Abstract PS5-08-25: ReDiscover-2, a phase 3 study of RLY-2608 + fulvestrant versus capivasertib + fulvestrant as treatment for locally advanced or metastatic PIK3CA-mutant HR+/ HER2- breast cancer following recurrence or progression on or after treatment with a CDK4/6 inhibitor (trial in progress)

Abstract Background: PIK3CA mutations constitutively activate PI3Kα and drive approximately 40% of HR+/HER2- breast cancer (BC). While the PI3K inhibitors alpelisib and inavolisib and the AKT inhibitor capivasertib have been approved by the FDA to treat this substantial patient population, these therapies cause significant toxicity, notably hyperglycemia, rash, and diarrhea, due to their non-selective targeting of the pathway. RLY-2608 was developed as a pan-mutant-selective allosteric PI3Kα inhibitor designed to optimize dose intensity and target inhibition with reduced toxicity and improved tolerability. The first-in-human ReDiscover study of RLY-2608 demonstrated encouraging antitumor activity with a median progression-free survival of 10.3 mo (95% CI: 7.2, 18.4) across a range of PIK3CA genotypes and a favorable safety profile when given in combination with fulvestrant in patients with PIK3CA-mutated HR+/HER2- advanced BC previously treated with a CDK4/6 inhibitor (Sammons, ASCO 2025). Based on these findings, RLY-2608 in combination with fulvestrant is being studied in this phase 3 study, ReDiscover-2 (NCT06982521), in patients with PIK3CA-mutated HR+/HER2- advanced BC following recurrence or progression on or after a CDK4/6 inhibitor. Methods: ReDiscover-2 is a global, multicenter, open-label, randomized phase 3 study comparing the efficacy and safety of RLY-2608 + fulvestrant to capivasertib + fulvestrant in adult patients with HR+/HER2- locally advanced or metastatic BC with PIK3CA mutation. Approximately 540 patients will be enrolled and randomized 1:1 to receive RLY-2608 (400 mg BID with food) + standard-dose fulvestrant or capivasertib (400 mg BID, 4 days on and 3 days off, with or without food) + standard-dose fulvestrant. Randomization will be stratified by PIK3CA mutation type (kinase vs non-kinase), visceral disease (yes vs no), and geographic region (Region 1 US, Canada, Western Europe, and Australia vs Region 2 Latin America and Eastern Europe vs Region 3 Asia). The primary endpoint is PFS assessed by blinded independent central review in patients having tumors with PIK3CA kinase domain mutations and in all patients. Overall survival is a key secondary endpoint within the same populations. Key eligibility criteria: ReDiscover-2 (NCT06982521) is open for enrollment. For further information, contact: clinicaltrials@relaytx.com. Citation Format: H. S. Rugo, C. Saura, K. Jhaveri, C. Barrios, S. Loi, F. Marmé, F. Bidard, Y. Park, P. Schmid, S. Sammons, G. Curigliano. ReDiscover-2, a phase 3 study of RLY-2608 + fulvestrant versus capivasertib + fulvestrant as treatment for locally advanced or metastatic PIK3CA-mutant HR+/ HER2- breast cancer following recurrence or progression on or after treatment with a CDK4/6 inhibitor (trial in progress) 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 PS5-08-25.