Background: PI3K pathway activation is a hallmark of hormone receptor-positive (HR+) BC cells resistant to endocrine therapy (ET). Preclinical and early clinical data suggest that combining the pan-PI3K inhibitor BUP (BKM120) with ET may provide clinical benefits in this setting. BELLE-2 (NCT01610284) is the first randomized Phase III trial to assess the efficacy and safety of a PI3K inhibitor combined with FULV in HR+ advanced BC, including a prospective analysis of whether PI3K pathway activation status measured in archival tumor tissue and ctDNA is predictive of clinical benefit. Methods: Postmenopausal women with HR+/HER2– locally advanced or metastatic BC refractory to aromatase inhibitor therapy were enrolled. After a 14-day run-in with FULV (500 mg), patients (pts) were randomized (1:1) to receive oral BUP (100 mg/day) or placebo (PBO) with FULV (500 mg per standard of care). Randomization of all pts was stratified by PI3K pathway status measured in archival tumor tissue (PIK3CA mutation or PTEN loss; activated, non-activated, unknown) and visceral disease status (present, absent). Baseline PIK3CA mutation status in ctDNA was assessed in a subset of 587 pts at trial entry. The primary endpoint was locally-assessed progression-free survival (PFS; RECIST v1.1) in the full population and PI3K pathway-activated group. Secondary endpoints included overall survival, safety, overall response rate (ORR), and clinical benefit rate (CBR). Results: 1147 pts received FULV with BUP or PBO, with 187 (16%) ongoing at data cut-off. Baseline characteristics were well balanced between the two arms: median age was 62 years, 98% had ECOG performance status of 0/1, 61% had visceral disease, 69% were sensitive to prior ET, 28% had received prior chemotherapy for metastatic BC. BELLE-2 met its primary endpoint in the full population (Table). In pts with PI3K pathway-activated tumor tissue, PFS increase for BUP+FULV vs PBO+FULV did not meet the planned endpoint. Among pts with PIK3CA status measured in ctDNA, median PFS, ORR, and CBR were significantly improved for BUP+FULV vs PBO+FULV in pts with PIK3CA-mutant tumors but not pts without.  Median PFS, monthsHR95% CI; P valueORRCBR BUP+FULVPBO+FULV    Full population N=11476.95.00.780.67–0.89;P<0.00112 vs 8%44 vs 42%PIK3CA- mutant ctDNA n=2007.03.20.560.39–0.80; P<0.00118 vs 4%47 vs 32%PIK3CA non-mutant ctDNA n=3876.86.81.050.82–1.34;P=0.64212 vs 11%43 vs 50%PI3K pathway- activated tumor tissue n=3726.84.00.760.60–0.97;P=0.01411 vs 8%40 vs 41% The most common Grade 3/4 adverse events (AEs; ≥5% of pts; BUP+FULV vs PBO+FULV) in all pts were increased alanine aminotransferase (26 vs 1%), increased aspartate aminotransferase (18 vs 3%), hyperglycemia (15 vs 0.2%), and rash (8 vs 0%). The most common reasons for treatment discontinuation were disease progression (54 vs 73%) and AEs (13 vs 2%). Conclusions: BELLE-2 met its primary endpoint in the full population. Prespecified analyses showed that characterizing PIK3CA mutation in ctDNA at trial entry identifies pts with endocrine- resistant HR+/HER2–advanced BC, for whom BUP+FULV results in meaningful clinical benefits. Citation Format: Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng L-M, Hurvitz S, Masuda N, Cortés J, De Laurentiis M, Arteaga CL, Jiang Z, Jonat W, Hachemi S, Le Mouhaër S, Di Tomaso E, Urban P, Massacesi C, Campone M. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-01.