Capivasertib Plus Paclitaxel Superior to Paclitaxel Alone for Metastatic TNBC

According to findings from a phase 2 randomized trial, Capivasertib in combination with paclitaxel improved progression-free survival (PFS) and overall survival in patients with metastatic triple-negative breast cancer (TNBC), especially amongst those with PIK3CA/AKT1/PTEN-altered tumors (J Clin Oncol. 2020;38[5]:423-433).

The purpose of the PAKT trial by Peter Schmid, MD, PhD, Barts Cancer Institute, Queen Mary University of London, United Kingdom, and co-investigators was to evaluate the safety and efficacy of adding capivasertib to paclitaxel as first-line therapy for TNBC.

“The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). The AKT inhibitor capivasertib has shown preclinical activity in TNBC models, and drug sensitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN,” wrote Schmid et al.

The double-blind, placebo-controlled recruited a total of 140 women with untreated metastatic TNBC. Patients were randomly assigned (1:1) paclitaxel 90 mg/m2 (days 1, 8, 15) and either 400 mg of capivasertib (daily) or a placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. 

PFS was the primary end point, while secondary end points included overall survival, tumor response, safety, and the PFS and OS in the subgroup with PIK3CA/AKT1/PTEN alterations.

Researchers found the median PFS in the capivasertib group and placebo group to be 5.9 and 4.2 months, respectively (hazard ratio [HR], 0.74; 95% CI, 0.50 to 1.08; 1-sided P = .06 [predefined significance level, 1-sided P = .10]). The median OS for the capivasertib group was 19.1 months and 12.6 months for the placebo group (HR, 0.61; 95% CI, 0.37-0.99; 2-sided P = .04). 

Furthermore, patients with PIK3CA/AKT1/PTEN-altered tumors (n = 28) had a median PFS of 9.3 months capivasertib and 3.7 months with the placebo (HR, 0.30; 95% CI, 0.11-0.79; 2-sided P = .01).

Adverse events grade ≥3 in those treated with capivasertib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13% vs 1%), infection (4% vs 1%), neutropenia (3% vs 3%), rash (4% vs 0%), and fatigue (4% vs 0%).

“Addition of the AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. Benefits were more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors,” wrote Schmid and colleagues.

“Capivasertib warrants further investigation for treatment of TNBC,” they concluded.—Alexandra Graziano