Randomized, double-blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer

Yung Jue Bang, Seock Ah Im, Keun Wook Lee, Jae Yong Cho, Eun Kee Song, Kyung Hee Lee, Yeul Hong Kim, Joon Oh Park, Hoo Geun Chun, Dae Young Zang, Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, Mark J. O'Connor, Xiaolu Yin, Woo Ho Kim

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Abstract

Purpose Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel. Patients and Methods In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m2 per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS). Results One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/ paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings. Conclusion Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.

Original languageEnglish
Pages (from-to)3858-3865
Number of pages8
JournalJournal of Clinical Oncology
Volume33
Issue number33
DOIs
Publication statusPublished - 2015 Nov 20

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bang, Y. J., Im, S. A., Lee, K. W., Cho, J. Y., Song, E. K., Lee, K. H., Kim, Y. H., Park, J. O., Chun, H. G., Zang, D. Y., Fielding, A., Rowbottom, J., Hodgson, D., O'Connor, M. J., Yin, X., & Kim, W. H. (2015). Randomized, double-blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. Journal of Clinical Oncology, 33(33), 3858-3865. https://doi.org/10.1200/JCO.2014.60.0320