval: ZA comparisonPresented by: Nick James


SRE Free Interval: Sr89 comparisonPresented by: Nick James


Total Skeletal Related Events by typePresented by: Nick James

Sr89 comparison No Sr89 Sr89ZA comparison No ZA ZAN (%)N (%)N (%)N(%)Symptomatic pathological Fractures16182311Spinal cord or nerve root compression39455232Cancer related surgery to bone1013185Radiation therapy to bone317258337238Change in antineoplastic therapy to treat bone pain16121711Hypercalcaemia0220Other1102Total399349449299


Total Skeletal Related Events by typePresented by: Nick James

Sr89 comparison No Sr89 Sr89ZA comparison No ZA ZAN (%)N (%)N (%)N(%)Symptomatic pathological fractures16182311Spinal cord or nerve root compression39455232Cancer related surgery to bone1013185Radiation therapy to bone317258337238Change in antineoplastic therapy to treat bone pain16121711Hypercalcaemia0220Other1102Total399349449299


Skeletal Related Events per patientPresented by: Nick James

Sr89 comparison No Sr89 Sr89ZA comparison No ZA ZAN(%)N(%)N(%)N(%)0196 (52)201 (53)185 (49)213 (56)192 (25)96 (25)91 (24)97 (26)232 (8)38 (10)33 (9)37 (10)328 (7)20 (5)38 (10)10 (3)411 (3)11 (3)13 (3)9 (2)5 or more19 (5)12 (4)21 (5)10 (3)Number of patients with at least one SRE182 (48)177 (47)196 (51)163 (44)


Overall survival: ZA ComparisonPresented by: Nick James


Overall survival: Sr89 ComparisonPresented by: Nick James


ConclusionsPresented by: Nick JamesSr89 but not ZA significantly increased bony clinical progression free survivalZA did however significantly increase SRE free interval and decrease total SRE numbers, mostly post-progressionNo significant differences in toxicity between armsNo impact on overall survival


AcknowledgementsPresented by: Nick James

Investigator/SiteInvestigator/SiteNick James/Emilio PorfiriQueen Elizabeth Hospital, BirminghamJanet BrownSt James University Hospital, LeedsDuncan McLarenWestern General Hospital, EdinburghAnna Tran/Richard Cowan Royal Albert Edward Infirmary, WiganJames WylieThe Christie Hospital, ManchesterCatherine HeathSouthampton General Hospital Chris ParkerRoyal Marsden Hospital, SuttonSerena HillmanWeston General Hospital, Weston-s-MareRob Jones/Martin RussellBeatson West of Scotland Cancer CentreRobert CrellinDorset County Hospital, DorchesterGraham MacDonaldAberdeen Royal InfirmaryNorma Sidek/Martin RussellForth Valley Royal Hospital, LarbertDavid DoddsWishaw General HospitalKatharine PiggotRoyal Free Hospital, LondonAudrey Cook/Roger OwenCheltenham General & Gloucester Royal HospitalsSusannah BrockThe Royal Bournemouth &Poole HospitalsHilary Glen/Jay Ansari/Rana MahmoodAyr & Crosshouse Hospitals, AyrUrsula HofmannCalderdale & Huddersfield Royal HospitalsChristopher ScraseIpswich HospitalSimon BrownBradford Royal InfirmaryJoanna GaleQueen Alexandra Hospital, PortsmouthPrabir ChakrabortiRoyal Derby HospitalJohn StaffurthVelindre Hospital, CardiffAlison BirtlePreston Royal Hospital Sharon BeesleyMaidstone Hospital, Kent


Presented by: Nick JamesSponsor : The University of Birmingham, UK

Trial Management StaffTrial CoordinatorsAnn Pope and Darren BartonTrial StatisticiansSarah Pirrie and Stuart CollinsTrial AdministratorGavin NixonData ManagersAlyssia Cooke

Data Monitoring CommitteeMario Eisenberger (Chair)Professor of Oncology & Urology, USAFred SaadProfessor of Surgery & Urology, CanadaMatthew Sydes Senior Scientist and Biostatistician, London

Trial Steering CommitteeRichard GrayProfessor of Medical Statistics, OxfordJohn AndersonConsultant Urologist, SheffieldNoel ClarkHonorary Professor in Urological Cancer/Consultant Urologist, ManchesterRobert ColemanProfessor of Medical Oncology, Sheffield

Other contributorsTrial Management Team LeaderJenny Barnwell, CRCTU, University of Birmingham (UoB)Health Economic AnalysisLazaros Andronis and Ilias Goranitis, UoBSkeletal Related Event sub-study auditAdam Daunton and David Liu, UoB Medical SchoolAnalysis of proteomic samples for biomarkersKaisheng Wen and Vivek Wadwha, UoB Cancer Sciences

FundersNIHR HTA, UKThis 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 costsNovartis: Educational grant, support for drug costsGE Healthcare: support for drug costs


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asco slides trapeze results jun2013 v22

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