Bang, Yung-Jue; Im, Seock-Ah; Lee, Keun-Wook; Cho, Jae Yong; Song, Eun-Kee; Lee, Kyung Hee; Kim, Yeul Hong; Park, Joon Oh; Chun, Hoo Geun; Zang, Dae Young; Fielding, Anitra; Rowbottom, Jacqui; Hodgson, Darren; O'Connor, Mark J; Yin, Xiaolu; Kim, Woo Ho
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2015Nov ; 33 ( 33 ) :3858-65.
PMID : 26282658
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Bang, Yung-Jue -
Im, Seock-Ah -
Lee, Keun-Wook -
Cho, Jae Yong -
Song, Eun-Kee -
Lee, Kyung Hee -
Kim, Yeul Hong -
Park, Joon Oh -
Chun, Hoo Geun -
Zang, Dae Young -
Fielding, Anitra -
Rowbottom, Jacqui -
Hodgson, Darren -
O'Connor, Mark J -
Yin, Xiaolu -
Kim, Woo Ho -
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/m(2) 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. CI - ??2015 by American Society of Clinical Oncology.
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MESH
Adenocarcinoma/classification/*drug therapy/mortality/pathology, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse, Ataxia Telangiectasia Mutated Proteins/*blood, Biomarkers, Tumor/blood, Biopsy, Needle, Disease-Free Survival, Double-Blind Method, Female, Follow-Up Studies, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local/classification/*drug therapy/mortality/parasitology, Paclitaxel/administration & dosage/adverse effects, Phthalazines/administration & dosage/adverse effects, Piperazines/administration & dosage/adverse effects, Proportional Hazards Models, Prospective Studies, Stomach Neoplasms/classification/*drug therapy/mortality/pathology, Survival Analysis, Treatment Outcome
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