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

Summary

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.

Introduction

Gastric cancer is the third leading cause of deaths from cancer worldwide,¹ and more than 50% of cases occur in eastern Asia.² Treatment options after failure of standard first-line platinum and fluoropyrimidine-based combination therapy are scarce.³ Paclitaxel is a widely used second-line therapy,⁴ and various targeted anticancer agents for use in combination with paclitaxel have been investigated as second-line therapies. After beginning this trial, paclitaxel in combination with ramucirumab, a monoclonal antibody VEGFR 2 antagonist, was approved in many countries as a second-line treatment option for advanced gastric cancer.3, 5 Despite improvements in overall survival brought about by the paclitaxel plus ramucirumab treatment combination, a need still remains for more effective and tolerable therapies for patients with advanced gastric cancer that has progressed after firstline treatment.

Research in context

Evidence before this study

We searched PubMed and oncology congress websites from Jan 1, 2004, to Jan 1, 2014, for information about gastric cancer treatments, with particular emphasis placed on publications relating to second-line treatments. The search terms used were “advanced gastric cancer” and “systemic therapy”. No language preferences were specified. At the time the GOLD study was developed, there was no single well-established standard of care for patients with advanced gastric cancer; first-line fluoropyrimidine-based and platinum-based combinations with or without a third drug (usually docetaxel or epirubicin) were the most widely used treatment combinations worldwide. A phase 2 study (Study 39; D0810C00039, NCT01063517) of olaparib combined with paclitaxel showed a significant improvement in overall survival versus placebo when combined with paclitaxel as second-line therapy in Asian patients with advanced gastric cancer. The phase 3 GOLD study was undertaken to confirm the results of that phase 2 study.

Added value of this study

The GOLD study confirmed that oral olaparib (100 mg twice daily, tablet formulation) in combination with weekly infusions of paclitaxel (80 mg/m²) was well tolerated in patients with advanced gastric cancer. Antitumour activity was insufficient to show a significant improvement in overall survival with olaparib.

Implications of all the available evidence

The GOLD study did not meet its primary objective of showing a significant improvement in overall survival in patients with advanced gastric cancer which had progressed following, or during, first-line chemotherapy and who were receiving olaparib and paclitaxel treatment compared with patients receiving placebo and paclitaxel. The GOLD study therefore was not able to confirm the findings of the previous phase 2 study in this setting. Olaparib continues to be investigated in a wide-reaching clinical programme in a variety of tumour types and patient populations, especially in patients with homologous recombination repair deficiencies.

Olaparib is an oral poly(ADP-ribose) polymerase (PARP) inhibitor that blocks DNA base-excision repair and causes synthetic lethality in tumours with homologous recombination repair deficiencies.⁶ Olaparib (capsule formulation, 400 mg twice daily) is approved in more than 40 countries for patients with advanced BRCA-mutated ovarian cancer. Because the capsule pill burden is high at the approved dose (16 large capsules per day), a tablet formulation was developed to reduce pill burden. A phase 2 study (Study 39; D0810C00039, NCT01063517) of olaparib tablets combined with paclitaxel versus placebo combined with paclitaxel as second-line therapy in Asian patients with advanced gastric cancer did not meet its primary endpoint of progression-free survival; however, a significant improvement in the secondary endpoint of overall survival was recorded.⁷ In Study 39, a greater overall survival benefit was noted in patients with ataxia-telangiectasia mutated protein (ATM)-negative tumours. The ATM protein is a key activator of the DNA damage response to double-strand breaks.8, 9 Therefore, patients with DNA repair-deficient tumours through loss of expression of the ATM protein might benefit from PARP inhibitor treatment.⁷ Up to 22% of metastatic tumours from patients with gastric cancer might have low or undetectable ATM expression.¹⁰

We report the primary analyses from a subsequent phase 3 study (the GOLD trial) in Asian patients with advanced gastric cancer that had progressed following first-line therapy.