Background
Oncogenic PIK3CA mutations constitutively activate PI3Kα and drive approximately 40% of hormone receptor–positive (HR+)/HER2-negative (HER2–) breast cancer; however, the toxicity (hyperglycemia, rash, diarrhea, stomatitis) of non-selective inhibitors limits their tolerability and efficacy. Zovegalisib is the first oral, pan-mutant-selective, allosteric PI3Kα inhibitor designed to overcome these limitations. We report efficacy and safety of zovegalisib plus standard-dose fulvestrant in patients with PIK3CA-mutant, HR+/HER2– breast cancer treated in the first-in-human study, ReDiscover (NCT05216432).
Methods
Previously treated adult patients with advanced HR+/HER2– breast cancer and PIK3CA mutation per local assessment were eligible. Patients were eligible to enroll with measurable or non-measurable disease. Key objectives were investigator-assessed efficacy per RECIST 1.1 and adverse events (AEs) per CTCAE v5.0.
Results
As of March 26, 2025, safety was assessed in 118 patients treated across zovegalisib doses 100 to 1000 mg twice a day (BID), and efficacy in the 52 patients without detectable PTEN/AKT co-alterations treated at the recommended phase 2 dose (RP2D; 600 mg BID). All patients received prior endocrine therapy and CDK4/6 inhibitor with 50% having 2 or more prior systemic therapies for advanced disease, including 55% with prior fulvestrant or SERD and 28% with prior chemotherapy or antibody-drug conjugate. Median follow-up was approximately 12.0 months. At MBCC 2026 (ASCO 2025 encore), Sammons S et al presented updated results from ReDiscover. The RP2D provided exposure in the target therapeutic range and rapid clearance of mutant PIK3CA ctDNA. Overall, 31 of 52 patients had measurable disease with 26/31 (83.9%) achieving disease control, 25 of 31 (80.6%) experiencing radiographic tumor reduction, and 12 of 31 achieving an objective response (38.7%; 95% CI, 21.8-57.8) with median time-to-response of 8 weeks. Median progression-free survival was 10.3 months (95% CI, 7.2-18.4) across all 52 RP2D patients, and 11.0 months (95% CI, 7.3-22.0) in 30 patients receiving zovegalisib at the RP2D as second-line treatment. Treatment-related AEs (TRAEs) at the RP2D were generally low-grade, manageable, and reversible. The most common TRAEs were hyperglycemia (51.6% any grade; 3.1%, grade 3), nausea (50.0%; 1.6%, grade 3), fatigue (42.2%; 9.4%, grade 3), creatinine increased (39.1%; 3.1%, grade 3), and diarrhea (39.1%; 3.1%, grade 3). There was no grade 4/5 TRAEs; and severe, off-target stomatitis and rash were absent or rare.
Conclusion
Zovegalisib demonstrates favorable safety/tolerability along with highly encouraging progression-free survival observed across PIK3CA genotypes in patients with PIK3CA-mutant HR+/HER2– advanced breast cancer previously exposed to CDK4/6 inhibitors. These data validate zovegalisib as the first allosteric pan-mutant selective PI3Kα inhibitor and support advancing zovegalisib plus fulvestrant to pivotal testing. The ReDiscover-2 trial (NCT06982521) is currently enrolling worldwide.
