Early-Phase Data With Zovegalisib/Atirmociclib/Fulvestrant Sets the Stage for Phase 3 Study in Breast Cancer

The first-line combination of zovegalisib (RLY-2608), atirmociclib (PF-07220060), and the aromatase inhibitor fulvestrant (Faslodex) generated responses in heavily pretreated, CDK4/6 inhibitor–exposed patients with PI3Kα-mutated hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, according to findings from the dose-finding portion of the phase 1 ReDiscover trial (NCT05216432).¹

At a median follow-up of 7.4 months, the triplet elicited an overall response rate (ORR) of 44% among 34 response-evaluable patients in this population, and a tumor reduction rate of 85%. Notably, patients had received a median of 2 prior lines of therapy, and ORRs were similar across subgroups of patients with kinase and non-kinase PIK3CA mutations. Moreover, this ORR is approaching the 53% to 55% ORRs historically seen with current first-line standard-of-care doublets in this population, according to a news release.

As of the data cutoff of April 13, 2026, 77% of patients remained on study. However, the data are not yet mature enough to show a median progression-free survival (PFS) estimate.

Based on the ReDiscover results, a phase 3 trial investigating first-line zovegalisib plus atirmociclib and an aromatase inhibitor in patients with endocrine-sensitive disease is planned for initiation in 2027.

“[Although] PI3Kα inhibition has demonstrated meaningful benefit in breast cancer, its use in the frontline setting has been limited by tolerability challenges with earlier agents,” Don Bergstrom, MD, PhD, president of R&D at Relay Therapeutics, stated in the news release. “We believe that combining the selective profiles of zovegalisib and atirmociclib with endocrine therapy has the potential to enable a well-tolerated, all-oral triplet regimen, and these initial data support advancing this combination into phase 3 development for patients with frontline metastatic breast cancer.”

What is the design of ReDiscover?

This ongoing, first-in-human trial is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of zovegalisib plus fulvestrant and CDK inhibitors in patients at least 18 years of age with advanced solid tumors, including PIK3CA-mutated, HR-positive, HER2-negative metastatic breast cancer.^1,2 Patients also need to have an ECOG performance status of 0 or 1.²

A total of 69 patients with breast cancer have been enrolled onto the study, 62 of whom were treated at or below the potential phase 3 dose.¹ All patients had received prior therapy with a CDK4/6 inhibitor and at least 1 endocrine therapy for the management of advanced disease. Patients were permitted to have received a prior PI3K pathway inhibitor. Among the enrolled patients, 21% had received 3 or more prior therapies in the metastatic setting, 63% had visceral disease, 29% had received prior chemotherapy, and 47% were pre-diabetic.

Notably, expansion cohorts of the trial investigating zovegalisib plus atirmociclib and fulvestrant, as well as zovegalisib plus atirmociclib and an aromatase inhibitor, are ongoing.

Primary end points include the determination of the maximum tolerated dose and/or recommended phase 2 dose of zovegalisib, as well as safety.² Secondary end points include PIK3CA gene status in plasma circulating tumor DNA and tumor tissue, pharmacokinetic parameters, ORR, duration of response, disease control rate, and clinical benefit rate.

What data have been seen regarding the safety profile of zovegalisib plus atirmociclib and fulvestrant in breast cancer?

Dose reductions and discontinuations of zovegalisib due to treatment-related adverse effects (TRAEs) occurred in 10% and 3% of safety-evaluable patients (n = 62), respectively.¹ The AEs observed were consistent with those previously reported with each individual drug. Although almost half of patients were pre-diabetic, no grade 3 hyperglycemia was seen.

In total, 40% of patients experienced grade 3 or higher TRAEs, most of which were neutropenia. However, no febrile neutropenia was reported.

What is the pharmacokinetic profile of zovegalisib plus atirmociclib and fulvestrant in breast cancer?

Investigators reported that the addition of atirmociclib increased zovegalisib exposure by over two-fold, regardless of atirmociclib dose. Moreover, the presence of zovegalisib in the regimen did not affect atirmociclib exposure. Based on these findings, the phase 3 dose of zovegalisib is planned at 150 mg twice daily.

What is the design of the phase 3 trial evaluating zovegalisib, atirmociclib, and an aromatase inhibitor in breast cancer?

This trial is enrolling patients with endocrine-sensitive HR-positive, HER2-negative, advanced or metastatic PIK3CA-mutated breast cancer. The investigational combination of zovegalisib plus atirmociclib and an aromatase inhibitor will be compared with a control regimen of a CDK4/6 inhibitor of investigator’s choice plus an aromatase inhibitor.

PFS will serve as the primary end point. OS will be a key secondary end point.

References

1. Relay Therapeutics announces clinical data for zovegalisib plus atirmociclib triplet combination supportive of further development in frontline metastatic breast cancer. News release. Relay Therapeutics. April 27, 2026. Accessed April 27, 2026. https://ir.relaytx.com/news-releases/news-release-details/relay-therapeutics-announces-clinical-data-zovegalisib-plus
2. First-in-human study of mutant-selective PI3Kα inhibitor, RLY-2608, as a single agent in patients with advanced solid tumors and in combination with endocrine therapy +/​- a CDK4/​6 or CDK4 inhibitor in patients with advanced solid tumors or advanced breast cancer. ClinicalTrials.gov. Updated September 22, 2025. Accessed April 27, 2026. https://clinicaltrials.gov/study/NCT05216432