Adding capivasertib to paclitaxel improved the progression-free survival (PFS) in patients with metastatic triple-negative breast cancer (TNBC) who had not received prior treatment for metastatic disease. Predominantly patients with PIK3CA/AKT1/PTEN-altered tumours had a more pronounced PFS and overall survival (OS) benefit, as reported by Schmid et al. in the Journal of Clinical Oncology¹Schmid P et al. J Clin Oncol. 2019; doi:10.1200/JCO.19.00368..

“The PAKT study is one of few trials to demonstrate PFS and OS benefits in metastatic TNBC,” first author Dr Schmid and his colleagues wrote in the Journal of Clinical Oncology¹Schmid P et al. J Clin Oncol. 2019; doi:10.1200/JCO.19.00368..

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 paclitaxel¹Schmid P et al. J Clin Oncol. 2019; doi:10.1200/JCO.19.00368.. 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.

Reference

1. Schmid P et al. J Clin Oncol. 2019; doi:10.1200/JCO.19.00368.