Keele Research Repository

Background: The PI3K/AKT signalling pathway is frequently activated in triple-negative breast cancer (TNBC). AZD5363 is a highly-selective, oral, small molecule AKT inhibitor. The PAKT trial investigated the addition of AZD5363 to paclitaxel as 1st-line therapy for TNBC. Methods: This investigator-led, double-blind, placebo-controlled, randomised phase II trial, recruited women with previously untreated, metastatic TNBC at 42 sites in 6 countries. Patients were randomly assigned (1:1) to paclitaxel 90mg/m2 (days 1, 8, & 15) with either AZD5363 (400mg BD) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS), PFS in the subgroup with PIK3CA/AKT1/PTEN-alterations, response, and safety. Results: Between 05/2014 and 06/2017, 140 patients were randomised to paclitaxel + AZD5363 (n = 70) or paclitaxel + placebo (n = 70). Median duration of follow-up was 18.2 months (95% CI, 13.6 to 24.0). In the ITT analysis, median PFS was 5.9 months (m) for AZD5363 compared to 4.2m for placebo (hazard ratio [HR], 0.75; 95% CI, 0.52 to 1.08; one-sided p = 0.06; two-sided p = 0.11 [predefined significance level of 0.10, one-sided]). Median OS was 19.1m for AZD5363 compared to 12.6m for placebo (HR, 0.64; 95% CI, 0.40 to 1.01; one-sided p = 0.02; two-sided p = 0.04). Results for the subgroup with PIK3CA/AKT1/PTEN-altered tumours will be presented. Most common grade 3 or worse adverse events were diarrhoea (12% [8/68] of AZD5363-treated patients vs 1% [1/70] of placebo-treated patients), infection (4% vs 1%), neutropenia (3% vs 3%), rash (4% vs 0) and fatigue (4% vs 0). Conclusions: The trial met its primary endpoint. Addition of AZD5363 to 1st-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. AZD5363 warrants further investigation for the treatment of TNBC. Clinical trial information: NCT02423603.