Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial

Yung Jue Bang, Rui Hua Xu, Keisho Chin, Keun Wook Lee, Se Hoon Park, Sun Young Rha, Lin Shen, Shukui Qin, Nong Xu, Seock Ah Im, Gershon Locker, Phil Rowe, Xiaojin Shi, Darren Hodgson, Yu Zhen Liu, Narikazu Boku

Research output: Contribution to journalArticle

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Abstract

Background Olaparib combined with paclitaxel has previously shown a significant improvement in overall survival versus placebo plus paclitaxel as second-line therapy in a phase 2 study in Asian patients with advanced gastric cancer, especially in those with ataxia-telangiectasia mutated protein (ATM)-negative tumours. Here, we report the primary efficacy and safety analyses from a subsequent phase 3 trial. Methods This double-blind, randomised, placebo-controlled, phase 3 study (GOLD) recruited Asian patients aged 18 years or older (≥20 years if Japanese) with advanced gastric cancer that had progressed following, or during, first-line chemotherapy. Patients were randomly assigned (1:1) to receive oral olaparib (100 mg twice daily) plus paclitaxel (80 mg/m2 intravenously) or matching placebo plus paclitaxel. Randomisation was done through an interactive voice response system and no stratification factors were used. Patients and investigators were masked to treatment allocation. Two co-primary populations were assessed: the overall population of all patients and patients whose tumours were ATM-negative (identified after randomisation, before the data cutoff date, March 28, 2016). The primary endpoint in both populations was overall survival (defined as the time from the date of randomisation until death from any cause before data cutoff); a significant difference was defined as p<0·025. Efficacy was assessed in the intention-to-treat populations and safety in patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01924533 (study ID, D081BC00004), and is ongoing but no longer recruiting participants. Findings Between Sept 3, 2013, and March 28, 2016, 643 patients were enrolled from 58 study sites in hospitals and medical centres in China, Japan, South Korea, and Taiwan. 525 eligible patients were randomly assigned: 263 to receive olaparib plus paclitaxel and 262 to receive placebo plus paclitaxel. 94 patients were determined to have ATM-negative tumours before unmasking for the primary analysis (48 in the olaparib plus paclitaxel group and 46 in the placebo plus paclitaxel group). Overall survival did not differ between treatment groups in the overall patient population (median overall survival 8·8 months [95% CI 7·4–9·6] in the olaparib group vs 6·9 months [6·3–7·9] in the placebo group; HR 0·79 [97·5% CI 0·63–1·00]; p=0·026) or in the ATM-negative population (12·0 months [7·8–18·1] vs 10·0 months [6·4–13·3]; 0·73 [0·40–1·34]; p=0·25). In the overall patient population, the most common grade 3 or worse adverse events in the olaparib plus paclitaxel group were neutropenia (78 [30%] of 262 patients), leucopenia (42 [16%]), and decreased neutrophil count (40 [15%]); in the placebo plus paclitaxel group, they were neutropenia (59 [23%] of 259 patients), leucopenia (27 [10%]), and decreased white blood cell count (21 [8%]). Adverse events with an outcome of death causally related to study treatment (according to investigator assessment) were reported in two patients: liver injury in one patient (<1%) in the olaparib plus paclitaxel group and cardiac failure in one patient (<1%) in the placebo plus paclitaxel group. Interpretation The GOLD study did not meet its primary objective of showing a significant improvement in overall survival with olaparib in the overall or ATM-negative population of Asian patients with advanced gastric cancer. The study generated informative efficacy and safety data regarding the use of olaparib in combination with a chemotherapeutic agent and provides a foundation for future studies in this difficult-to-treat patient population. Funding AstraZeneca.

