Zovegalisib Plus Fulvestrant Shows Durable PFS in PI3Kα-Mutated HR+/HER2− Metastatic Breast Cancer

An updated analysis of the phase 1/2 ReDiscover trial (NCT05216432) demonstrated that zovegalisib (RLY-2608) combined with fulvestrant (Faslodex) at the recommended phase 3 dose of 400 mg twice daily (BID) administered with food yielded a median progression-free survival (PFS) of 11.1 months in heavily pretreated patients with PI3Kα-mutated, hormone receptor–positive (HR+)/HER2-negative (HER2−) metastatic breast cancer who had previously received a CDK4/6 inhibitor. The data were presented at the ESMO Anticancer Therapies Congress 2026 in Paris, France, on March 16, 2026.¹

Among 57 efficacy-evaluable patients in the 400 mg BID cohort, the median follow-up was 12.0 months. The median PFS was similar regardless of PI3Kα mutation subtype, reaching 11.2 months in patients harboring kinase domain mutations (n = 33) and 11.0 months in those with nonkinase domain mutations (n = 24; 95% CI for overall cohort; 7.3-13.0 months). Among 35 patients with measurable disease, the confirmed objective response rate (ORR) was 43% (n = 15/35). In the subset of patients receiving the regimen as second-line therapy, the ORR was 52% (n = 11/21).

Zovegalisib plus fulvestrant has received FDA breakthrough therapy designation for the patient population enrolled in the phase 3 ReDiscover-2 trial (NCT06982521), which is currently enrolling globally.

“As supported by the data presented, the 400 mg BID fed regimen maintains robust efficacy with a safety profile consistent with mutant-selective PI3Kα inhibition,” said Don Bergstrom, MD, PhD, president of Research and Development at Relay Therapeutics, in a news release. “These results further support our decision to advance this regimen into the ongoing phase 3 ReDiscover-2 trial and reinforce our confidence in selectively targeting PI3Kαmutations as a potentially differentiated approach for CDK4/6-experienced patients.”

Background and Mechanistic Rationale

PIK3CA, the gene encoding PI3Kα, is among the most commonly mutated kinase-encoding genes across solid tumor types, and activating mutations are identified in approximately 40% of HR+/HER2− breast cancers. Existing PI3Kα inhibitors including alpelisib (Piqray) and the AKT inhibitor capivasertib (Truqap), which is approved in combination with fulvestrant, target the active site of PI3Kα or downstream effectors. Inhibition of wild-type PI3Kα and off-isoform activity with these agents contributes to dose-limiting toxicities such as hyperglycemia and diarrhea, often necessitating dose reductions or treatment discontinuation.^2,3

Zovegalisib was designed to address these limitations through an allosteric binding mechanism that confers selectivity for mutant over wild-type PI3Kα and selectivity across PI3K isoforms. The compound was identified using Relay Therapeutics’ Dynamo® computational platform, which leverages cryo-electron microscopy structural data and long time-scale molecular dynamics simulations to characterize conformational differences between wild-type and mutant PI3Kα. Relay describes zovegalisib as the first known allosteric, pan-mutant, isoform-selective PI3Kα inhibitor to enter clinical development.¹

Safety and Tolerability

Sixty patients were evaluable for safety in the 400 mg BID fed cohort as of the January 13, 2026, data cutoff. The overall treatment-related adverse event (TRAE) profile was described as primarily low-grade, manageable, and reversible.

Hyperglycemia, which represents the primary dose-limiting toxicity associated with orthosteric PI3Kα inhibitors such as alpelisib, was predominantly grade 1 with the 400 mg fed zovegalisib regimen. No grade 4 or grade 5 hyperglycemia events were observed. Among the limited cases of grade 2 or grade 3 hyperglycemia, the majority occurred in patients who were prediabetic at baseline. Only 4 of 60 patients (6.7%) discontinued treatment due to TRAEs—a discontinuation rate notably lower than that observed in trials of orthosteric PI3Kα inhibitors, where TRAE-driven discontinuation rates have reached 25% or higher.^2,3

The tolerability profile observed is consistent with the proposed mechanism of zovegalisib: by sparing wild-type PI3Kα and other PI3K isoforms, the drug may reduce the off-target metabolic effects that drive hyperglycemia and other class-effect toxicities seen with broader PI3K pathway inhibition.

Dose Optimization: From 600 mg Fasted to 400 mg Fed

Earlier cohorts in the ReDiscover phase 1/2 trial evaluated zovegalisib at 600 mg BID in the fasted state. The 400 mg BID fed regimen was subsequently investigated based on pharmacokinetic modeling suggesting that food intake increases drug absorption, enabling dose reduction while maintaining adequate systemic exposure.

Pharmacokinetic analyses from the current data cut (January 13, 2026) confirmed that mean drug concentrations with the 400 mg fed regimen approach the IC90 in the majority of patients, and that nearly all patients maintained drug exposure above the IC80 throughout the dosing interval, comparable to the exposure achieved with the 600 mg fasted dose.

Phase 3 ReDiscover-2 Trial

The phase 3 ReDiscover-2 trial is an ongoing, randomized study evaluating zovegalisib 400 mg BID fed plus fulvestrant vs capivasertib plus fulvestrant in patients with PI3Kα-mutated, HR+/HER2− advanced breast cancer who have progressed on prior CDK4/6 inhibitor therapy.⁴ The trial initiated enrollment in mid-2025 and is enrolling at sites globally. The active comparator arm of capivasertib plus fulvestrant received FDA approval in November 2023 for patients with PIK3CA/AKT1/PTEN-altered HR+/HER2− advanced breast cancer following progression on endocrine-based therapy.⁵

REFERENCES

1. Relay Therapeutics announces data from zovegalisib + fulvestrant at the phase 3 dose of 400mg BID fed at ESMO Targeted Anticancer Therapies Congress 2026. News release. Relay Therapeutics. March 16, 2026. Accessed March 17, 2026. https://tinyurl.com/2rjej6bb

2. André F, Ciruelos E, Rubovszky G, et al; SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904

3. Turner NC, Oliveira M, Howell SJ, et al; CAPItello-291 Study Group. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131

4. Phase 3 study of RLY-2608 + fulvestrant vs capivasertib + fulvestrant as treatment for locally advanced or metastatic PIK3CA-mutant HR+/​HER2- breast cancer (ReDiscover-2). ClinicalTrials.gov. Updated March 3, 2026. Accessed March 17, 2026. https://clinicaltrials.gov/study/NCT06982521

5. FDA approves capivasertib with fulvestrant for breast cancer. News release. FDA. November 16, 2023. Accessed March 17, 2026. https://tinyurl.com/2m5rh4jz