Abstract PS5-07-27: INAVO123: Phase 3 study of first-line inavolisib / placebo + a cyclin-dependent kinase 4/6 inhibitor + letrozole in participants with <i>PIK3CA</i> -mutated, hormone receptor-positive, HER2-negative, endocrine-sensitive advanced breast cancer

Abstract BACKGROUND: Standard of care for PIK3CA-mutated (mut), hormone receptor-positive (HR+), HER2-negative (HER2-), endocrine-sensitive advanced breast cancer (aBC) is endocrine therapy + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), but progression is expected due to resistance. Inavolisib (INAVO) is a highly potent and selective PI3Kαi that also promotes degradation of mut p110α. INAVO120 (NCT04191499) showed that first-line (1L) treatment with INAVO + palbociclib (PALBO) + fulvestrant (FULV) resulted in a significantly improved progression-free survival (PFS) benefit vs placebo (PBO) + PALBO + FULV (stratified hazard ratio 0.43; 95% confidence interval 0.32-0.59; p &amp;lt; 0.0001) in patients with PIK3CAmut, HR+, HER2-, endocrine-resistant aBC, and is now approved by the Food and Drug Administration for use in such patients. TRIAL DESIGN: INAVO123 evaluates 1L INAVO + a CDK4 / 6i + letrozole (LET) vs PBO + a CDK4 / 6i + LET in participants (pts) with PIK3CAmut (determined by central circulating tumor DNA [ctDNA] or existing local tumor tissue / ctDNA testing), HR+, HER2-, endocrine-sensitive (as defined in the protocol) aBC. Pts will be randomized 1:1 to INAVO (9 mg oral daily [QD]) or PBO + a CDK4/6i (e.g. PALBO 125 mg oral QD 21 days on, 7 days off) + LET (2.5 mg oral QD) in 28-day cycles. Pts will receive treatment until disease progression, unacceptable toxicity, withdrawal of pt consent, death, or study termination. ELIGIBILITY: Pts must have measurable disease, fasting glucose &amp;lt; 126 mg/dL, and glycated hemoglobin &amp;lt; 6.5%. Pre- and perimenopausal women, and men, must receive luteinizing hormone-releasing hormone agonist. Pts with aBC who progressed while on / within 12 months of ending adjuvant therapy are ineligible. AIMS: Primary endpoint: PFS. Secondary endpoints: overall survival, confirmed overall response rate, duration of response, clinical benefit rate, patient-reported outcomes, and safety. STATISTICAL METHODS: PFS will be assessed via a stratified log-rank test with a two-sided significance level of 0.05 and Kaplan-Meier methods. Stratification factors: de novo HR+ aBC (yes vs no) and visceral metastases (yes vs no). An independent data monitoring committee will oversee safety and interim efficacy. ACCRUAL: Target randomization is 450 pts across &amp;gt; 200 centers, globally. Citation Format: R. Basho, K. Jhaveri, J. King, S. Kümmel, Y. Park, V. Krishnan, P. Gyamfi, X. Liu, V. Khor, A. Mani, J. Cortés. INAVO123: Phase 3 study of first-line inavolisib / placebo + a cyclin-dependent kinase 4/6 inhibitor + letrozole in participants with PIK3CA-mutated, hormone receptor-positive, HER2-negative, endocrine-sensitive advanced breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-27.