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.
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.
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.
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.
Urologic oncology. 2019 Sep 12 [Epub ahead of print]
Daniel J George, Susan Halabi, Patrick Healy, Darius Jonasch, Monika Anand, Julia Rasmussen, Sarah Y Wood, Charles Spritzer, John F Madden, Andrew J Armstrong
Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC; Department of Medicine/Division of Medical Oncology, Duke University, Durham, NC; Department of Surgery/Division of Urology, Duke University, Durham, NC. Electronic address: ., Department of Biostatistics and Bioinformatics, Duke University, Durham, NC., Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC., Department of Radiology, Duke University, Durham, NC., Department of Pathology/Division of Pathology Clinical Services, Duke University, Durham, NC., Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC; Department of Medicine/Division of Medical Oncology, Duke University, Durham, NC; Department of Surgery/Division of Urology, Duke University, Durham, NC. Electronic address: .