The combination of olaparib plus paclitaxel failed to significantly improve overall survival compared with placebo plus paclitaxel in Asian patients with advanced gastric cancer, according to the phase III results of the GOLD study published in Lancet Oncology.
Despite positive phase II results that showed that the combination significantly improved overall survival in these patients, especially those with ataxia-telangiectasia mutated protein (ATM)-negative tumors, overall survival did not differ between the two groups in the subsequent phase III trial.
“To further understand the biology responsible for the study results, olaparib should be investigated further in patients with advanced gastric cancer in larger studies, as monotherapy, and in studies involving alternative combinations of therapeutic agents,” wrote Yung-Jue Bang, MD, PhD, of Seoul National University College of Medicine, and colleagues.
The phase II trial of olaparib plus paclitaxel compared with placebo/paclitaxel showed a significant improvement in median overall survival (13.1 months vs 8.3 months; hazard ratio [HR], 0.56; 95% CI, 0.35–0.87; P = .005) for the entire population, and in those with ATM-negative tumors (not yet reached vs 8.2 months; HR, 0.35; 95% CI, 0.17–0.71; P = .002). However, the study failed to show an improvement in progression-free survival for the combination.
In the phase III trial, 525 Asian patients aged 18 or older with advanced gastric cancer were randomly assigned to 100 mg oral olaparib plus paclitaxel or placebo plus paclitaxel. Ninety-four patients had ATM-negative tumors.
The median overall survival was 8.8 months for the combination group compared with 6.9 months for the placebo group. Among patients with ATM-negative tumors, the median overall survival was 12 months for the combination compared with 10 months for placebo.
The researchers suggested that underdosing may be a reason why the study was negative “because the dose of olaparib selected for the GOLD study (100 mg twice daily) was much lower than the 300 mg twice daily dose investigated during the monotherapy phase of GOLD and in other phase III studies of olaparib monotherapy.”
The most common grade 3 or worse adverse events in the combination group were neutropenia, leucopenia, and decreased neutrophil count. Among patients assigned to placebo the most common grade 3 events were neutropenia, leucopenia, and decreased white blood cell count. One patient in each group had adverse events with an outcome of death causally related to study treatment.
“The expectations of the benefit of olaparib might have been set too high to achieve a positive result; the ATM-negative population might have been too small to determine a difference between treatment groups; and the heterogeneity of protein staining for ATM in gastric cancer could have contributed to the results observed,” the researchers wrote. “Further molecular analyses are ongoing to determine whether genetic markers might better explain the findings of the study, and these will be reported separately.”