Background: Endocrine therapy with a CDK4/6 inhibitor (CDKi) is standard of care (SOC) for patients (pts) with estrogen-receptor-positive (ER+) metastatic breast cancer (mBC). Resistance to therapy may arise from mutations in ESR1, PIK3CA, and activation of receptor tyrosine kinase signaling pathways. In this study, gedatolisib (G), a PI3KCA/mTOR inhibitor, was added to a CDKi (palbociclib, P) + letrozole (L) or fulvestrant (F) for treatment of pts with ER+/HER2- mBC. Methods: This phase 1b study (NCT02684032) comprises a dose escalation phase evaluating the dose-limiting toxicity and maximum tolerated dose of G+P+L/F and a dose expansion phase assessing the objective response rate of G+P+L/F, compared with historical data for P+L or P+F. Response was assessed using RECIST v1.1. Genomic and transcriptomic analyses were performed on archival pt tumor biopsies. Longitudinal plasma ctDNA analysis was performed on samples taken at baseline, on-treatment, and end-of-treatment. Unsupervised data analysis was conducted. Results: Genomic information was available for 25 of 35 pts with measurable disease (G+P+L: 11; G+P+F: 14). No relationship was observed between responses (1 complete response [CR] and 11 partial responses [PR]) and baseline PIK3CA pathway alterations. Pt tumor tissue analysis (n = 25) confirmed pts with FGF3/4/19 amplification (n = 4) had larger changes in tumor size in response to G+P+L/F (p = 0.029). Of the 6 pts with an ESR1 mutation, 1 pt with an ESR1 Y537S mutation exhibited a partial response (PR) to G+P+L. Longitudinal plasma ctDNA analysis (73-gene panel) revealed that decreases in PIK3CA and PTEN were most associated with clinical response. Plasma sample analysis (n = 21) showed that pts with somatic alterations in EGFR (n = 4) had a greater response to therapy (p = 0.066), compared with pts without somatic EGFR alterations. Transcriptomic profiling also revealed responsive patients had higher levels of EGFR expression. Pts exhibiting CR/PR had a lower somatic tumor mutation burden at Cycle 5 Day 1 compared with baseline (p = 0.0013). Conclusions: The addition of G to SOC endocrine + CDKi therapy may help overcome resistance due to activation of FGFR or EGFR signaling pathways and the ESR1 Y537S mutation. Somatic frequency changes of PI3K pathway alterations were most correlated with clinical response. Genomic data analysis from dose expansion samples is currently ongoing. Clinical trial information: NCT02684032.