Intergroup Randomized Phase III Study of Androgen Deprivation Therapy +

Radiation Therapy in Locally Advanced Prostate Cancer

NCIC CTG PR.3/ MRC PR07/ SWOG JPR3 NCIC CTG PR.3/ MRC PR07/ SWOG JPR3 P. R. Warde, M. D. Mason, M. R. Sydes, M. K. Gospodarowicz, P. R. Warde, M. D. Mason, M. R. Sydes, M. K. Gospodarowicz,

G. P. Swanson, P. Kirkbride, E. Kostashuk, J. Hetherington, G. P. Swanson, P. Kirkbride, E. Kostashuk, J. Hetherington, K. Ding, W. R. Parulekar K. Ding, W. R. Parulekar

On behalf of all trial collaboratorsOn behalf of all trial collaborators

Prostate Cancer

Represents a substantial health burden in industrialized nations Most common malignancy in men and second to lung cancer as a cause

of cancer mortality

Risk stratification into low, intermediate, high risk disease based on PSA, Biopsy Gleason Score, T Category

High risk disease (> cT2c and/or PSA > 20 ng/ml and/or Gleason > 8)

• CaPSURE Database– 44% in 1990-1994

– 29% in 2001-2004– 24% in 2004-2007

Jemal et al CA Cancer J Clin. 2009;59(4):225-49D’Amico et al JAMA 1998; 280:969-974Cooperberg et al World J Urol 2008;26:211-218

Background Results with RT alone disappointing

• Initial data from EORTC and RTOG studies suggested major benefit from addition of adjuvant ADT

• Question remained whether improved results due to early use of ADT and benefit of RT still felt to be inconclusive

• > 60% of Urologists, Radiation Oncologists in Canada, UK felt utility of RT in locally advanced prostate cancer not established

MRC PR02 randomised trial 1992• 277 patients T2-T4 N0 M0

– RT alone vs Orchiectomy alone vs RT + Orchiectomy• Closed early to accrual • No evidence of survival benefit to addition of RT

Fellows et al Br J Urol. 1992 Sep;70(3):304-9

NCIC CTG PR.3/MRC PR07/SWOG JPR3

Objectives In patients with Locally advanced/High risk prostate

cancer, to evaluate the impact of the addition of External Beam RT to ADT on• Primary outcome measure was overall survival• Secondary outcome measures of

– Disease specific survival– Time to disease progression– Symptomatic local control– Quality of Life

NCIC CTG PR.3/MRC PR07/SWOG JPR3:Study Scheme

Initial PSA Level: < 20 vs 20-50 vs > 50 μg/L Hormonal Therapy: orchiectomy vs LHRH analogue+ anti androgen Method of lymph node staging: clinical vs radiological vs surgical Gleason Score: < 8 vs 8-10 Prior hormonal therapy: yes vs no Centre

Continuous Androgen Deprivation Therapy

+ Radiotherapy

Continuous Androgen Deprivation Therapy

T3/T4 N0/NXor

T2 and PSA > 40 μg/Lor

T2 and PSA > 20 μg/L and GS: 8-10

Treatment

Androgen Deprivation Therapy• Bilateral Orchiectomy

or • LHRH agonist

– Antiandrogen for 2 weeks, optional to continue

Radiotherapy• 45 Gy/25 F/5 weeks to pelvis• 20-24 Gy/10-12 F/2-2.5 weeks to prostate• If treating physician felt patient inappropriate for whole pelvis

then RT given to prostate only

Statistical Parameters/Study Conduct

1995: Study ActivationSample size=650 based on based on 35% 10 year survival in ADT alone arm, α=.05 (one sided), 80% chance of detecting 10% improvement (target HR 0.76)

2002: Amendment (low event rate) Sample size=1200Target HR 0.76 (survival), α=.025 (one sided), β=.2

2005: (June): Study closed to accrual Accrued: 1205

2009: (August): 2nd interim analysis to DSMC, Median follow-up 6.0 years

Disclose results to investigators

2012: Final Analysis

PR.3 Cumulative AccrualNCIC CTG TRIAL PR.3Cumulative Accrual

Actual Expected

# Pa

tient

s

0

200

400

600

800

1000

1200

1400

Time01MAR95 01MAR00 01MAR05 01MAR10

Flowchart

Randomized (n=1205)Randomized (n=1205)

Androgen Deprivation Androgen Deprivation n=602n=602

Androgen Deprivation + RT Androgen Deprivation + RT n=603n=603

Ineligible: n= 3Ineligible: n= 3No data > 2 years: n=42No data > 2 years: n=42

Efficacy Analysis: n= 602Efficacy Analysis: n= 602Safety Analysis: n=596Safety Analysis: n=596

Efficacy Analysis: n= 603Efficacy Analysis: n= 603Safety Analysis: n=595Safety Analysis: n=595

Ineligible: n= 5Ineligible: n= 5No data > 2 years: n=61No data > 2 years: n=61

Baseline CharacteristicsCharacteristic ADT Alone ADT+RT

Median Age 69.7 years 69.7 years

T Category

< T2c

T3/T4

11%

89%

10%

88%Gleason Score

< 7

8-10

81%

18%

81%

18%PSA ng/ml

<20

20-50

>50

37%

38%

25%

36%

38%

26%

Overall Survival

320 Deaths, 175 ADT alone, 145 RT+ADT 320 Deaths, 175 ADT alone, 145 RT+ADT

HR=0.77 (95% C.I. 0.61-0.98) P=0.0331

# at Risk

ADT

ADT+RT

ADT ADT+RT

Perc

enta

ge

0

20

40

60

80

100

0 3 6 9

602

603

509

512

Time (Years)213

232

51

60

7 yr OS 74%

7 yr OS 66%

Causes of Death

ADT Alone (175) ADT+RT (145) Total (320)

