A prospective randomized trial RADIOTHERAPY COMBINED WITH ANDROGEN DEPRIVATION (ADT) vs ADT IN CLINICALLY LOCALLY ADVANCED PROSTATE CANCER A prospective randomized trial N. Mottet, M Peneau, JJ Mazeron, V Molinié and P Richaud

Disclosures Protocol fully funded by Takeda France N. Mottet: Advisor and paid consultant for Takeda Received compensations for lectures and clinical trials Protocol fully funded by Takeda France Protocol independently written from the company Data monitoring and statistical analysis performed by Mapi An IDMC committee had full access to all data

BACKGROUND Radiotherapy with prolonged ADT: superior to radiotherapy alone [EORTC 22863, 22961, RTOG 8531, 9202] ADT: sometimes used alone in locally advanced PCa. However - Combined modality superior to ADT (NSAA) [Widmark Lancet 2009] - No data available with an LHRH agonist Rational for a randomized trial: 3 years ADT ± Radiotherapy.

STUDY PROTOCOL Age < 80, Karnofsky over 70 STUDY POPULATION Prostate Cancer histologically confirmed T3/T4 or pT3 ( biopsy) N0/M0 Never treated except TURP for obstructive syndrome PRIMARY ENDPOINT 5 years overall Progression free survival: biological and clinical Expected benefit: 15% at 5 years SECONDARY CRITERIA Survival (Overall and specific) Quality of life (QLQ-c30 and QLQ-PR25) Tolerance to treatment (SOMALENT)

Treatment period : 3 years (ADT) STUDY DESIGN R1 – M0b < 90 days Treatment period : 3 years (ADT) (1 visit / 6 months) Without treatment period : 2 years (1 visit / 6 months) Post protocol follow-up R1 R2 2 months M6 M12 M18 M24 M30 M36 V V V V 3,5 4 4,5 5 M0b randomization M0a Selection M6 M12 M18 M24 M30 M36 V V V V 3,5 4 4,5 5 Centralized PSA (Hybritech) / 6 months Acute toxicity RTOG: M6

TREATMENT ADT: Leuprorelin SR 11.25 mg SC / 3 months + Flutamide 750 mg / day, Month 1 Radiotherapy : Total dose 70 ± 4 Gy. 35 fractions (±2) Pelvis (4 fields technique) 48 ± 2 Gy Prostate boost: 3D conformal Standardized planning OF NOTE Radiotherapy quality control: independent committee validated each treatment Independent Data monitoring committee

POPULATION Planed number of patients = 256 40 French sites From March 2000 to December 2008 LVLP Inclusion: 2000 – 2003 Data base locked: 07/2009 Median follow up: 67 months Included patients N=273 Randomised patients N=264 ADT group N=131 Combined group N=133 ITT Population N=263 ADT group N=130 Combined group N=133 PP Population N=237 ADT group N=128 Combined group N=109

PATIENTS ADT ADT+RT N 130 133 Mean Age , year (SD) 70.47 (5.64) 70.47 (5.64) 70.71 (5.66) KARNOFSKI mean (SD) 96.11 (5.89) 96.62 (5.06) GLEASON (SD) < 7 (%) ≥ 7 (%) 6.4 ( 1.28) 51.9 % 48.1 % 6.6 (1.25) 45.9 % 54.1 % T3N0M0 (%) 93.1 % 92.5 % PSA (ng/ml) mean < 20 (%) 20 – 50 (%) ≥ 50 (%) 51.77 38.2 % 39.7 % 22.1 % 41.5 35.3 % 41.4 % 23.3 % Testosterone mean (SD) ng/ml 4.56 (1.84) 4.50 (1.72) Score Gleason moyen initial: 6,4. Après relecture: 7,3

RESULTS 1 5 years overall PFS (ASTRO definition) % patients Years ADT group Combined group ADT group Combined group ADT group Combined group Median PFS: 7.7 vs 1.7 years p < 0.0001

RESULTS 2 5 years overall PFS (Phoenix definition) ADT group Combined group % patients Years ADT group Combined group Median PFS: 6.96 vs 3.46 years p = 0.0005

PFS AND BASELINE PSA (Phoenix definition ) 100% Baseline PSA<20 ng/ml: ADT group combined group p=0.001 Baseline 20<PSA<50 ng/ml: ADT group combined group p = 0.0053 Baseline PSA>=50 ng/ml: ADT group combined group 90% 80% 70% 60% 50% % patients 40% 30% 20% RR : 5.22 [3.05; 8.95]; p=0.0011 10% 0% 1 2 3 4 5

CLINICAL PFS ITT population ADT group Combined group % patients Years ADT group Combined group 88.7% vs 62.3% p < 0.001

LOCO-REGIONAL PFS ITT population ADT group Combined group % patients RR : 3.7 [1.9; 7.4] p<0.0002 Years ADT group Combined group 90.3% vs 70.77% p < 0.0002

METASTATIC PFS ITT population ADT group Combined group % patients Years ADT group Combined group 97% vs 89.23% p = 0.0183

OVERALL SURVIVAL ITT population ADT group Combined group % patients Years ADT group Combined group At 5 years: 71.5% vs 71.4% p = 0.7882

SPECIFIC SURVIVAL ITT population ADT group Combined group % patients % patients Years Years ADT group Combined group At 5 years: 93.2% vs 86.1% p = 0.11

SUMMARY In patients with locally advanced PCa, addition of local radiotherapy to 3 years of LHRH significantly reduces the progression risk (biological, clinical, metastatic). The benefit appears to be related mainly to improved loco-regional control. A prolonged follow up is needed to see a potential survival impact

CONCLUSION This reduction of disease progression confirms that radiotherapy combined with ADT should be one standard for patients with a locally advanced disease and a significant life expectancy.