ReDiscover-2, a phase 3 study of zovegalisib (zovega, RLY-2608) + fulvestrant (fulv) versus capivasertib (capi) + fulv 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.

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TPS1148 Background: PIK3CA mutations constitutively activate PI3Kα and drive ~40% of HR+/HER2- breast cancer (BC). The PI3K inhibitors alpelisib and inavolisib and the AKT inhibitor capi are approved therapeutic options; however, they are limited by significant toxicity, notably hyperglycemia, rash, and diarrhea, due to non-selective targeting of the pathway. Zovega is 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 zovega demonstrated encouraging antitumor activity with a median progression-free survival (PFS) of 10.3 mo (95% CI: 7.2, 18.4) across a range of PIK3CA genotypes and a favorable safety profile when combined with fulv in patients with PIK3CA -mutated HR+/HER2- advanced BC previously treated with a CDK4/6 inhibitor. Based on these findings, zovega in combination with fulv is being studied in this phase 3 study, ReDiscover-2 (NCT06982521), in 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 zovega + fulv to capi + fulv in patients with PIK3CA -mutated HR+/HER2- advanced BC. Approximately 540 patients will be randomized 1:1 to receive zovega (400 mg BID with food) + standard-dose fulv or capi (400 mg BID, 4 days on and 3 days off, with or without food) + fulv. Randomization will be stratified by PIK3CA mutation type, visceral disease, and geographic region. 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: ≥18 years of age with ECOG performance status of 0-1; confirmed diagnosis of HR+/HER2- locally advanced or metastatic BC with radiological or objective evidence of recurrence or progression; presence of one or more oncogenic PIK3CA mutations without evidence of AKT or PTEN alterations; measurable disease per RECIST v1.1 or evaluable bone-only disease; previous treatment for HR+/HER2- advanced BC with at least 1 and no more than 2 lines of endocrine therapy (ET) (prior fulv is allowed) or 1 prior line of CDK4/6 inhibitor therapy; HbA1c <7.0% (<53 mmol/mol) and fasting plasma glucose <140 mg/dL (Type 1 diabetes or Type 2 diabetes requiring antihyperglycemic medication are excluded); no prior PI3K, AKT, or mTOR inhibitors. ReDiscover-2 (NCT06982521) is open for enrollment. For information: clinicaltrials@relaytx.com. Clinical trial information: NCT06982521 .

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