Tersolisib (LY4064809/STX-478) mutant-selective PI3Kα inhibitor shows 19–35% ORR with low hyperglycemia in PIK3CA-mutant HR+/HER2- ABC

Tersolisib is an oral, allosteric, CNS-penetrant, pan-mutant-selective PI3Kα inhibitor designed to spare wild-type PI3Kα and potentially reduce PI3K-inhibitor class toxicities; in the PIKALO-1 Phase 1/2 trial (NCT05768139), it was tested as monotherapy (≥1 prior therapy), with fulvestrant (1–2 prior therapies), or with fulvestrant + a CDK4/6 inhibitor (≤2 prior therapies) in PIK3CA-mutant HR+/HER2- advanced breast cancer (193 treated; median 2 prior therapies; 81% prior CDK4/6i; 47% prior SERD; 54% prediabetes/diabetes allowed if HbA1c<8%/FBG<140). In efficacy-evaluable patients, ORR was 19% (9/48) with tersolisib, 35% (11/31) with tersolisib+fulvestrant, and 27% (13/48) with tersolisib+fulvestrant+CDK4/6i, with DCR 67%, 87%, and 79%, respectively (including unconfirmed PRs); this looks directionally in the range of what’s achievable with biomarker-selected endocrine-targeted standards like capivasertib+fulvestrant (mPFS 7.3 vs 3.1 months in CAPItello-291; HR 0.50) and alpelisib+fulvestrant (SOLAR-1 mPFS 11.0 vs 5.7 months; HR 0.65), but cross-trial comparison is limited here by immature time-to-event outcomes. Safety: hyperglycemia was 16%/0% (any grade/G≥3) without baseline prediabetes/diabetes vs 37%/1% with prediabetes/diabetes; common TEAEs included neutropenia 39%/27%, fatigue 35%/4%, diarrhea 34%/<1%, nausea 31%/1%, with relatively low rash 4%/0% and stomatitis 12%/<1%; tersolisib dose reduction/discontinuation occurred in 11%/<1%, and ctDNA PIK3CA mutant fraction decreased across doses, supporting target engagement; a Phase 3 first-line study (PIKALO-2; NCT07174336) is planned/ongoing.