First results of a phase II trial to assess the efficacy of efavirenz in patients with metastatic androgen-independent prostate cancer.

Abstract

251 Background: This Phase II trial assessed the efficacy of efavirenz, a non-nucleoside reverse transcriptase inhibitor in patients with asymptomatic HRPC [hormone refractory prostate cancer] who progressed, before docetaxel based chemotherapy. Preclinical studies showed that efavirenz, via Line-1 inhibition, could block proliferation and induced re-differentiation of prostate cancer cell line. We then investigated if efavirenz treatment can delay biological and clinical progression. Methods: The primary objective was to assess the efficacy of efavirenz in patients, with no clinical symptom related to disease progression. Each patient received efavirenz 600 mg/day until objective biological progression or study discontinuation. It was possible to increase the dose (up to 1200 mg daily) in case of PSA progression at 3 months. Efficacy was measured in terms of 3-month non-progression. Based on a 2-stage Simon’s design, a total of 16 non-progressions out of 54 eligible patients were required to claim efficacy. Results: 61 patients were enrolled in the study with 53 eligible for the primary endpoint. At baseline, median age was 71 years and median PSA level was 49.6 ng/mL. A total of 15/53 (28%) non-progressions were observed at 3 months. As patients are still being followed, overall survival, PSA progression free survival and symptomatic progression free survival at one year will be presented. Sixty patients were assessable for toxicity. Of these, 9 (15%) experienced at least one grade III/IV toxicity i.e. neuropsychiatric adverse events already reported in efavirenz-treated HIV patients. With regard to pharmacokinetics (PK), preliminary data indicates variability in the 3-month efavirenz concentration. Ongoing preliminary analyses suggest a better response in patients with elevated (>3000ng/ml) plasmatic concentration. Conclusions: Current analyses do not allow to claim efficacy of Efavirenz at the 600 mg dose. The ongoing analysis of the relationship between plasmatic concentration of efavirenz and treatment efficacy could confirm that higher doses of efavirenz may constitute an efficient treatment. A phase I dose escalation study is currently being performed.