Original languageEnglish
Pages (from-to)1637-1651
Number of pages15
JournalThe Lancet Oncology
Volume18
Issue number12
DOIs
Publication statusPublished - 2017 Dec

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Paclitaxel
Stomach Neoplasms
Placebos
Ataxia Telangiectasia Mutated Proteins
Therapeutics
Population
Random Allocation
Survival
olaparib
Leukopenia
Neutropenia
Research Personnel
Safety
Neoplasms
Republic of Korea
Patient Safety
Taiwan
Leukocyte Count
Double-Blind Method

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Bang, Yung Jue ; Xu, Rui Hua ; Chin, Keisho ; Lee, Keun Wook ; Park, Se Hoon ; Rha, Sun Young ; Shen, Lin ; Qin, Shukui ; Xu, Nong ; Im, Seock Ah ; Locker, Gershon ; Rowe, Phil ; Shi, Xiaojin ; Hodgson, Darren ; Liu, Yu Zhen ; Boku, Narikazu. / Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD) : a double-blind, randomised, placebo-controlled, phase 3 trial. In: The Lancet Oncology. 2017 ; Vol. 18, No. 12. pp. 1637-1651.
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abstract = "Background Olaparib combined with paclitaxel has previously shown a significant improvement in overall survival versus placebo plus paclitaxel as second-line therapy in a phase 2 study in Asian patients with advanced gastric cancer, especially in those with ataxia-telangiectasia mutated protein (ATM)-negative tumours. Here, we report the primary efficacy and safety analyses from a subsequent phase 3 trial. Methods This double-blind, randomised, placebo-controlled, phase 3 study (GOLD) recruited Asian patients aged 18 years or older (≥20 years if Japanese) with advanced gastric cancer that had progressed following, or during, first-line chemotherapy. Patients were randomly assigned (1:1) to receive oral olaparib (100 mg twice daily) plus paclitaxel (80 mg/m2 intravenously) or matching placebo plus paclitaxel. Randomisation was done through an interactive voice response system and no stratification factors were used. Patients and investigators were masked to treatment allocation. Two co-primary populations were assessed: the overall population of all patients and patients whose tumours were ATM-negative (identified after randomisation, before the data cutoff date, March 28, 2016). The primary endpoint in both populations was overall survival (defined as the time from the date of randomisation until death from any cause before data cutoff); a significant difference was defined as p<0·025. Efficacy was assessed in the intention-to-treat populations and safety in patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01924533 (study ID, D081BC00004), and is ongoing but no longer recruiting participants. Findings Between Sept 3, 2013, and March 28, 2016, 643 patients were enrolled from 58 study sites in hospitals and medical centres in China, Japan, South Korea, and Taiwan. 525 eligible patients were randomly assigned: 263 to receive olaparib plus paclitaxel and 262 to receive placebo plus paclitaxel. 94 patients were determined to have ATM-negative tumours before unmasking for the primary analysis (48 in the olaparib plus paclitaxel group and 46 in the placebo plus paclitaxel group). Overall survival did not differ between treatment groups in the overall patient population (median overall survival 8·8 months [95{\%} CI 7·4–9·6] in the olaparib group vs 6·9 months [6·3–7·9] in the placebo group; HR 0·79 [97·5{\%} CI 0·63–1·00]; p=0·026) or in the ATM-negative population (12·0 months [7·8–18·1] vs 10·0 months [6·4–13·3]; 0·73 [0·40–1·34]; p=0·25). In the overall patient population, the most common grade 3 or worse adverse events in the olaparib plus paclitaxel group were neutropenia (78 [30{\%}] of 262 patients), leucopenia (42 [16{\%}]), and decreased neutrophil count (40 [15{\%}]); in the placebo plus paclitaxel group, they were neutropenia (59 [23{\%}] of 259 patients), leucopenia (27 [10{\%}]), and decreased white blood cell count (21 [8{\%}]). Adverse events with an outcome of death causally related to study treatment (according to investigator assessment) were reported in two patients: liver injury in one patient (<1{\%}) in the olaparib plus paclitaxel group and cardiac failure in one patient (<1{\%}) in the placebo plus paclitaxel group. Interpretation The GOLD study did not meet its primary objective of showing a significant improvement in overall survival with olaparib in the overall or ATM-negative population of Asian patients with advanced gastric cancer. The study generated informative efficacy and safety data regarding the use of olaparib in combination with a chemotherapeutic agent and provides a foundation for future studies in this difficult-to-treat patient population. Funding AstraZeneca.",
author = "Bang, {Yung Jue} and Xu, {Rui Hua} and Keisho Chin and Lee, {Keun Wook} and Park, {Se Hoon} and Rha, {Sun Young} and Lin Shen and Shukui Qin and Nong Xu and Im, {Seock Ah} and Gershon Locker and Phil Rowe and Xiaojin Shi and Darren Hodgson and Liu, {Yu Zhen} and Narikazu Boku",
year = "2017",
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language = "English",
volume = "18",
pages = "1637--1651",
journal = "The Lancet Oncology",
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Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD) : a double-blind, randomised, placebo-controlled, phase 3 trial. / Bang, Yung Jue; Xu, Rui Hua; Chin, Keisho; Lee, Keun Wook; Park, Se Hoon; Rha, Sun Young; Shen, Lin; Qin, Shukui; Xu, Nong; Im, Seock Ah; Locker, Gershon; Rowe, Phil; Shi, Xiaojin; Hodgson, Darren; Liu, Yu Zhen; Boku, Narikazu.