Disease 89 51 140

Cardiac/Stroke 24 24 48

Other Cancer 26 31 57

Other 24 31 55

Unknown 12 8 20

Disease Specific Survival

HR=0.57 (95% C.I. 0.37-0.78) p=0.001

140 Deaths from Prostate Cancer 140 Deaths from Prostate Cancer 89 ADT alone, 51 RT+ADT89 ADT alone, 51 RT+ADT

# at Risk

ADTADT+RT

ADT ADT+RT

Perc

enta

ge

0

20

40

60

80

100

0 3 6 9

602

603

509

512

Time (Years)213

232

51

60

7 yr DSS 90%

7 yr DSS 79%

Late ToxicityGrade < 2 Grade > 3

GastrointestinalDiarrhea

ADT Alone 8% 0.7%

ADT +RT 14% 1.3%

Rectal BleedingADT Alone 5% 0.5%

ADT +RT 12% 0.3%

GenitourinaryADT Alone 42% 2.3%

ADT +RT 44% 2.3%

Relevance 2010 Treatment Trends 1990-2007

• CaPSURE Database– ADT as Primary Therapy for high risk disease

• 1990-1994 36.7%• 2004-2007 45.5%

Significant variation in current treatment practices highlights the importance of randomized phase III data to define treatment standards

• SPCG-7/SFUO-3 study – RT + HT vs HT alone in 977 patients, T1b-T3, N0 – Improved Cancer-Specific (RR 0.44) and Overall Survival (RR 0.68)

• Current study– Improved Cancer-Specific (HR 0.57) and Overall Survival (RR 0.77)

Widmark et al Lancet. 2009 Jan 24;373(9660):301-8.Cooperberg et al J Clin Oncol 2010; 28:1117-1123

Conclusions

Combined Modality Therapy (ADT+RT) in Management of Locally Advanced/High Risk Prostate Cancer• Improved Overall Survival• Improved Disease Specific Survival• RT Well tolerated with no significant toxicity

Should be Considered Standard of Care for this group of patients• Optimal duration of androgen deprivation therapy remains

undefined• Benefit of RT in modern era may be greater with dose

escalation

Acknowledgements

QEII Health Sciences Center McGill University - Dept. Oncology CHUM - Hopital Notre-Dame Ottawa Health Research Institute - Civic Division Cancer Centre of Southeastern Ontario at Kingston Ottawa Health Research Institute - General Division Juravinski Cancer Centre at Hamilton Health Sciences Humber River Regional Hospital Odette Cancer Centre Univ. Health Network-Princess Margaret Hospital London Regional Cancer Program Windsor Regional Cancer Centre Regional Cancer Program of the Hopital Regional Algoma District Cancer Program Thunder Bay Regional Health Science Centre CancerCare Manitoba Saskatoon Cancer Centre Tom Baker Cancer Centre Cross Cancer Institute BCCA - Vancouver Cancer Centre BCCA - Fraser Valley Cancer Centre BCCA - Cancer Centre for the Southern Interior

We would like to thank all the patients and their families We would like to thank all the patients and their families who participated on this trial through the following centres:who participated on this trial through the following centres:

ECOG Coordinating Center Southwest Oncology Group, Data Operations Center

Sutton Coldfield, Good Hope Hospital Eastbourne Hospital Southport & Formby District General Hospital Burton upon Trent, Queen's Hospital Aberdeen Royal Infirmary SOUTH AFRICA: Groote Schuur Hospital Wolverhampton, New Cross Hospital Sandwell General Hospital Grimsby, Diana Princess of Wales Hospital Swindon, The Great Western Hospital Warwick Hospital St Leonards-on-Sea, Conquest Hospital Bolton, Royal Bolton Hospital Taunton & Somerset Hospital Cambridge, Addenbrooke's Hospital Northwood, Mount Vernon Hospital Preston, Royal Preston Hospital Hereford County Hospital Southampton, Royal South Hants Hospital

Acknowledgements continued Sussex Oncology Centre Bournemouth & Christchurch Hospitals Warrington Hospital York District Hospital Bury St Edmunds, West Suffolk Hospital Truro, Royal Cornwall Hospital Southend General Hospital Bristol Oncology Centre Leeds, Cookridge Hospital NEW ZEALAND: Auckland Hospital Glasgow, Beatson Oncology Centre Northampton Oncology Centre Croydon, Mayday Hospital Chester, Countess of Chester Maidstone, The Kent Cancer Centre Wakefield, Pinderfields Hospital Bath, Royal United Hospital Wrexham Maelor Hospital Norwich, Norfolk & Norwich Hospital Scunthorpe General Hospital United Lincolnshire Trust Oxford, Churchill Hospital Blackpool Victoria Hospital

Brighton Hospitals Leeds, St.James's University Hospital Leicester Royal Infirmary Yeovil District Hospital Shrewsbury, Royal Shrewsbury Hospital Rhyl, Glan Clwyd Hospital Coventry, Walsgrave Hospital Gloucestershire Hospitals Berkshire, Royal Berkshire & Battle Hospitals Manchester, Christie Hospital Belfast, Belfast City & Belvoir Park Hospitals Nottingham City Hospital Clatterbridge Centre for Oncology Exeter, Royal Devon & Exeter Torbay Hospital Royal Marsden Hospitals Middlesbrough, The James Cook University Hospital RUSSIA: Obninsk, MRRC RAMS Swansea, Singleton Hospital Newcastle General Hospital Cottingham, Castle Hill Hospital Cardiff, Velindre Hospital & UHW Sheffield, Weston Park & Royal Hallamshire