Phase II study of atorvastatin in combination with radiotherapy and temozolomide in patients with glioblastoma (ART): Final analysis report

Abstract

Background: Glioblastoma is the one of most fast-growing primary brain tumor in adult and it carries the worst prognosis. Atorvastatin is an inhibitor of HMG-CoA reductase, a rate-limiting enzyme in the mevalonate pathway. Preclinical studies demonstrate encouraging anticancer activity of statins. The primary objective of the study was to evaluate the efficacy of Atorvastatin in addition to the standard therapy in patients with glioblastoma. Methods: In this open-label, prospective, single-arm, phase II study, eligible patients received Atorvastatin in combination with standard therapy comprising radiotherapy and Temozolomide (TMZ). The primary endpoint is progression free survival (PFS) at 6 months. A minimum of 80% power required at least 32 eligible patients with planned final analysis after at least 1 year from last recruited patient. Results: From January 2014 to December 2016, 36 evaluable patients were enrolled. Median age was 52 (20-69); 22% were > 60 years of age and 62% were male. 97% of patients underwent resection. All patients have received Atorvastatin for a median of 6.2 (0.3-28 ) months duration, 80% of patients have discontinued this because of disease progression. At a median follow-up of 19 months, PFS-6 rate was 66% with median PFS of 7.6 months. Median overall survival was 19.9 months (4.8 - 42.5 months). Grades 3 and 4 hematological adverse events, including neutropenia and thrombocytopenia occurred in 7% and 12 % of patients respectively. On multivariate analysis, worse survival was associated in patients with baseline high LDL level (p = 0.046) and better survival was seen in patients received adjuvant TMZ (p =0.001) and methylated tumors (p = 0.013). Conclusions: This study did not meet its primary endpoint of PFS-6 compared to historical controls. However, this study proves the fact that high LDL level was found to be an important independent predictor of poor cancer-related outcome. Future clinical trials testing statins should aim to enroll patients with slow-growing tumors.