TIP125 ReDiscover-2, a Phase 3 Study of Zovegalisib (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)

Background

PIK3CA mutations constitutively activate PI3Kα and drive approximately40% of hormone receptor–positive (HR+)/HER2-negative (HER2–) breast cancer. The PI3K inhibitors (i) alpelisib and inavolisib and the AKTi capivasertib are approved therapeutic options; however, they are limited by significant toxicity, notably hyperglycemia, rash, and diarrhea, due to non-selective targeting of the pathway. Zovegalisib (RLY-2608) 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 zovegalisib demonstrated encouraging antitumor activity with a median progression-free survival (PFS) of 10.3 months (95% CI, 7.2-18.4) across a range of PIK3CA genotypes and a favorable safety profile when combined with fulvestrant in patients with PIK3CA-mutated HR+/HER2– advanced breast cancer previously treated with a CDK4/6 inhibitor. Based on these findings, zovegalisib in combination with fulvestrant is being studied in this phase 3 study, ReDiscover-2 (NCT06982521), in PIK3CA-mutated HR+/HER2– advanced breast cancer following recurrence or progression on or after a CDK4/6i.

Methods

ReDiscover-2 is a global, multicenter, open-label, randomized phase 3 study comparing the efficacy and safety of zovegalisib plus fulvestrant to capivasertib plus fulvestrant in patients with PIK3CA-mutated HR+/HER2– advanced breast cancer. Approximately 540 patients will be randomly assigned 1:1 to receive zovegalisib (400 mg BID with food) plus standard-dose fulvestrant or capivasertib (400 mg BID, 4 days on and 3 days off, with or without food) plus fulvestrant. Randomization will be stratified by PIK3CA mutation type, visceral disease, and geographic region. The primary end point 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 end point within the same populations.

Key eligibility criteria

• 18 years or older with ECOG performance status of 0 to 1
• Confirmed diagnosis of HR+/HER2– locally advanced or metastatic breast cancer with radiological or objective evidence of recurrence or progression
• Presence of 1 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 breast cancer with:

• At least 1 and no more than 2 lines of endocrine therapy (ET). Prior fulvestrant is allowed.
• 1 prior line of CDK4/6 inhibitor therapy
• Hemoglobin A_1c less than 7.0% (<53 mmol/mol) and fasting plasma glucose less than 140 mg/dL. Type 1 diabetes, or type 2 diabetes requiring antihyperglycemic medication, are excluded
• No prior PI3K, AKT, or mTOR inhibitors or any agent whose mechanism of action is to inhibit the PI3K/AKT/mTOR pathway
  

ReDiscover-2 (NCT06982521) is open for enrollment. For further information, contact: clinicaltrials@relaytx.com.