Adding olaparib to second-line paclitaxel therapy for recurrent or metastatic gastric adenocarcinoma improved overall survival but not progression-free survival in a phase II clinical trial, investigators reported online Aug. 17 in Journal of Clinical Oncology.

The greatest survival benefit occurred in patients whose cancers had low expression of the ataxia telangiectasia mutated (ATM) gene, suggesting that ATM status may predict response to this treatment, said Dr. Yung-Jue Bang Seoul (Korea) National University, and his associates.

Low ATM expression is thought to reflect a deficiency in DNA repair. Tumors with low ATM levels were particularly sensitive to olaparib in previous studies, so Dr. Bang and his associates compared outcomes with paclitaxel plus olaparib (62 patients) against paclitaxel plus placebo (62 patients) in this prospective double-blind study conducted at multiple medical centers in Korea.

ATM status was determined by testing archived tumor samples. Fourteen percent of the study population had low ATM levels.

Compared with paclitaxel plus placebo, paclitaxel plus olaparib produced a statistically significant and clinically meaningful improvement in overall survival. After a median of 8.4 months of follow-up (range, 0.3-26.2 months), median overall survival was 13.1 months with the combination therapy vs. 8.3 months with paclitaxel plus placebo, for a hazard ratio of 0.56.

In the subgroup of patients with low ATM, median overall survival was not reached by patients receiving combined therapy and was 8.2 months for those receiving paclitaxel alone, for an HR of 0.35.

However, the primary end point of this study wasn’t overall survival but progression-free survival, and adding olaparib to paclitaxel produced a numerical but not a statistically significant improvement in progression-free survival. Median progression-free survival was 3.91 months with combined therapy vs. 3.55 months with paclitaxel alone, for an HR of 0.80. In the subgroup of patients with low ATM, median progression-free survival was 5.29 months with combined therapy vs. 3.68 months with paclitaxel alone, for an HR of 0.74.

“The difference between PFS and OS [outcomes] probably results from the relatively small sample size and the exploratory nature of this phase II trial, which was powered to determine whether olaparib/paclitaxel was sufficiently active to warrant assessment in a phase III trial. The sample size was calculated to detect a promising, but not definitive, benefit. The progression-free survival HRs of 0.80 and 0.74 … are considered quite promising for further exploration in a phase III trial,” Dr. Bang and his associates said (J Clin Oncol. 2015 Aug 17. doi: 10.1200/JCO.2014.60.0320 ]).

The combination therapy was “generally well tolerated,” and there were no unexpected safety findings. The most common adverse event in both study groups was neutropenia. Rates of grade 3 or higher adverse events were similar between the two study groups: 75.4% with combined therapy and 74.2% with paclitaxel plus placebo. The rate of serious adverse events was higher with paclitaxel alone (37.1%) than with the addition of olaparib (27.9%). No serious adverse events were judged to be related to olaparib.

“Overall, our results provide strong evidence of a treatment effect for olaparib/paclitaxel in this setting, and the clinical signals justify further investigation of this combination in a phase III trial,” they added.

Such a phase III trial is now under way (NCT01924533).