There is limited knowledge on the benefit of the α-subunit specific PI3K inhibitor alpelisib in later lines of therapy for advanced ER+HER2- and triple negative breast cancer (TNBC). We conducted a phase 2 multi-cohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2- and TNBC. In the intention to treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. Decline in PI3K pathway mutant ctDNA levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit and improved progression free-survival (HR 0.24 95% CI 0.083 - 0.67, P = 0.0065). Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression free survival (HR 0.22 95% CI 0.078 - 0.60, P = 0.003).