Lab studies have shown that gastric cancer cell lines with low levels of ataxia telangiectasia mutated (ATM)—which plays a key role in activating the repair response to DNA damage—are particularly sensitive to olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor. PARP inhibitors target tumors with deficiencies in the repair of double-strand DNA breaks, such as those caused by BRCA1/2 mutations. Low levels of ATM may lead to outcomes similar to that of BRCA1/2 mutations in that ATM plays a key role in repairing cellular damage; among gastric tumor cell lines, thirteen to 22% have low or undetectable levels of ATM.

Based on these findings, a research team from Seoul National University College of Medicine carried out a randomized, double-blind, phase II trial that assessed the efficacy of olaparib in combination with paclitaxel for patients with advanced gastric cancer (AGC). The study, “A Randomized, Double-Blind Phase II Trial of Olaparib Plus Paclitaxel in Patients with Recurrent or Metastatic Gastric Cancer,” was published online, ahead of print August 17, 2015. The researchers’ goal was to see if adding olaparib to the standard, second-line treatment of paclitaxel led to an improvement in progression-free survival (PFS) among patients with AGC, with a focus on patients with AGC who have low levels of ATM.

A possible application for PARP inhibitors in non-BRCA mutated tumors

The study, which randomized 124 patients to either the paclitaxel plus olaparib group or to the paclitaxel plus placebo group found that those in the treatment group did not experience greater progression-free survival (PFS) compared to the placebo group (PFS equaled 3.91 and 3.55 months, respectively). However, in both the general patient study population and among patients with low levels of ATM, those who received the combined paclitaxel plus olaparib did experience a significant improvement in overall survival (OS); those in the treatment group lived 13.1 months compared to 8.3 months in the placebo group. Among patients with low ATM, a greater OS was observed in the treatment group, compared with the placebo group.

The study’s first author, Yung-Jue Bang, MD, PhD, commented on these findings.

“Our results—in addition to suggesting that olaparib in combination with paclitaxel may prolong the overall survival of patients with AGC, compared with paclitaxel alone as second-line treatment—show that the expression of ATM may be a useful predictive biomarker for selecting patients with AGC who are most likely to benefit from olaparib treatment. This study suggests that PARP inhibitors may be effective in tumors with DNA repair deficiencies caused by mechanisms other than BRCA mutations.”

Patients in the treatment group received 100 mg tablets of oral olaparib twice a day plus 80 mg/m² of paclitaxel intravenously on days one, eight, and 15 of a 28-day cycle, for six to 10 cycles, followed by maintenance monotherapy with 200 mg of olaparib. The placebo group received paclitaxel plus a placebo, followed by a maintenance placebo. Tumors were assessed every eight weeks until week 40, and then every 16 weeks until the patient progressed.

Dr. Bang and his coauthors are currently carrying out a Phase III trial evaluating paclitaxel plus olaparib for patients with advanced gastric cancer.

Addressing an unmet need for additional treatments in advanced gastric cancer

The study reported in JCO addresses a need for additional treatments for AGC. Fewer than 20% of patients with metastatic or recurrent gastric cancer survive five years or more and for patients with metastatic or recurrent gastric cancer, there are few treatment options.

“Currently, there are few specific treatment options available for patients with recurrent and metastatic gastric cancer who progress following first-line therapy with fluoropyrimidine and platinum-based combination chemotherapies,” said Dr. Bang. “Although the taxane paclitaxel treatment is active after first-line failure, and has therefore become a widely used second-line therapy, it often fails to provide adequate efficacy when given alone. Adding targeted agents to second-line paclitaxel may improve clinical benefit.”

Yung-Jue Bang, MD, PhD, is a Professor of Medical Oncology at Seoul National University College of Medicine and President of the Biomedical Research Institute at Seoul National University Hospital. Dr. Bang has been an ASCO member since 1991.

Abstract of the original JCO article.

PDF of the original JCO article.

Bang YJ, Im SA,Lee KW, et al. A randomized, double-blind phase II trial of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer.  J Clin Oncol. Epub 2015 August 17.

The Exclusive Coverage series on ASCO.org highlights selected research from JCO and JOP with additional perspective provided by the lead or corresponding author.

@ 2014 American Society of Clinical Oncology