A phase III study exploring the combination of olaparib and paclitaxel missed its primary endpoint of improvement in overall survival compared with paclitaxel and placebo for patients with advanced gastric cancer.
Sean Bohen, MD, PhD
The combination of olaparib (Lynparza) and paclitaxel failed to improve overall survival (OS) compared with paclitaxel and placebo in the phase III GOLD trial for patients with advanced gastric cancer, according to a statement from the developer of the PARP inhibitor, AstraZeneca.
The study included 525 patients from China, Japan, South Korea, and Taiwan with gastric and gastroesophageal junction tumors who progressed following frontline therapy. The primary endpoint of the study was OS, with secondary endpoints focused on progression-free survival (PFS), safety, and response. Data from the study were not yet released and should be presented at an upcoming medical meeting, according to AstraZeneca.
“While there was a numerical trend for survival benefit with Lynparza plus paclitaxel in the GOLD trial, we are disappointed that this did not reach statistical significance," Sean Bohen, MD, PhD, executive vice president, Global Medicines Development and chief medical officer at AstraZeneca, said in a statement.
The phase III trial enrolled adult patients with at least one lesion that was detectable by imaging. In both arms, weekly paclitaxel was administered at 80 mg/m2. Oral olaparib was administered at 100 mg twice daily throughout each cycle until paclitaxel was discontinued, at which point the dose was increased to 300 mg twice daily.
Tumors samples from resected tissue or a biopsy were tested for ATM expression, with 18% of the participants testing negative. According to AstraZeneca, outcomes were similar between the ATM-negative group and the entire population. Additionally, adverse events (AEs) with the combination were similar to those seen with single-agent paclitaxel.
"The particular regimen in the GOLD study, at a low dose and in combination with chemotherapy, differs from other phase III trials in the Lynparza programme," said Bohen. "We look forward to presenting the GOLD data and remain confident in Lynparza’s clinical activity in a range of tumor types, including its approved use in BRCA-mutated ovarian cancer.”
Prior to the GOLD trial, a phase II trial had shown activity for olaparib plus paclitaxel, especially in those with low ATM expression. In this study, 123 patients were treated with either olaparib and paclitaxel (n = 61) or paclitaxel and placebo (n = 62). Fourteen percent of patients tested negative for ATM expression. Patients received 6 to 10 cycles of paclitaxel followed by a 200 mg twice-daily maintenance dose of olaparib.
Across the full population, the PFS was 3.91 months with olaparib versus 3.55 months with paclitaxel alone (HR, 0.80; 80% CI, 0.62-1.03; one-sided P = .131), which missed the primary endpoint of the study. The median OS was 13.1 versus 8.3 months, with and without olaparib, respectively (HR, 0.56; 80% CI, 0.41-0.75; P = .005). Objective response rates were similar in each arm.
In those with low ATM expression, the median PFS with olaparib was 5.29 versus 3.68 months with paclitaxel alone (HR, 0.74; 80% CI, 0.51-1.08; one-sided P = .157). The median OS was not reached with olaparib versus 8.2 months with paclitaxel (HR, 0.35; 80% CI, 0.22-0.56; P = .002).
Grade ≥3 AEs occurred in 75.4% of patients treated with olaparib plus paclitaxel compared with 74.2% of those receiving paclitaxel alone. Serious AEs were higher in the paclitaxel/placebo arm compared with olaparib (37.1% vs 27.9%). The most common AE that led to a dose modification was neutropenia (54.1% with olaparib vs 37.1% with placebo).
Outside of gastric cancer, a number of phase III studies continue to assess the PARP inhibitor for patients with cancer across a variety of indications, including breast cancer, pancreatic cancer, and prostate cancer. A study is exploring the agent has an adjuvant treatment for patients with BRCA-mutant, HER2-negative breast cancer (NCT02032823), and another is assessing frontline olaparib for patients with germline BRCA-mutant pancreatic cancer (NCT02184195). Phase III studies are also assessing the combination of olaparib with the angiogenesis inhibitor cediranib (NCT02502266, NCT02446600).
Olaparib is currently approved in the United States as a treatment for women with BRCA-mutant advanced ovarian cancer following three or more prior lines of chemotherapy. Additionally, the agent has received a breakthrough therapy designation as a potential treatment for men with BRCA1/2 or ATM-mutated metastatic castration-resistant prostate cancer.
Bang Y-J, Im S-A, Lee K-W, et al. 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 [published online August 17, 2015]. J Clin Oncol. doi: 10.1200/JCO.2014.60.0320.