A Phase II Trial Evaluating the Efficacy and Safety of Efavirenz in Metastatic Castration-Resistant Prostate Cancer

Abstract

Background. Preclinical studies demonstrated that nonnucleoside reverse transcriptase inhibitors used for the treatment of HIV could antagonize tumor development. This led us to assess the efficacy of efavirenz in patients with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter phase II study. Methods. We used a Simon two-stage design and a 3-month prostate-specific antigen (PSA) nonprogression rate of 40% as a primary objective. Patients received 600 mg efavirenz daily with the possibility of a dose increase in case of PSA progression. Exploratory analyses included pharmacokinetics of efavirenz plasma concentrations and correlations with clinical outcomes. Results. Among 53 assessable patients, we observed 15 instances of PSA nonprogression at 3 months, corresponding to a nonprogressionrate of 28.3% (95% confidence interval: 16.8%-42.3%). The exploratory analysis revealed that for the 7 patients inwhomoptimalplasmaconcentrationofefavirenzwasachieved, PSA progression was observed in only 28.6% compared with 81.8% of patients with suboptimal plasma concentrations of efavirenz. Conclusion. Although 600 mg efavirenz did not statistically improve the PSA nonprogression rate, our exploratory analysis suggests that higher plasma concentrations of this drug (i.e., use of increased dosages) may be of potential benefit for the treatment of mCRPC.

LINE-1 as a therapeutic target for castration-resistant prostate cancer

“…-34.5.) (130). Despite the fact that primary objective of the trial was not met, it was striking to note a high variability in plasma concentrations of the drug that was actually comparable with previously reported concentrations in HIV patients ranging from 125 to 15,230 ng/ml (131,132).…”

“…Before the approval of efavirenz for HIV treatment, a phase I study established the safety of 1800 mg/day single dosage and 1200 mg/day repeated dosage in healthy patients. In our phase II study, 13 patients received a dose of 1200 mg/day without any serious adverse event (Grade 3 or 4), indicating that higher dosages are well tolerated in prostate cancer patients despite their relatively advanced age (130). Indeed, although the median age of the treated patients was higher compared to other efavirenz toxicity studies, the safety profile of this NNRTI was confirmed and no new or unexpected adverse events were noticed, confirming that it is overall well tolerated with most adverse events being of grade 1 or 2.…”

Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells

“…So far there exists only one clinical trial in which NNRTIs were used to treat cancer in HIV-negative patients [45]. Fifty-three patients with metastatic castration-resistant prostate cancer were treated with EFV 600mg once daily.…”

Activation of LINE-1 Retrotransposon Increases the Risk of Epithelial-Mesenchymal Transition and Metastasis in Epithelial Cancer

“…Despite a lack of understanding of how L1 inhibition regulates cellular processes, Efavirenz is currently undergoing a phase II trial in castration-resistant metastatic prostate cancer [66]. Importantly, this trial has revealed that patients with the highest plasma concentrations of efavirenz (>3000 ng/ml) showed less progression of their cancers compared with patients who received suboptimal concentrations of Efavirenz.…”