Phase 2 inavolisib PI3Kα inhibitor + ribociclib CDK4/6 inhibitor + fulvestrant ER degrader in HR+ ABC

This Phase 2 multicenter, randomized, double-blind, placebo-controlled Roche/Genentech study tests whether adding inavolisib (a PI3Kα inhibitor) to ribociclib (a CDK4/6 inhibitor marketed by Novartis as Kisqali) plus fulvestrant (an estrogen receptor degrader marketed as Faslodex by AstraZeneca) improves outcomes versus placebo + ribociclib + fulvestrant in first-line endocrine-resistant HR-positive, HER2-negative unresectable locally advanced/metastatic breast cancer. Eligibility is biomarker-defined: tumors must be PIK3CA wild-type (no PIK3CA mutation) and have chromosome 8p heterozygous loss, a subgroup the sponsor is targeting to see if PI3K-pathway suppression still adds benefit even without the canonical PIK3CA driver. The core scientific angle is extending PI3K-combination benefit beyond PIK3CA-mutant disease into an alternative genomic context (8p loss) that may reflect pathway dependence and poor prognosis biology. Today’s care for endocrine-resistant HR+/HER2− metastatic disease commonly starts with endocrine therapy plus a CDK4/6 inhibitor when feasible, with a switch to fulvestrant-based regimens (and later-line targeted agents or chemotherapy) as resistance emerges; this trial evaluates an upfront triplet strategy to deepen and prolong disease control.