Impact of Time of Administration, Fasting, and a Low-Carbohydrate Diet on Alpelisib-Associated Hyperglycemia and Efficacy: A Pilot Randomized Controlled Phase IIb Trial.

Background: Alpelisib plus fulvestrant improves outcomes in PIK3CA-mutated, hormone receptor-positive, HER2-negative metastatic breast cancer. However, on-target hyperglycemia often leads to dose modification or discontinuation. We aimed primarily to determine whether evening alpelisib after a ≥5 h fast with low-carbohydrate guidance reduces severe hyperglycemia versus standard morning dosing, and secondarily, to assess time to first grade 3-4 hyperglycemia, efficacy, and quality of life (QoL). Methods: ITACA was an open-label, randomized, phase IIb trial in three Croatian centers. Patients progressing on endocrine therapy were randomized 1:1 to evening alpelisib 300 mg after a ≥5 h fast with low-carbohydrate guidance or standard morning alpelisib, both with fulvestrant. The primary endpoint was the exposure-adjusted incidence rate (EAIR) of first grade 3-4 hyperglycemia within 90 days or 30 days post-discontinuation. Secondary endpoints were time to first grade 3-4 hyperglycemia, efficacy, and QoL. Results: Forty-two patients were randomized (21 per arm). Median age was 60 vs. 63 years in the evening vs. morning arms. In the safety set, EAIR of first grade 3-4 hyperglycemia was 378 vs. 742 per 100 person-years (11/21 vs. 14/20 patients with ≥1 event, unadjusted IRR 0.51, 95% CI 0.23-1.12). Adjusted Poisson models favored evening dosing. Analyses suggested delayed onset (median 73 vs. 9.5 days), with no detriment in efficacy or QoL. Conclusions: Evening alpelisib preceded by fasting and low-carbohydrate guidance may improve metabolic tolerability without compromising efficacy or QoL. These findings support evaluation in a larger trial incorporating prospective metabolic adherence and pharmacokinetic assessments.