Combination treatment with capivasertib and paclitaxel falls short of prolonging overall survival (OS) compared with placebo plus paclitaxel in patients with metastatic triple-negative breast cancer (TNBC), either in the overall or PIK3CA/AKT1/PTEN-altered populations, as shown in the CAPItello-290 trial.
However, progression-free survival (PFS) is numerically higher in the combination therapy, especially among patients with PIK3CA/AKT1/PTEN-altered tumours. In addition, “the safety of capivasertib‒paclitaxel was generally manageable and consistent with prior studies,” according to the researchers.
A total of 812 patients with previously untreated metastatic TNCB were randomly allocated 1:1 to receive either paclitaxel 80 mg/m2 (day 1, weeks 1‒3; 4-week cycle) plus capivasertib 400 mg or placebo twice daily (days 2‒5, weeks 1‒3). Retrospective central molecular testing was used to analyse PIK3CA/AKT1/PTEN tumour alterations.
Survival
Of the patients, 30.7 percent had PIK3CA/AKT1/PTEN-altered tumours. In the overall population, the median OS at the final analysis was 17.7 months with capivasertib plus paclitaxel and 18.0 months with placebo plus paclitaxel (hazard ratio [HR], 0.92, 95 percent confidence interval [CI], 0.78‒1.08; p=0.3239). [Ann Oncol 2026;37:650-662]
In patients with PIK3CA/AKT1/PTEN-altered tumours, the median OS was 20.4 months in both arms (HR, 1.05, 95 percent CI, 0.77‒1.43; p=0.7602).
The median PFS in the overall population did not significantly differ between the treatment arms but numerically favoured the capivasertib‒paclitaxel combination (5.6 vs 5.1 months; HR, 0.72, 95 percent CI, 0.61‒0.84). This finding also extended to those with PIK3CA/AKT1/PTEN alterations (7.5 vs 5.6 months; HR, 0.70, 95 percent CI, 0.52‒0.95).
“The reason for the numerical improvement in PFS failing to translate into improved OS is unclear,” the researchers said. “The study enrolled a population that reflected the target population for patients with inoperable, locally advanced or metastatic TNBC in the first-line setting.”
In addition, no major imbalances were seen in baseline characteristics, treatment exposure, or subsequent therapies between arms.
“It is, however, notable that the median OS in the control arm in both the overall (18.0 months) and PIK3CA/AKT1/PTEN-altered populations (20.4 months) was longer than in the phase II PAKT study (13.5 months and 11.0 months, respectively),” according to the researchers. [J Clin Oncol 2020;38:423-433; J Clin Oncol 2020;38:423-433]
Safety profile
With regard to safety, diarrhoea was the most common adverse event (AE) of grade ≥3 severity (12.7 percent vs 0.7 percent) in the overall population. Treatment discontinuation due to AEs occurred in 8.5 percent of patients in the combination arm and 4.9 percent in the placebo arm. Unfortunately, 4.2 percent of all patients died due to AEs.
“The safety profile of capivasertib–paclitaxel was broadly consistent with the known AE profiles of the individual agents, with no new signals identified,” the researchers said. “Many of the most frequent AEs were grade 1/2, and there was a low rate of AEs leading to discontinuation of capivasertib, suggesting that the tolerability profile was manageable.”
Capivasertib, an oral, potent, and selective inhibitor of all three Akt serine/threonine kinase isoforms, have been shown in a previous study to reduce cell proliferation and promote cell death in TNBC cells with or without PIK3CA/AKT1/PTEN alterations when combined with paclitaxel. [Mol Cancer Ther 2012;11:873-887; Ann Oncol 2024;35(suppl 2):S371]