Phase 2 clinical trial of TORC1 inhibition with everolimus in men with metastatic castration-resistant prostate cancer.

Published

Journal Article

BACKGROUND: Activation of the PI3K-Akt-mTOR signaling pathway is common in advanced castration resistant prostate cancer (CRPC), typically through PTEN loss. Preclinical studies suggest that Akt-driven CaP cells are genetically susceptible to mammalian target of rapamycin (mTOR, or TORC1) inhibition. Everolimus is a Food and Drug Administration-approved inhibitor of TORC1. MATERIALS AND METHODS: We performed a phase II study of everolimus in patients with mCRPC, who were refractory to standard of care hormonal and chemotherapeutic agents. Patients received everolimus 10 mg daily until unacceptable adverse events or disease progression. The primary efficacy outcome was confirmed 50% or greater prostate-specific antigen (PSA) response, using a 2 stage design with futility rules. Paired biopsies were utilized to assess for treatment effect on downstream TORC1 targets as well as tumor cell proliferation and apoptosis. RESULTS: Out of 35 men enrolled with heavily pretreated mCRPC, 32 were evaluable for clinical efficacy. No PSA responses were observed, the median progression-free survival time was 3.6 months (95% confidence interval = 2.9-4.8) and the median overall survival time was 10.4 months (95% confidence interval = 5.8-15.8). Several patients had declines in serum PSA upon cessation of everolimus. Thus, the study was closed due to clinical futility. The most common toxicities were mucositis, fatigue, anorexia, hypertriglyceridemia, and thrombocytopenia and were largely low grade. Pathologic evaluation of paired metastatic biopsies demonstrated consistent inhibition of pS6, a downstream mTOR pharmacodynamics biomarker, but the tumor proliferation marker Ki-67 increased with therapy. CONCLUSIONS: Everolimus demonstrated predictable toxicity in advanced and heavily pretreated patients with mCRPC. No clinical or clear pathologic effects despite downstream TORC1 target inhibition, suggesting that single agent everolimus has no clinical utility in men with mCRPC.

Full Text

Duke Authors

Cited Authors

  • George, DJ; Halabi, S; Healy, P; Jonasch, D; Anand, M; Rasmussen, J; Wood, SY; Spritzer, C; Madden, JF; Armstrong, AJ

Published Date

  • March 2020

Published In

Volume / Issue

  • 38 / 3

Start / End Page

  • 79.e15 - 79.e22

PubMed ID

  • 31522863

Pubmed Central ID

  • 31522863

Electronic International Standard Serial Number (EISSN)

  • 1873-2496

Digital Object Identifier (DOI)

  • 10.1016/j.urolonc.2019.08.015

Language

  • eng

Conference Location

  • United States