In this PACUPod episode, hosts Britany and Seth dissect the INAVO120 phase III trial evaluating inavolisib, a PI3K-alpha inhibitor, combined with palbociclib and fulvestrant in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer. They discuss the clinical context, trial design (randomized, double-blind, placebo-controlled), patient population, endpoints (overall survival as primary, with progression-free survival and objective response rate as secondary), key results (approximate hazard ratio of 0.75 indicating a 25% reduction in risk of death), and safety considerations with a focus on hyperglycemia and metabolic monitoring. The episode covers management strategies for toxicities, drug interactions via CYP pathways, comparisons to prior PI3K inhibitors such as alpelisib (SOLAR-1), real-world applicability, sequencing considerations, and future directions for precision oncology. Practical takeaways for clinicians include molecular profiling importance, multidisciplinary management, and how this trial informs treatment paradigms for patients with endocrine-resistant, PIK3CA-mutated breast cancer.