Background: Previous results from the Phase 2 FAKTION trial (NCT01992952) showed progression free survival (PFS) in patients with aromatase inhibitor (AI) resistant ER+/HER2− advanced breast cancer was significantly longer with fulvestrant plus capivasertib vs fulvestrant plus placebo. At the time of analysis, PFS benefit associated with capivasertib was not restricted to patients with activating mutations in PIK3CA (E542K, E545K, H1047R or H1047L) or PTEN protein null. We report now mature overall survival (OS) data with enhanced biomarker analysis. Methods: For the enhanced analysis, available tissue and plasma samples were sent for targeted next generation sequencing (NGS) with Foundation One CDx and GuardantOMNI assays. ‘Pathway altered’ (PA) was defined as any activating mutation in PIK3CA (exons 1,4,7,9,20) or AKT1 (E17K only) or inactivating alterations in PTEN. For samples not tested by targeted NGS, previously reported digital droplet PCR (ddPCR) results for PIK3CA were used, in addition to tissue AKT1 ddPCR analysis performed after the initial publication. Concordance between mutations identified by ddPCR and subsequent NGS was 97%. Results: In January 2022, 108 OS events were reported (77% maturity) in the intention to treat (ITT) population. The median OS was 29.3 vs 23.4 months (mo) in the capivasertib (n = 69) vs placebo (n = 71) arms respectively (HR 0.66, 95% CI 0.45–0.97; p = 0.035). In the enhanced biomarker analysis, 76 participants were classified as PA compared to 59 in the original analysis. In the PA group, OS was 39.0 vs 20.0 mo in the capivasertib vs placebo arms respectively (HR 0.46, 95% CI: 0.27–0.79; p = 0.005). Within the pathway non-altered (PNA) group, median OS was 26.0 vs 25.2 mo in the capivasertib vs placebo arms respectively (HR 0.86, 95% CI: 0.49–1.52; p = 0.60). In the updated PFS analysis, the advantage in the ITT population persisted with capivasertib vs placebo (median 10.3 vs 4.8 mo, HR 0.56, 95% CI: 0.38–0.81; p = 0.002). PFS analysis against the updated biomarker subgroups shows a significant improvement in PFS in the PA group: 12.8 vs 4.6 mo in the capivasertib vs placebo arms respectively (HR 0.44, 95% CI: 0.26–0.72; p = 0.001). In the PNA group, median PFS was 7.7 vs 4.9 mo in the capivasertib vs placebo arms respectively (HR 0.70, 95% CI: 0.40–1.25; p = 0.23). Conclusions: Updated analysis of the FAKTION trial data show a significant improvement in OS in the ITT population. Enhanced subgroup analysis suggests that the benefit of capivasertib in both PFS and OS may be predominantly in patients with PIK3CA/AKT1/PTEN pathway altered tumours, but further elucidation will be forthcoming from the ongoing Phase 3 CAPItello-291 study in which participants with PA and PNA tumours have been recruited. Clinical trial information: NCT01992952.