Approximately 40% of hormone receptor-positive (HR+), HER2-negative (HER2–) breast cancers harbour activating mutations in PIK3CA (encoding the catalytic subunit of PI3Kα); these mutations are generally associated with a poor prognosis but also responsiveness to inhibitors of the PI3K–AKT pathway. Now, data from the phase III INAVO120 trial demonstrate that addition of the selective PI3Kα inhibitor and degrader inavolisib to standard-of-care first-line endocrine plus CDK4/6 inhibitor therapy for advanced-stage disease is feasible and increases efficacy.

In INAVO120, 325 patients with metastatic recurrence of PIK3CA-mutant HR+, HER2– breast cancer during, or within 12 months of completing, adjuvant endocrine-based therapy were randomly assigned (1:1) to receive palbociclib and fulvestrant plus either inavolisib or placebo. The requirement for early disease relapse enriched for patients with a poor prognosis: 83% had received chemotherapy, 80% had visceral metastases, 52% had liver metastases and 51% had ≥3 metastases. Notably, however, only 1% of patients had received a CDK4/6 inhibitor as part of adjuvant therapy. Progression-free survival (PFS) was the primary end point.