Bang YJ, et al. - In this double-blind, randomised, placebo-controlled, phase 3 trial, researchers assessed olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD). The primary objective of the GOLD study showing a significant improvement in overall survival with olaparib in the overall or ATM-negative population of Asian patients with advanced gastric cancer was not met. The study produced informative efficacy and safety data regarding the use of olaparib in combination with a chemotherapeutic agent. It provided a foundation for future studies in this difficult-to-treat patient population.

Methods

• Researchers performed a double-blind, randomised, placebo-controlled, phase 3 study (GOLD) which recruited Asian patients aged 18 years or older (≥20 years if Japanese) with advanced gastric cancer that had progressed following, or during, first-line chemotherapy.
• They randomly assigned patients (1:1) to receive oral olaparib (100 mg twice daily) plus paclitaxel (80 mg/m² intravenously) or matching placebo plus paclitaxel.
• They performed randomisation through an interactive voice response system and used no stratification factors.
• They masked patients and investigators to treatment allocation.
• Assessment of two co-primary populations was performed: the overall population of all patients and patients whose tumours were ATM-negative (identified after randomisation, before the data cutoff date, March 28, 2016).
• In both populations, the primary endpoint was overall survival (defined as the time from the date of randomisation until death from any cause before data cutoff); a significant difference was defined as p<0·025.
• In the intention-to-treat populations, efficacy was assessed and in patients who received at least one dose of treatment, safety was assessed.

Results

• From Sept 3, 2013, to March 28, 2016, researchers enrolled 643 patients from 58 study sites in hospitals and medical centres in China, Japan, South Korea, and Taiwan.
• They randomly assigned 525 eligible patients: 263 to receive olaparib plus paclitaxel and 262 to receive placebo plus paclitaxel.
• Determination of 94 patients was performed to have ATM-negative tumours before unmasking for the primary analysis (48 in the olaparib plus paclitaxel group and 46 in the placebo plus paclitaxel group).
• They observed no differences in terms of overall survival between treatment groups in the overall patient population (median overall survival 8·8 months [95% CI 7·4–9·6] in the olaparib group vs 6·9 months [6·3–7·9] in the placebo group; HR 0·79 [97·5% CI 0·63–1·00]; p=0·026) or in the ATM-negative population (12·0 months [7·8–18·1] vs 10·0 months [6·4–13·3]; 0·73 [0·40-·34]; p=0·25).
• The most common grade 3 or worse adverse events in the olaparib plus paclitaxel group in the overall patient population were neutropenia (78 [30%] of 262 patients), leucopenia (42 [16%]), and decreased neutrophil count (40 [15%]); in the placebo plus paclitaxel group, they were neutropenia (59 [23%] of 259 patients), leucopenia (27 [10%]), and decreased white blood cell count (21 [8%]).
• In two patients, adverse events with an outcome of death causally related to study treatment (according to investigator assessment) were reported: liver injury in one patient (<1%) in the olaparib plus paclitaxel group and cardiac failure in one patient (<1%) in the placebo plus paclitaxel group.