In: The Lancet Oncology, Vol. 18, No. 12, 12.2017, p. 1637-1651.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD)

T2 - a double-blind, randomised, placebo-controlled, phase 3 trial

AU - Bang, Yung Jue

AU - Xu, Rui Hua

AU - Chin, Keisho

AU - Lee, Keun Wook

AU - Park, Se Hoon

AU - Rha, Sun Young

AU - Shen, Lin

AU - Qin, Shukui

AU - Xu, Nong

AU - Im, Seock Ah

AU - Locker, Gershon

AU - Rowe, Phil

AU - Shi, Xiaojin

AU - Hodgson, Darren

AU - Liu, Yu Zhen

AU - Boku, Narikazu

PY - 2017/12

Y1 - 2017/12

N2 - Background Olaparib combined with paclitaxel has previously shown a significant improvement in overall survival versus placebo plus paclitaxel as second-line therapy in a phase 2 study in Asian patients with advanced gastric cancer, especially in those with ataxia-telangiectasia mutated protein (ATM)-negative tumours. Here, we report the primary efficacy and safety analyses from a subsequent phase 3 trial. Methods This double-blind, randomised, placebo-controlled, phase 3 study (GOLD) recruited Asian patients aged 18 years or older (≥20 years if Japanese) with advanced gastric cancer that had progressed following, or during, first-line chemotherapy. Patients were randomly assigned (1:1) to receive oral olaparib (100 mg twice daily) plus paclitaxel (80 mg/m2 intravenously) or matching placebo plus paclitaxel. Randomisation was done through an interactive voice response system and no stratification factors were used. Patients and investigators were masked to treatment allocation. Two co-primary populations were assessed: the overall population of all patients and patients whose tumours were ATM-negative (identified after randomisation, before the data cutoff date, March 28, 2016). The primary endpoint in both populations was overall survival (defined as the time from the date of randomisation until death from any cause before data cutoff); a significant difference was defined as p<0·025. Efficacy was assessed in the intention-to-treat populations and safety in patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01924533 (study ID, D081BC00004), and is ongoing but no longer recruiting participants. Findings Between Sept 3, 2013, and March 28, 2016, 643 patients were enrolled from 58 study sites in hospitals and medical centres in China, Japan, South Korea, and Taiwan. 525 eligible patients were randomly assigned: 263 to receive olaparib plus paclitaxel and 262 to receive placebo plus paclitaxel. 94 patients were determined to have ATM-negative tumours before unmasking for the primary analysis (48 in the olaparib plus paclitaxel group and 46 in the placebo plus paclitaxel group). Overall survival did not differ between treatment groups in the overall patient population (median overall survival 8·8 months [95% CI 7·4–9·6] in the olaparib group vs 6·9 months [6·3–7·9] in the placebo group; HR 0·79 [97·5% CI 0·63–1·00]; p=0·026) or in the ATM-negative population (12·0 months [7·8–18·1] vs 10·0 months [6·4–13·3]; 0·73 [0·40–1·34]; p=0·25). In the overall patient population, the most common grade 3 or worse adverse events in the olaparib plus paclitaxel group were neutropenia (78 [30%] of 262 patients), leucopenia (42 [16%]), and decreased neutrophil count (40 [15%]); in the placebo plus paclitaxel group, they were neutropenia (59 [23%] of 259 patients), leucopenia (27 [10%]), and decreased white blood cell count (21 [8%]). Adverse events with an outcome of death causally related to study treatment (according to investigator assessment) were reported in two patients: liver injury in one patient (<1%) in the olaparib plus paclitaxel group and cardiac failure in one patient (<1%) in the placebo plus paclitaxel group. Interpretation The GOLD study did not meet its primary objective of showing a significant improvement in overall survival with olaparib in the overall or ATM-negative population of Asian patients with advanced gastric cancer. The study generated informative efficacy and safety data regarding the use of olaparib in combination with a chemotherapeutic agent and provides a foundation for future studies in this difficult-to-treat patient population. Funding AstraZeneca.

