On April 27, 2026 Relay Therapeutics, Inc. (Nasdaq: RLAY), a clinical-stage, small molecule precision medicine company developing potentially life-changing therapies for patients living with cancer and genetic disease, reported plans to move zovegalisib + atirmociclib, Pfizer’s investigational, potential first-in-class CDK4 inhibitor, into Phase 3 development for frontline patients with PI3Kα-mutated, HR+/HER2- metastatic breast cancer.

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"While PI3Kα inhibition has demonstrated meaningful benefit in breast cancer, its use in the frontline setting has been limited by tolerability challenges with earlier agents," said Don Bergstrom, M.D., Ph.D., President of R&D at Relay Therapeutics. "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."

Zovegalisib + Atirmociclib Data Demonstrate Potential Best-in-Class Triplet Profile

Zovegalisib is currently being evaluated in ReDiscover, an ongoing first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of zovegalisib in combination with fulvestrant and CDK inhibitors in patients with PI3Kα-mutated, HR+/HER2- metastatic breast cancer. These data are from the zovegalisib + atirmociclib + fulvestrant dose finding portion of the study.

As of the April 13, 2026 data cut-off date, 69 total patients were enrolled, with 62 patients at or below the potential Phase 3 dose and 34 patients with measurable disease evaluable for response. All patients had previously received a CDK4/6 inhibitor and at least one prior endocrine therapy in the advanced setting and could have received a PI3K pathway inhibitor. These heavily pre-treated patients had received a median of 2 prior therapies (21% received 3+ prior therapies) in the metastatic setting with 63% having visceral disease, 29% having received chemotherapy, and 47% being pre-diabetic. The median follow-up was 7.4 months.

Expansion cohorts of zovegalisib + atirmociclib + fulvestrant and zovegalisib + atirmociclib + aromatase inhibitor (AI) in the ReDiscover study are ongoing.

Safety and Tolerability of Triplet is Critical for Potential Long-Term Treatment in Frontline Endocrine Sensitive Breast Cancer

Early safety and tolerability data for zovegalisib in combination with atirmociclib and fulvestrant (N=62) reinforce the potential of this regimen moving forward in frontline endocrine sensitive patients. As of the April 13, 2026 data cut-off date:

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Only two patients (3%) discontinued zovegalisib and six patients (10%) dose reduced zovegalisib due to treatment-related adverse events (TRAEs)
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Adverse events were consistent with those previously reported by each molecule
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Grade 3 hyperglycemia was 0% despite 47% of patients being pre-diabetic
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Overall grade 3+ TRAE rate in these median third-line patients is 40%
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Neutropenia accounts for the majority of the grade 3+ events
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No instance of febrile neutropenia was observed

Overall Response Rate in Median Third Line Patients is Approaching ORR Seen in Frontline Breast Cancer with Standard of Care

As of the April 13, 2026 data cut-off date, 34 patients had measurable disease to be evaluated for response:

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Objective response rate (ORR) was 44% (15/34) and was also 44% in both kinase and non-kinase patients
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ORR in these heavily pre-treated patients has approached that of current standard of care doublets in 1L patients, ranging from 53% to 55% ORR
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Nearly all patients experienced tumor reduction (85%, 29/34)
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48 of 62 patients (77%) remain on study as of the data cut-off date, with a median follow-up of 7.4 months
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The data are not yet mature enough to estimate median progression-free survival

Pharmacokinetics

Pharmacokinetic analyses demonstrated that atirmociclib increased the exposure of zovegalisib by about two and half-fold (regardless of atirmociclib dose), while zovegalisib had no impact on atirmociclib exposure. Subject to regulatory feedback, the potential Phase 3 dose of zovegalisib will be 150mg twice daily (BID), which maintains average concentration of zovegalisib just below IC90 throughout the dosing interval.

Preliminary Phase 3 Trial Design in Frontline Endocrine Sensitive Patients

The planned study, subject to regulatory feedback, is a randomized Phase 3 trial evaluating zovegalisib in combination with atirmociclib and aromatase inhibitor (AI) in frontline endocrine sensitive patients with PIK3CA-mutated, HR+/HER2- advanced or metastatic breast cancer.

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Population: Frontline endocrine sensitive patients with HR-positive, HER2-negative advanced or metastatic breast cancer harboring a PIK3CA mutation
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Experimental arm: Zovegalisib + atirmociclib + AI

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Control arm: CDK4/6 inhibitor (investigator’s choice) + AI
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Key endpoints: Median progression-free survival (primary) and overall survival (secondary)

Pfizer to Supply Atirmociclib and Palbociclib Through Supply Agreement

Pfizer has agreed to supply atirmociclib for the experimental arm in combination with zovegalisib and the palbociclib portion of the control arm for use in the planned study. Relay Tx will sponsor, fully operationalize and fund the planned Phase 3 trial. Relay Tx retains full global rights for zovegalisib.

Next Steps

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Conduct regulatory interactions to finalize Phase 3 design and dose with the goal of initiating the study in early 2027
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Continued execution of Phase 1/2 dose finding and expansion as part of the ReDiscover study, allowing for larger sample size and longer follow up at potential Phase 3 dose for future disclosures
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Continued execution of ongoing ReDiscover-2 Phase 3 trial in second line breast cancer
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Present initial data for zovegalisib in vascular anomalies at ISSVA 2026 (May 20, 2026 in Philadelphia)

Conference Call Information

Relay Therapeutics will host a conference call and live webcast today, April 27, at 8:30 a.m. ET. Registration and dial-in for the conference call may be accessed through Relay Therapeutics’ website under Events in the News & Events section through the following link: View Source An archived replay of the webcast will be available following the event.

About Zovegalisib

Zovegalisib is the lead program in Relay Therapeutics’ efforts to discover and develop mutant selective inhibitors of PI3Kα, the most frequently mutated kinase in all cancers and all vascular anomalies. Zovegalisib has the potential, if approved, to address a significant portion of the approximately 140,000 patients with HR+/HER2- breast cancer with a PI3Kα mutation and the estimated 170,000 patients with vascular anomalies driven by a PI3Kα mutation per year in the United States, one of the largest patient populations for a precision medicine.

Traditionally, the development of PI3Kα inhibitors has focused on the active, or orthosteric, site. The therapeutic index of orthosteric inhibitors is limited by the lack of clinically meaningful selectivity for mutant versus wild-type (WT) PI3Kα and off-isoform activity. Toxicity related to inhibition of WT PI3Kα and other PI3K isoforms results in sub-optimal inhibition of mutant PI3Kα with reductions in dose intensity and frequent discontinuation. The Dynamo platform enabled the discovery of zovegalisib, the first known allosteric, pan-mutant, and isoform-selective PI3Kα inhibitor, designed to overcome these limitations. Relay Therapeutics solved the full-length cryo-EM structure of PI3Kα, performed computational long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to support the design of zovegalisib. Zovegalisib is currently being evaluated in multiple metastatic breast cancer studies and a first-in-human study designed to treat patients with PIK3CA (PI3Kα) mutation driven vascular anomalies. For more information on zovegalisib, please visit here.

(Press release, Relay Therapeutics, APR 27, 2026, View Source [SID1234664802])