Background: Standard-of-care (SoC) endocrine therapy (ET) for pts with HR+, HER2– LA/mBC was transformed by combinations with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is); a CDK4/6i-based combination is approved in high-risk early BC. However, in most pts, mechanisms of resistance that emerge during or after treatment with a CDK4/6i and ET combination lead to relapse/disease progression. Dysregulating mutations in PIK3CA, occurring in ~40% of HR+, HER2– BCs, represent a common mechanism of resistance to CDK4/6is and ET combinations. ALP (a selective PI3Kα inhibitor; PI3Kαi) + FUL is approved for pts with HR+, HER2–, PIK3CAmut LA/mBC, but its widespread implementation in clinical practice has been challenging. As such, there is a significant need to develop PI3Kαis with a better therapeutic index. INAVO is a highly potent and selective PI3Kαi that also facilitates the degradation of mutated PI3Kα isoform. INAVO has demonstrated manageable safety/tolerability, alone and in combination with SoC treatments in HR+, HER2–, PIK3CAmut LA/mBC. Moreover, an ongoing Phase I trial showed that INAVO + FUL elicited encouraging preliminary antitumor activity in heavily pretreated pts, including a CDK4/6i-based regimen. Methods: INAVO121 (NCT05646862) is a Phase III, randomized, open-label study evaluating INAVO + FUL vs. ALP + FUL in pts with HR+, HER2–, PIK3CAmut LA/mBC (confirmed by circulating-tumor DNA or tumor tissue), who progressed during or after a CDK4/6i-based regimen with adequate hematologic and organ function. Up to two prior lines of systemic therapy in LA/mBC, including one line of chemotherapy are allowed. Pts are randomized 1:1 to receive INAVO (9 mg oral daily; PO QD) + FUL (500 mg intramuscularly on Days [D] 1 and 15 of Cycle [C] 1, then D1 of subsequent cycles), or ALP (300 mg PO QD) + FUL. Randomization is stratified by visceral disease (yes vs. no) and prior CDK4/6i therapy (adjuvant vs. metastatic setting). Pts will receive treatment until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints include overall survival, BICR-objective response rate, BICR-best overall response, BICR-duration of response, BICR-clinical benefit rate, safety, tolerability, pt-reported outcomes, and pharmacokinetics. The study is open for enrollment, targeting 400 pts at ~200 sites globally. A stratified log-rank test at an overall 0.05 significance level (two-sided) will be used for the primary endpoint analysis. Median PFS will be estimated using Kaplan–Meier methodology. An independent data monitoring committee will be in place for safety and efficacy. Clinical trial information: NCT05646862.