Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08).

BACKGROUND The phosphatase and tensin homolog (PTEN) tumor suppressor gene is deregulated in many advanced prostate cancers, leading to activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway and thus increased cell survival. OBJECTIVE To evaluate everolimus, an inhibitor of mTOR, in patients with metastatic castration-resistant prostate cancer (mCRPC), and to explore potentially predictive serum biomarkers by proteomics, the significance of PTEN status in tumor tissue, and the impact of everolimus on immune cell subpopulations and function. DESIGN, SETTING, AND PARTICIPANTS A total of 37 chemotherapy-naive patients with mCRPC and progressive disease were recruited to this single-arm phase 2 trial (ClinicalTrials.gov identifier NCT00976755). INTERVENTION Everolimus was administered continuously at a dose of 10mg daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was progression-free survival (PFS) at 12 wk defined as the absence of prostate-specific antigen (PSA), radiographic progression, or clinical progression. Groups were compared using Wilcoxon rank-sum tests or Fisher exact tests for continuous and discrete variables, respectively. Time-to-event end points were analyzed using the Kaplan-Meier method and univariate Cox regression. RESULTS AND LIMITATIONS A total of 13 patients (35%; 95% confidence interval, 20-53) met the primary end point. Confirmed PSA response ≥50% was seen in two (5%), and four further patients (11%) had a PSA decline ≥30%. Higher serum levels of carboxypeptidase M and apolipoprotein B were predictive for reaching the primary end point. Deletion of PTEN was associated with longer PFS and response. Treatment was associated with a dose-dependent decrease of CD3, CD4, and CD8 T lymphocytes and CD8 proliferation and an increase in regulatory T cells. Small sample size was the major limitation of the study. CONCLUSIONS Everolimus activity in unselected patients with mCRPC is moderate, but PTEN deletion could be predictive for response. Several serum glycoproteins were able to predict PFS at 12 wk. Prospective validation of these potential biomarkers is warranted. TRIAL REGISTRATION This study is registered with ClinicalTrials.gov with the identifier NCT00976755. Results of this study were presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology (June 3-7, 2011; Chicago, IL, USA) and the annual meeting of the German, Austrian, and Swiss Societies for Oncology and Hematology (September 30-October 4, 2011; Basel, Switzerland).