Alpelisib/Fulvestrant Improves PFS in Post-CDK4/6 HR+/HER2- Breast Cancer

In patients with CDK4/6 inhibitor–pretreated, PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer, alpelisib (Piqray) combined with fulvestrant (Faslodex) achieved a significant and clinically meaningful enhancement in progression-free survival (PFS) compared to fulvestrant by itself, thereby satisfying the primary end point of the phase 3 EPIK-B5 study (NCT05038735).¹

Findings presented during the 2025 San Antonio Breast Cancer Symposium demonstrated that, as of the data cutoff of October 15, 2024, the median PFS per RECIST 1.1 criteria by blinded independent central review (BICR) among patients who received alpelisib plus fulvestrant (n = 94) was 7.4 months (95% CI, 5.52-9.10) vs 2.8 months (95% CI, 1.94-3.84) with placebo plus fulvestrant (n = 94; HR, 0.52; 95% CI, 0.37-0.72; log-rank P <.0001). The overall response rates (ORRs) per BICR were 23.4% (95% CI, 15.3%-33.3%) and 4.3% (95% CI, 1.2%-10.5%), respectively.

“EPIK-B5 met its primary end point, demonstrating a PFS improvement that was statistically significant and clinically meaningful in patients with hormone receptor–positive, HER2-negative PIK3CA-mutated [disease] who progressed on previous treatment with CDK4/6 inhibitors,” Michelino De Laurentiis, MD, PhD, the chair of the Department of Breast and Thoracic Oncology at National Cancer Institute IRCCS "Fondazione Pascale" in Napoli, Italy said during the presentation.

In May 2019, the FDA approved alpelisib plus fulvestrant for the treatment of postmenopausal women and men with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.² The regulatory decision was supported by data from the phase 3 SOLAR-1 trial (NCT02437318) which showed that patients who received the combination achieved a significant PFS benefit compared with those who received fulvestrant alone (HR, 0.65; 95% CI, 0.50-0.85; P = .001).

Study Design

EPIK-B5 enrolled adult postmenopausal women and men with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer who experienced disease progression or relapse on or after treatment with a CDK4/6 inhibitor and an aromatase inhibitor.¹ Patients were required to have at least 1 measurable lesion per RECIST 1.1 criteria as assessed by the investigator, have received no more than 1 prior line of chemotherapy, excluding neoadjuvant/adjuvant chemotherapy, and adequate tumor tissue for PIK3CA mutational status assessment by a central laboratory.

Patients were randomly assigned 1:1 to receive alpelisib at 300 mg in combination with fulvestrant at 500 mg or placebo plus fulvestrant. Crossover to the combination arm was permitted at the time of disease progression per RECIST 1.1 criteria by BICR.

The primary end point was PFS per BICR. Secondary end points included ORR, duration of response, and time to response based on BICR assessment. Overall survival (OS), safety, ECOG performance status, quality, and time to second disease progression were also secondary end points.

At baseline, the median ages in the combination and placebo arms were 62.0 years and 61.5 years, respectively. Most patients in both arms had an ECOG performance status of 0 (56.4% vs 63.8%), visceral metastasis (71.3% vs 71.3%), and had received a prior CDK4/6 inhibitor for at least 6 months (86.2% vs 89.4%). Patients in both arms received prior adjuvant chemotherapy (28.7% vs 31.9%) and metastatic chemotherapy (12.8% vs 18.1%).

Additional Efficacy and Safety

At a data cutoff of May 26, 2025, updated OS data revealed that patients in the combination (n = 105) and placebo (n = 107) achieved a median OS of 29.5 months and 23.8 months, respectively. The HR for OS was 0.64 (95% CI, 0.41-0.99; nominal P = .021).

In terms of safety, the most common any-grade adverse effects (AEs) in the combination arm (n = 92) that occurred in at least 10% of patients were hyperglycemia (72.8%), diarrhea (51.1%), nausea (44.6%), decreased appetite (30.4%), and rash (30.4%). The most common any-grade AEs in the placebo arm (n = 94) were asthenia (16.0%), arthralgia (16.0%), increased alanine aminotransferase levels (14.9%), and increased gamma-glutamyl transferase levels (14.9%). Patients in the combination and placebo arms experienced any-grade AEs at respective rates of 100% and 86.2%; grade 3 or higher AEs occurred at rates of 70.7% and 33.0%, respectively.

“There were no new safety signals and the safety profile is in line with what we already know [about alpelisib],” De Laurentiis said in his conclusion. “These data confirm and extend the SOALR-1 findings and support the use of alpelisib plus fulvestrant as an effective treatment option for patients with hormone receptor–positive, HER2-negative PIK3CA-mutated [breast cancer] after progression on CDK4/6 inhibitors.”

DISCLOSURES: De Laurentiis reported holding consultancy roles for Novartis, Pfizer, Eli Lilly, MDS, Pierre Fabre, Seagen, Gilead Sciences, Ipsen, and Daiichi Sankyo Europe GmbH. He is also on the speaker’s bureaus for Novartis, Roche, Lilly, Pfizer, Daiichi Sankyo, MSD, Bristol-Myers Squibb, Sanofi, Genzyme, and AstraZeneca. He is a stockholder in Arvinas, Novartis, Pfizer, Lilly, Pierre Fabre, AstraZeneca, MSD, Seagen, Gilead, Sciences, Ipsen, Exact Sciences, TOMA Biosciences, Daiichi Sankyo Europe GmbH, and Veracyte.

REFERENCES

1. De Laurentiis M, Magalhaes Ferreira A, Gilgorov J, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer after a CDK4/6 inhibitor (EPIK-B5): phase III, randomized, double-blind, placebo-controlled, multicenter study. Presented at: 2025 San Antonio Breast Conference Symposium; December 9-12, 2024; San Antonio, TX. Abstract RF7-02.

2. FDA approves alpelisib for metastatic breast cancer. FDA. Updated May 28, 2019. Accessed December 11, 2025. https://tinyurl.com/npxexhjw