Abstract PD10-07: Efficacy of mutant-selective PI3Kα inhibitor RLY-2608 in combination with fulvestrant in patient (pt) subset populations, including pts with PIK3CA-mutant HR+/HER2- advanced breast cancer (BC) pre-treated with fulvestrant or other S

Abstract Background Oncogenic mutations in PIK3CA are present in approximately 40% of HR+/HER2- BC and define a validated target for therapeutic inhibition in this setting. Approved inhibitors yield modest efficacy in combination with endocrine therapy (ET) due to dose-limiting toxicities associated with non-selective PI3K inhibition. RLY-2608 is the first oral, pan-mutant-selective, allosteric α-selective PI3K inhibitor (PI3Kαi) designed to overcome these limitations. The FIH ReDiscover (NCT05216432) study investigated RLY-2608 + fulvestrant (F) in pts with PIK3CA-mutant, HR+/HER2- BC who had been previously treated with CDK4/6i and ET. Here, we report subgroup efficacy analyses according to baseline characteristics, including prior selective estrogen receptor degrader (SERD) treatment and ESR1 mutation status. Methods Previously treated adult pts with evaluable HR+/HER2- advanced BC and PIK3CA mutation per local assessment were eligible. Pts received the RP2D of RLY-2608 (600 mg BID fasted) + standard-dose F. Key objectives were investigator-assessed efficacy per RECIST v1.1 and adverse events (AEs) per CTCAE v5.0. Objective response rate (ORR) is defined as the rate of any confirmed complete or partial response (CR or PR). Progression-free survival (PFS) is defined as the time from date of first dose to the date of progression per RECIST v1.1 or death by any cause in the absence of progression. Tumor response in pts with measurable disease and PFS in pts with evaluable disease, without detectable PTEN/AKT co-alterations, were assessed according to baseline characteristics including prior treatment history (prior SERD vs no prior SERD) and presence of ESR1 mutation. PIK3CA and ESR1 ctDNA were assessed at baseline and at C2D1 of study treatment as a pharmacodynamic marker of biologic activity. Safety was assessed in all pts. Results As of 26MAR25, 64 pts with evaluable disease were treated with the RP2D of RLY-2608 + F. Efficacy was evaluated in the subgroup of 52 pts without detectable PTEN/AKT co-alterations, of whom 42% received ≥2 prior systemic therapies for advanced BC; 52% had received any prior SERD; 31% had detectable ESR1 mutation at baseline. 31/52 pts had measurable disease with 12/31 achieving an objective response (ORR 38.7%, 95% CI 21.8-57.8) and 25/31 (80.6%) experiencing any radiographic tumor reduction. Of 31 pts with measurable disease, 16 received prior SERD with 7/16 achieving a confirmed PR (ORR 43.8%, 95% CI 19.8-70.1). In the 10 pts with measurable disease who had detectable ESR1 mutation at baseline, 6 achieved a confirmed PR (ORR 60.0%, 95% CI 26.2-87.8). Across all 52 pts treated at the RP2D, mPFS was 10.3 mo (95% CI 7.2-18.4). In 27 pts who received prior SERD, the mPFS was 11.0 mo (5.6 NR), and in 16 pts with detectable ESR1 mutation at baseline the mPFS was 8.8 mo (95% CI 3.0-18.4). 97% of pts with paired results experienced decline or clearance of PIK3CA ctDNA across genotypes, and all of those with ESR1 mutation at baseline and paired results experienced ctDNA decline or clearance. Treatment-related AEs (TRAEs) were generally low-grade, manageable, and reversible. Hyperglycemia, when reported, was low grade with most pts not requiring medication management. Severe stomatitis and rash were absent or rare. There were no grade 4/5 TRAEs. Conclusion RLY-2608 + F demonstrates promising efficacy in pts with PIK3CA-mutated HR+/HER2- advanced BC who have progressed on CDK4/6i. These data also highlight the activity of RLY-2608 in pts with prior exposure and resistance to SERD where benefit from fulvestrant is not expected, and support the ongoing pivotal investigation of RLY-2608 + F. Citation Format: C. Saura, G. Curigliano, A. Italiano, E. Felip, A. Schram, P. Tolosa, A. Schott, B. Pistilli, A. Guerrero Zotano, S. Ehsani, K. Wisinski, R. Nanda, J. McGuinness, M. Wei, J. Liu, V. Debien, A. Marra, K. Jhaveri, S. Isakoff, S. Loi, L. Schwartzberg, K. Yeung, M. George, E. Hamilton, C. Perez, C. Ma, N. Unni, J. Rodon, A. Spira, E. Puente-Poushnejad, A. Wagner, L. Xu, D. Havkins, F. Ramirez, S. Landergan, G. Tan, A. Timm, E. Kwak, D. Bergstrom, S. Sammons, A. Varkaris. Efficacy of mutant-selective PI3Kα inhibitor RLY-2608 in combination with fulvestrant in patient (pt) subset populations, including pts with PIK3CA-mutant HR+/HER2- advanced breast cancer (BC) pre-treated with fulvestrant or other SERD [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 PD10-07.