Alpelisib is a selective inhibitor of phosphoinositide 3-kinase (PI3K)α, shown to improve outcomes for PIK3CA-mutant, hormone receptor–positive metastatic breast cancers when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA (ctDNA) among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (NCT01870505). The trial’s primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function PTEN mutations in 25% of patients with resistance. ESR1 activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.