Zovegalisib Plus Fulvestrant Yields Durable Efficacy in PIK3CA+, HR+/HER2– Advanced Breast Cancer

Treatment with the combination of zovegalisib (RLY-2608) and fulvestrant (Faslodex) generated durables responses in patients with hormone receptor (HR)–positive, HER2-negative unresectable or metastatic breast cancer harboring PIK3CA mutations, according to data from the phase 2 ReDiscover trial (NCT05216432 ) presented at the 43rd Annual Miami Breast Cancer Conference.¹

Findings showed that evaluable patients treated with the recommended phase 2 dose (RP2D) of the pan-mutant–selective PI3Kα inhibitor zovegalisib (600 mg twice per day) in combination with fulvestrant (n = 31) achieved an overall response rate (ORR) of 38.7% (95% CI, 21.8%-57.8%). Moreover, reductions in tumor size were reported in 80.6% of patients.

Notably, activity was observed irrespective of prior therapy and PIK3CA/ESR1 mutation status. In patients harboring PIK3CA kinase mutations (n = 15), the ORR was 66.7% (95% CI, 38.4%-88.2%), and those previously treated with fulvestrant (n = 15) experienced an ORR of 40.0% (95% CI, 16.3%-67.7%).

“The promising efficacy and safety data observed in this first-in-human study suggest that zovegalisib has broad therapeutic potential in PIK3CA-mutant, HR-positive/HER2-negative breast cancer,” lead study author Sarah L. Sammons, MD, and colleagues wrote in a poster presentation of the data.

Sammons is a senior physician and associate director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

What is driving the rationale behind the ReDiscover trial?

Within the HR-positive, HER2-negative breast cancer population, approximately 40% of cases are driven by oncogenic PIK3CA mutations.

Sammons and colleagues noted that currently approved second-line agents include non-selective PI3K pathway inhibitors that have been associated with off-target toxicity.Zovegalisib is the first pan-mutant–selective inhibitor designed with the intention of mitigating off-target effects of PI3K inhibition.

ReDiscover was a multi-arm, open-label, first-in-human study that evaluated zovegalisib in patients with advanced solid tumors harboring PIK3CA mutations. The analysis presented Miami Breast focused on patients with breast cancer treated with the recommended dose of zovegalisib in combination with fulvestrant.

To be included in the zovegalisib plus fulvestrant arm, patients needed to have HR-positive/HER2-negative unresectable or metastatic breast cancer not amenable to curative therapy and harbor at least 1 oncogenic PIK3CA mutation in the blood or tumor, per local assessment. Other key inclusion criteria comprised evaluable disease per RECIST 1.1 criteria; prior treatment with at least 1 CDK4/6 inhibitor in the adjuvant and/or metastatic settings; at least 1 prior line of anti-estrogen therapy; and a hemoglobin A1c (HbA1c) level below 7%. No prior treatment with a PI3Kα inhibitor, AKT inhibitor, or mTOR inhibitor was permitted, and patients could not have received more than 1 prior line of chemotherapy in the metastatic setting.

In the combination arm, zovegalisib was administered at doses ranging from 100 mg to 1000 mg twice per day in combination with fulvestrant for 28-day cycles. The RP2D of zovegalisib was established at 600 mg twice per day.

Key end points included determining the maximum tolerated dose and RP2D; safety and tolerability; pharmacokinetics and pharmacodynamics; and preliminary efficacy per RECIST 1.1 criteria.

Among all patients treated at the RP2D (n = 64), the median age was 59.0 years (range, 34-80), and 59.4% had an ECOG performance status of 0. PIK3CA kinase mutations were recorded in 48.4% of patients, with the remainder harboring non-kinase mutations. Notably, 34.4% of patients in this group had a body mass index of at least 30 or a HbA1C level of at least 5.7%. ESR1 mutations were reported in 28.6% of patients.

Measurable disease was reported in 65.6% of patients, and 59.4% of patients had visceral metastases. Prior lines of therapy in the advanced setting included 1 (56.3%) and 2 or more (43.8%). All patients received a prior CDK4/6 inhibitor in the advanced setting, 51.6% received prior fulvestrant, and 28.1% received prior chemotherapy or an antibody-drug conjugate.

At data cutoff, 28.1% of patients were still receiving treatment. Among the 71.9% of patients to discontinue treatment, reasons for discontinuation included progressive disease (60.9%), consent withdrawal (4.7%), adverse effects (AEs; 3.1%), and physician decision (3.1%).

What additional data were reported for the RP2D of zovegalisib plus fulvestrant?

Data also demonstrated that at a median follow-up of 12.5 months, evaluable patients (n = 52) achieved a median progression-free survival (PFS) of 10.3 months (95% CI, 7.2-18.4) and a 6-month PFS rate of 69.3%. The clinical benefit rate in this group was 67.3%.

Subgroup data showed that the median PFS was 11.0 months (95% CI 7.3-22.0) in patients treated in the second-line (n = 30) at a median follow-up of 12 months; 9.2 months (95% CI, 5.4-not reached [NR]) in patients treated in the third-line or later (n = 22) at a median follow-up of 14.1 months; and 18.4 months (95% CI, 9.2-NR) in patients harboring PIK3CA kinase mutations (n = 29) at a median follow-up of 12.5 months.

Regarding safety, the most common treatment-related AEs (TRAEs) reported at the RP2D included hyperglycemia (any-grade, 51.6%; grade 3, 3.1%), nausea (50.0%; 1.6%), fatigue (42.2%; 9.4%), increased creatinine levels (39.1%; 3.1%), and diarrhea (39.1%; 3.1%). No grade 4 or 5 TRAEs were reported, and instances of severe, off-target stomatitis and rash were rare.

What’s next for zovegalisib plus fulvestrant?

Based on data from ReDiscover, the phase 3 ReDiscover-2 trial (NCT06982521) is evaluating zovegalisib plus fulvestrant vs capivasertib plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer harboring a PIK3CA mutation who have received prior treatment with a CDK4/6 inhibitor.²

References

1. Sammons SL, Saura C, Italiano A, et al. Updated efficacy of mutant-selective PI3Kα inhibitor zovegalisib (RLY-2608, zovega) in combination with fulvestrant in patients with PIK3CA-mutant HR+/HER2- advanced breast cancer: ReDiscover trial. Presented at: 43rd Annual Miami Breast Cancer Conference; March 5-8, 2026; Miami, FL.
2. 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 7, 2026. https://clinicaltrials.gov/study/NCT06982521