PHASE II STUDIES Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study Abdullah K. Altwairgi 1 & Waleed A. Alghareeb 1 & Fouad H. AlNajjar 2 & Hussain Alhussain 3 & Eyad Alsaeed 3 & Ali Abdullah O. Balbaid 3 & Sadeq Aldanan 4 & Yasser Orz 5 & Abdullah A. Alsharm 1 Received: 28 June 2020 /Accepted: 21 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Summary Glioblastoma is a fast-growing primary brain tumor observed in adults with the worst prognosis. Preclinical studies have demonstrated the encouraging anticancer activity of statins. This study evaluated the efficacy of atorvastatin in combination with standard therapy in patients with glioblastoma. In this prospective, open-label, single-arm, phase II study, patients were treated with atorvastatin in combination with the standard glioblastoma therapy comprising radiotherapy and temozolomide. The primary endpoint was progression-free survival (PFS) at 6 months (PFS-6). Among 36 patients enrolled from January 2014 to January 2017, the median age was 52 (20–69) years; 22% of the patients were aged ≥60 years, and 62% were male. Patients received atorvastatin for a median duration of 6.2 (0.3–28) months. At a median follow-up of 19 months, the PFS-6 rate was 66%, with a median PFS of 7.6 (5.7–9.4) months. In terms of Grade ≥ 3 hematological adverse events, thrombocytopenia and neutropenia occurred in 7% and 12% of patients, respectively. In multivariate analyses, high baseline low-density lipoprotein levels were associated with worse survival (P = 0.046). Atorvastatin was not shown to improve PFS-6. However, this study identified that high low-density lipoprotein levels are an independent predictor of poor cancer-related outcomes. Future clinical trials testing statins should aim to enroll patients with slow-growing tumors. Clinical trial information: NCT0202957 (December 12, 2013) Keywords Atorvastatin . Statins . Cancer . Glioblastoma . Low-density lipoprotein cholesterol Introduction Primary tumors of the central nervous system (CNS) are as- sociated with a high mortality rate and are responsible for 2.9% of all cancer-related deaths [1]. Glioblastoma is an ag- gressive CNS tumor arising from the glial cells of the brain or spinal cord [2] and is the most common primary brain tumor in adults, accounting for 59% of all malignant gliomas [2]. The standard therapy for newly diagnosed glioblastoma patients is maximal surgical resection, followed by radiother- apy with concomitant and adjuvant temozolomide (TMZ). However, there is an urgent need for more effective first-line treatments as most patients die within 2 years of diagnosis [3]. Statins, commonly administered to lower blood cholesterol levels, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase [4]. This leads to the disruption of critical cellular functions such as protein synthesis, cell signal- ing, membrane integrity, and cell cycle progression [5], which in turn leads to the inhibition of tumorigenesis, tumor growth, and metastasis. Like TMZ, statins cause cell cycle arrest in the Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00992-5) contains supplementary material, which is available to authorized users. * Abdullah K. Altwairgi aaltwairqi@kfmc.med.sa; drtwairqi@gmail.com 1 Medical Oncology Department, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia 2 Clinical Pharmacy Department, King Fahad Medical City, Riyadh, Saudi Arabia 3 Radiation Oncology Department, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia 4 Pathology Department, King Fahad Medical City, Riyadh, Saudi Arabia 5 National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia Investigational New Drugs https://doi.org/10.1007/s10637-020-00992-5