Etoricoxib and anastrozole in adjuvant early breast cancer: ETAN trial (phase III)

Background: Preclinical data clearly demonstrated that cyclooxigenase activates growth-promoting and anti-apoptotic pathways as well as aromatase. However, data from clinical trial are poor, mainly due to the severe restrictions that the FDA has imposed to the COX-2 inhibitors in 2004 because of their serious adverse events. Methods: We designed a phase III, placebo-controlled prospective trial in which postmenopausal hormone-receptor positive early breast cancer (EBC) women were randomized 1:1 to receive anastrozole (1 mg/die) upfront in combination with placebo or etoricoxib (60 mg/die). Combined treatment was planned for 24 months. Patients were allowed to discontinue the etoricoxib or placebo for toxicity (censored). Anastrozole was continued for 5 years. The primary end-point was the 5-years event free survival (EFS). The secondary end-point was to compare the risk of fracture and the muscle-skeletal events in the two groups. Chi-Square tests for categorical data and time to event provided two-sided p values. Results: Since 2003 to 2006 we enrolled 182 patients. A number of 93 patients was enrolled in the treatment arm and N=89 in the control. The median treatment duration was 14 months in ETAN group and 12 in PAN group. A number of 37 patients in the treatment arm and 33 in the control discontinued etoricoxib after the FDA alert on COX-2 inhibitors. To a 5 years follow-up, the median EFS was 56.9 and 53.14 months [HR: 1.9; 95%CI (1.03 – 3.59), p= .03] in the treatment arm and control, respectively. There were no significative differences in terms of fractures [RR: 0.58, 95%CI (0.14-2.38), p= .45]. Muscle-skeletal pain was significative lower in the treatment arm (50/73) than the control (16/67) [RR: 2.1, 95%CI (1.29-3.43), p= .002]. None of the patients in the treatment arm developed serious adverse event. Conclusions: Our data demonstrated a small but significative advantage in terms of EFS and muscle-skeletal events when etoricoxib is added to anastrozole in adjuvant setting. Data are strongly limited from the study drop-out, but the very long follow-up and the absence of major toxicity encourage larger phase III confirmatory trials.