The majority of women with hormone receptor (HR)+, HER2– breast cancer respond to endocrine therapy, although acquired resistance is common. Now, data from a phase III trial demonstrate the efficacy of the potent α-isoform-specific phosphatidylinositol 3-kinase-α (PI3Kα) inhibitor alpelisib.

In this international, multicentre trial, a cohort of 572 patients with locally confirmed HR+, HER2– advanced-stage breast cancer, of whom 341 had confirmed PIK3CA alterations, were randomized (1:1) to receive alpelisib plus fulvestrant or placebo plus fulvestrant. Progression-free survival (PFS) specifically in patients with PIK3CA-mutant disease was the primary end point.

After a median follow-up duration of 20 months, patients in the alpelisib group with PIK3CA-mutant disease had a median PFS of 11.0 months versus 5.7 months in the placebo group (hazard ratio for disease progression or death 0.65, 95% CI 0.50–0.85; P < 0.001). This difference was not observed in comparisons of the outcomes of patients with PIK3CA-wild-type disease (median PFS 7.4 versus 5.6 months respectively, hazard ratio 0.85, 95% CI 0.58–1.25).

Grade 3 or 4 adverse events were observed in 64.4% and 11.6% of patients in the alpelisib group, versus 30.3% and 5.2% among those receiving placebo, resulting in treatment discontinuations in 25% versus 4.2% of patients, respectively. Among these events, grade 3 hyperglycaemia (including diabetes mellitus, insulin resistance and metabolic syndrome) was observed in 32.7% of patients receiving alpelisib.

These findings confirm the feasibility and efficacy of targeting PI3Kα using alpelisib in the approximately 40% of patients with PIK3CA-mutant advanced-stage HR+, HER2– breast cancer and confirm the role of PIK3CA mutations as a biomarker. The high risk of hyperglycaemia-related adverse events, which the investigators considered to be an on-target effect, indicates the need for close on-treatment monitoring.