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

N. Mottet: Advisor and paid consultant for TakedaReceived 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 PROTOCOLSTUDY POPULATION

Age < 80, Karnofsky over 70Prostate Cancer histologically confirmedT3/T4 or pT3 ( biopsy) N0/M0Never treated except TURP for obstructive syndrome

PRIMARY ENDPOINT5 years overall Progression free survival:

biological and clinicalExpected benefit: 15% at 5 years

SECONDARY CRITERIASurvival (Overall and specific)Quality of life (QLQ-c30 and QLQ-PR25)Tolerance to treatment (SOMALENT)

STUDY DESIGN

M0aSelection

R1 R2

M0brandomization

2 months

R1 – M0b < 90 days

Centralized PSA (Hybritech) / 6 months Acute toxicity RTOG: M6

M6 M12 M18 M24 M30

M6 M12 M18 M24 M30 M36

V3,5 V4 V4,5V5

V3,5 V4 V4,5V5

Post protocolfollow-up

Treatment period : 3 years (ADT)(1 visit / 6 months)

Without treatment period : 2 years

(1 visit / 6 months)

M36

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

Included patientsN=273

ITT Population N=263

ADT groupN=130

Combined groupN=133

Randomised patientsN=264

ADT groupN=131

Combined groupN=133

PP PopulationN=237

ADT groupN=128

Combined groupN=109

Planed number of patients = 25640 French sites

From March 2000 to December 2008 LVLP

Inclusion: 2000 – 2003Data base locked: 07/2009

Median follow up: 67 months

ADT ADT+RT

N 130 133

Mean Age , year (SD) 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 (%)

51.7738.2 %39.7 %22.1 %

41.535.3 %41.4 %23.3 %

Testosterone mean (SD) ng/ml 4.56 (1.84) 4.50 (1.72)

PATIENTS

Median PFS: 7.7 vs 1.7 years p < 0.0001

RESULTS 1 5 years overall PFS (ASTRO definition)

ADT group

Combined group

% p

atie

nts

Years

ADT group

Combined group

ADT group

Combined group

Median PFS: 6.96 vs 3.46 years p = 0.0005

RESULTS 2 5 years overall PFS (Phoenix definition)

ADT group

Combined group

% p

atie

nts

Years

ADT group

Combined group

PFS AND BASELINE PSA (Phoenix

definition )

RR : 5.22 [3.05; 8.95]; p=0.0011

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 2 3 4 5

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 groupcombined group

% p

atie

nts

CLINICAL PFS ITT population

88.7% vs 62.3% p < 0.001

ADT group

Combined group

% p

ati

ents

ADT group

Combined group

Years

LOCO-REGIONAL PFS ITT population

90.3% vs 70.77% p < 0.0002

RR : 3.7 [1.9; 7.4] p<0.0002

% p

atie

nts ADT group

Combined group

ADT group

Combined group

Years

97% vs 89.23% p = 0.0183

METASTATIC PFS ITT population

% p

atie

nts

ADT group

Combined group

ADT group

Combined group

Years

OVERALL SURVIVAL ITT

population

At 5 years: 71.5% vs 71.4% p = 0.7882

ADT group

Combined group

% p

ati

ents

ADT group

Combined group

Years

SPECIFIC SURVIVAL ITT population

At 5 years: 93.2% vs 86.1% p = 0.11

% p

atie

nts

ADT group

Combined group

ADT group

Combined group

Years

% p

atie

nts

Years

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.