PAKT Trial

The phase 2, placebo-controlled, PAKT trial (NCT02423603) randomised 140 patients with metastatic TNBC in a 1:1 fashion to either receive capivasertib with paclitaxel, or placebo with paclitaxel. Eligible patients had not received treatment for locally advanced or metastatic disease; prior adjuvant or neoadjuvant therapy was allowed if completed ≥12 months before enrolment in the study. The primary endpoint was the PFS, and OS was one of the secondary endpoints. Patients were stratified by tumour PIK3CA/AKT1/PTEN alteration status.

Results

After a median follow-up of 18.2 months, the PFS measured 5.9 months and 4.2 months in the capivasertib and placebo groups, respectively (HR, 0.74; 95% CI, 0.50-1.08; P=0.06). The median OS was prolonged in patients receiving capivasertib plus paclitaxel; patients in the experimental arm had a median OS of 19.1 months vs 12.6 months for those receiving placebo plus paclitaxel (HR=0.61; 95% CI, 0.37- 0.99; 2-sided P=0.04).

Subgroup analysis showed a significant improvement in PFS and OS for patients with PIK3CA/AKT1/PTEN-altered tumours. In this subgroup, the median PFS was 9.3 months in the capivasertib-group vs 3.7 months in the placebo group (HR=0.30; 95% CI, 0.11-0.79; 2-sided P=0.01). Although the median OS was not yet reached for capivasertib, subgroup patients receiving the AKT-inhibitor plus paclitaxel had a 63% relative risk reduction for death due to any cause compared to those in the placebo plus paclitaxel group (HR=0.37; 95% CI, 0.12-1.12; 2-sided P=0.07).

Safety

The drug combination was generally well-tolerated. The toxicity profile was comparable with those of other AKT inhibitors, with a higher percentage of adverse effects including diarrhoea (13% vs. 1%), infection (4% vs. 1%) and fatigue (4% vs. 0%) in patients receiving capivasertib with paclitaxel than placebo with paclitaxel.

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