AB - Background Olaparib combined with paclitaxel has previously shown a significant improvement in overall survival versus placebo plus paclitaxel as second-line therapy in a phase 2 study in Asian patients with advanced gastric cancer, especially in those with ataxia-telangiectasia mutated protein (ATM)-negative tumours. Here, we report the primary efficacy and safety analyses from a subsequent phase 3 trial. Methods This double-blind, randomised, placebo-controlled, phase 3 study (GOLD) recruited Asian patients aged 18 years or older (≥20 years if Japanese) with advanced gastric cancer that had progressed following, or during, first-line chemotherapy. Patients were randomly assigned (1:1) to receive oral olaparib (100 mg twice daily) plus paclitaxel (80 mg/m2 intravenously) or matching placebo plus paclitaxel. Randomisation was done through an interactive voice response system and no stratification factors were used. Patients and investigators were masked to treatment allocation. Two co-primary populations were assessed: the overall population of all patients and patients whose tumours were ATM-negative (identified after randomisation, before the data cutoff date, March 28, 2016). The primary endpoint in both populations was overall survival (defined as the time from the date of randomisation until death from any cause before data cutoff); a significant difference was defined as p<0·025. Efficacy was assessed in the intention-to-treat populations and safety in patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01924533 (study ID, D081BC00004), and is ongoing but no longer recruiting participants. Findings Between Sept 3, 2013, and March 28, 2016, 643 patients were enrolled from 58 study sites in hospitals and medical centres in China, Japan, South Korea, and Taiwan. 525 eligible patients were randomly assigned: 263 to receive olaparib plus paclitaxel and 262 to receive placebo plus paclitaxel. 94 patients were determined to have ATM-negative tumours before unmasking for the primary analysis (48 in the olaparib plus paclitaxel group and 46 in the placebo plus paclitaxel group). Overall survival did not differ between treatment groups in the overall patient population (median overall survival 8·8 months [95% CI 7·4–9·6] in the olaparib group vs 6·9 months [6·3–7·9] in the placebo group; HR 0·79 [97·5% CI 0·63–1·00]; p=0·026) or in the ATM-negative population (12·0 months [7·8–18·1] vs 10·0 months [6·4–13·3]; 0·73 [0·40–1·34]; p=0·25). In the overall patient population, the most common grade 3 or worse adverse events in the olaparib plus paclitaxel group were neutropenia (78 [30%] of 262 patients), leucopenia (42 [16%]), and decreased neutrophil count (40 [15%]); in the placebo plus paclitaxel group, they were neutropenia (59 [23%] of 259 patients), leucopenia (27 [10%]), and decreased white blood cell count (21 [8%]). Adverse events with an outcome of death causally related to study treatment (according to investigator assessment) were reported in two patients: liver injury in one patient (<1%) in the olaparib plus paclitaxel group and cardiac failure in one patient (<1%) in the placebo plus paclitaxel group. Interpretation The GOLD study did not meet its primary objective of showing a significant improvement in overall survival with olaparib in the overall or ATM-negative population of Asian patients with advanced gastric cancer. The study generated informative efficacy and safety data regarding the use of olaparib in combination with a chemotherapeutic agent and provides a foundation for future studies in this difficult-to-treat patient population. Funding AstraZeneca.

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