COPENHAGEN, Denmark — The addition of olaparib to paclitaxel demonstrated a trend toward an OS benefit in patients with advanced gastric cancer independently of ATM protein status, according to results of the phase 3 GOLD trial presented at the European Society for Medical Oncology Congress.
Although olaparib conferred greater benefits in PFS, overall response rate and health-related quality of life appeared among patients with ATM–negative tumors, overall, the study failed to demonstrate a statistically significant improvement in OS based on the prespecified study criteria.
A previously published phase 2 study showed that the addition of the PARP inhibitor olaparib (Lynparza, AstraZeneca) to paclitaxel significantly extended OS in Asian patients with advanced gastric cancer, especially among patients with ATM–negative tumors.
Based on these results, Yung-Jue Bang, MD, PhD, professor of medical oncology at Seoul National University College of Medicine and president of Biomedical Research Institute at Seoul National University Hospital, and colleagues conducted a phase 3 study to evaluate the addition of olaparib to paclitaxel in this patient population.
“ATM is a key sensor of the DNA damage response pathway, which might explain greater olaparib activity in patients whose DNA damage response mechanisms were not being activated by ATM,” Bang said during his presentation.
The analysis included data from 525 patients with advanced gastric cancer who had progressed on first-line treatment. Ninety-four patients (18%) had ATM–negative tumors.
Researchers randomly assigned patients 1:1 to receive 80 mg/m2 IV paclitaxel (days 1, 8, 15 per 28-day cycle) with placebo (n = 262; ATM negative, n = 46) or with 100 mg olaparib twice daily (n = 263, ATM negative, n = 47).
OS for all patients, and in ATM–negative patients, served as the co-primary endpoints. PFS, objective response rate and safety served as secondary endpoints.
In the full analysis set, median OS was 8.8 months among patients assigned olaparib and 6.9 months among patients assigned placebo (HR = 0.79; 97.5% CI, 0.63-1). The .0262 P value did not meet the study’s predefined criteria for significance of P < .025.
Among ATM–negative patients, median OS was 12 months among those assigned olaparib and 10 months among those assigned placebo (HR = 0.73; 97.5% CI, 0.4-1.34).
A subgroup analysis showed olaparib demonstrated a greater OS benefit in patients who underwent full or partial gastrectomy.
“This finding is consistent with what was observed in the previous phase 2 study; however, at this time, we don’t know what makes this difference,” Bang said.
Olaparib tended to demonstrate a benefit in terms of PFS (HR = 0.74; 97.5% CI, 0.45-1.29), ORR (37.5% vs. 16.1%; P = .0309) and time to deterioration of health-related quality of life (HR = 0.63; 97.5%; 0.34-1.16) among ATM–negative patients.
“These endpoints were numerically improved with the addition of olaparib, especially among the ATM–negative population,” Bang said.
More patients assigned olaparib experienced grade 3 or worse adverse events (78% vs. 62%), the most common of which was neutropenia (30% vs. 23%). Further, serious adverse events were more common in the olaparib arm (35% vs. 25%), as were adverse events leading to study discontinuation (16% vs. 10%).
“There was a trend toward a survival improvement in the overall population, and numerically improvements in secondary endpoints, particularly in ATM–negative patient,” Bang said. “Please note that, in combination with paclitaxel, we used low-dose olaparib, at 100 mg twice daily. The monotherapy dose currently under investigation in other olaparib phase 3 studies is 300 mg twice daily.” – by Alexandra Todak
Bang Y-J, et al. Abstract LBA25. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Disclosure: Bang reports research funding from and consultant roles with AstraZeneca. Please see the abstract for a list of all other researchers’ relevant financial disclosures.