RLY-2608, a first-in-class mutant-selective PI3Kα inhibitor, has demonstrated promising efficacy and improved tolerability when combined with fulvestrant in patients with PIK3CA-mutant hormone receptor-positive, HER2-negative advanced breast cancer, according to updated results from the phase 1 ReDiscover trial presented at the 2025 ASCO Annual Meeting.
The combination achieved a median progression-free survival of 10.3 months (95% CI, 7.2-18.4) at a median follow-up of 12.5 months in 52 patients. Response-evaluable patients (n = 31) experienced an overall response rate of 38.7% (95% CI, 38.4%-88.2%) per RECIST 1.1 criteria, with tumor reduction observed in 80.6% of patients.
Enhanced Efficacy in Specific Mutation Subtypes
Patients with kinase domain PIK3CA mutations showed particularly robust responses, achieving a 66.7% overall response rate (95% CI, 38.4%-88.2%) and an impressive median progression-free survival of 18.4 months (95% CI, 9.2-not reached). In the second-line population (n = 30), the median progression-free survival was 11.0 months (95% CI, 7.3-22.0).
"The combination of RLY-2608 plus fulvestrant is very promising at this juncture in the post-CDK4/6 inhibitor setting, and we are excited to move it into a pivotal phase 3 trial," said Dr. Sarah Sammons, associate director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute and lead investigator of the study.
Improved Safety Profile Addresses Key Tolerability Concerns
RLY-2608's mutant-selective mechanism, which spares wild-type PIK3CA receptors better than approved drugs like alpelisib or inavolisib, translated into meaningful tolerability improvements. Treatment-related adverse effects of any grade occurred in 96.9% of patients at the recommended phase 2 dose of 600 mg twice daily, with grade 3 or higher events in 35.9% of patients.
Hyperglycemia remained the most common side effect, occurring in 51.6% of patients at any grade, but was predominantly low-grade with 31% experiencing grade 1 hyperglycemia requiring no intervention. Only 3.1% of patients experienced grade 3 hyperglycemia.
"What's very nice about it, compared to other drugs in its class, is that I'm seeing less diarrhea in my patients, very little rash and very few oral mouth sores, which can be really distressing for patients," Sammons explained. The most common treatment-related side effects included hyperglycemia, nausea, and fatigue, all noted to be generally low-grade, manageable, and reversible.
Addressing Unmet Need in Post-CDK4/6 Setting
PIK3CA mutations occur in approximately 40% of patients with HR-positive, HER2-negative metastatic breast cancer and are associated with resistance to endocrine therapies and CDK4/6 inhibitors. The ReDiscover trial enrolled patients who had received at least one prior anti-estrogen therapy and a CDK4/6 inhibitor, with no more than one prior line of chemotherapy in the metastatic setting allowed.
The updated efficacy analysis excluded patients with concurrent PTEN or AKT alterations (approximately 10% of the population), as investigators believe mutant-specific inhibitors are most effective in patients with isolated PIK3CA mutations rather than downstream alterations.
Advancing to Pivotal Testing
Based on these results, RLY-2608 plus fulvestrant will advance to the phase 3 ReDiscover-2 study (NCT06982521), which is planned to open in 2025. The pivotal trial will compare the combination against capivasertib plus fulvestrant, the current standard of care for patients with PIK3CA-mutated, HR-positive/HER2-negative breast cancer in the post-CDK4/6 inhibitor setting.
Treatment discontinuation due to adverse events occurred in only 2% of patients in the phase 1 study, supporting the potential for improved long-term tolerability compared to existing PI3K pathway inhibitors. The combination demonstrated activity regardless of the number of prior therapy lines received or the presence of PIK3CA or ESR1 mutations.
