A Phase II study (Study 39, D0810C00039; NCT01063517) showed that the oral PARP inhibitor olaparib (Lynparza) combined with paclitaxel provided a statistically significant improvement in overall survival (OS) versus paclitaxel alone as second-line therapy in Asian patients (pts) with advanced gastric cancer. A greater OS benefit was seen in pts whose tumour was ATM protein negative by immunochemistry (ATM–). ATM is a key sensor of the DNA damage response pathway. We report final analyses from a subsequent Phase III study (GOLD, D081BC00004; NCT01924533). GOLD evaluated the efficacy and safety of olaparib (100 mg tablet bid, continuous) in combination with paclitaxel (80 mg/m2 iv on days 1, 8, 15 per 28-day cycle) (O/P) compared with placebo in combination with paclitaxel (P/P).
Pts were randomized 1:1 to O/P or P/P and treated until progression (RECIST 1.1), unmanageable toxicity or consent withdrawal. On discontinuation of paclitaxel (without progression), olaparib (300 mg bid) or placebo was given as monotherapy. The co-primary endpoints were OS for all pts (full analysis set [FAS]) and ATM– pts. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety.
521/525 randomized pts were treated (O/P = 261; P/P = 260), including 93/94 ATM– pts (O/P = 47; P/P = 46).
|All pts (FAS) (72.6% OS maturity)||N = 263||N = 262|
|Median OS, months||8.8||6.9||HR = 0.79; 97.5% CI 0.63, 1.00; P = 0.0262|
|Median PFS, months||3.7||3.2||HR = 0.84; 97.5% CI 0.67, 1.04; P = 0.0645|
|Adjusted ORR,* %||24.0||15.8||OR = 1.69; 97.5% CI 0.92, 3.17; P = 0.0548|
|ATM– pts (68.1% OS maturity)||n = 48||n = 46|
|Median OS, months||12.0||10.0||HR = 0.73; 97.5% CI 0.40, 1.34; P = 0.2458|
|Median PFS, months||5.3||3.7||HR = 0.74; 97.5% CI 0.45, 1.29; P = 0.2199|
|Adjusted ORR,* %||37.5||16.1||OR = 4.24; 97.5% CI 0.95, 23.23; P = 0.0309|
Due to Hochberg multiple testing procedure, statistical significance was P < 0.025 for each population *Response rate in pts with measurable disease only CI, confidence interval; HR, hazard ratio; OR, odds ratio HR 1 favours O/P; P values are two sided.In the O/P and P/P arms, respectively, grade ≥3 adverse events (AEs) were reported in 78% and 62% of pts, most frequently neutropenia (30% vs 23%). Serious AEs were reported in 35% and 25% of pts, and AEs leading to discontinuation occurred in 16% and 10% of pts.
A trend towards OS benefit, independent of ATM status, was observed for O/P compared with P/P in the FAS. O/P did not provide statistically significant increased OS, PFS or ORR in the FAS or ATM– pts compared with P/P. O/P followed by olaparib monotherapy was well tolerated with no new safety signals.
Clinical trial identification
D081BC00004; NCT01924533 2 May 2013
Legal entity responsible for the study
Y-J. Bang: I received research funds from AstraZeneca (through my institution), and I have consulted AstraZeneca. L. Shen: Personal fees received from: Hengrui Taiho Roche Novartis. S-A. Im: Research grant from AstraZeneca. G. Locker, X. Shi, D. Hodgson, Y-Z. Liu: AstraZeneca employee and own AstraZeneca stock. P. Rowe: AstraZeneca. All other authors have declared no conflicts of interest.