EPIK-B5 supports alpelisib plus fulvestrant for HR+, HER2– ABC

In the phase III EPIK-B5 study, adding alpelisib, an α-specific PI3K inhibitor, to fulvestrant improves progression-free survival (PFS) in men and postmenopausal women with HR+, HER2− advanced breast cancer (ABC) harbouring a PIK3CA mutation who have progressed on or after treatment with an aromatase inhibitor (AI) and a CDK4/6 inhibitor (CDK4/6i).

“The EPIK-B5 study did meet its primary endpoint of PFS,” said Dr Michelino de Laurentiis from the National Cancer Institute IRCCS ‘Fondazione Pascale’, Naples, Italy, at SABCS 2025.

At data cutoff (October 15, 2024), there was a statistically significant and clinically meaningful improvement in median PFS in participants on alpelisib plus fulvestrant as opposed to those who received placebo plus fulvestrant (7.4 vs 2.8 months; hazard ratio [HR], 0.52; p<0.0001).

Moreover, the objective response rate was nearly sixfold higher with the experimental regimen vs the comparator (23.4 percent vs 4.3 percent). [SABCS 2025, abstract RF7-02]

Overall survival

In the primary intention-to-treat analysis of overall survival (OS; data cutoff October 15, 2024), there was a clear trend toward longer OS in the alpelisib vs the placebo arm (median not evaluable vs 22.6 months; HR, 0.60; nominal p=0.026).

“Of note, these results were achieved despite a third of patients crossing over from the placebo to the alpelisib arm,” de Laurentiis said.

After an additional 6 months of follow-up, the updated OS analysis (data cutoff May 26, 2025) revealed a longer median OS with the investigational regimen than with the comparator, thus confirming the trend toward improved OS in the primary analysis (29.5 vs 23.8 months; HR, 0.64; p=0.021). Again, this was achieved despite having a 40-percent crossover rate.

However, the study was not powered to demonstrate an OS benefit, de Laurentiis noted.

Safety profile

The most common grade ≥3 adverse events (AEs) in the alpelisib arm were hyperglycaemia (32.6 percent), rash (13 percent), and maculopapular rash (7.6 percent). In the placebo arm, the most frequent were elevations in gamma-glutamyl transferase (7.4 percent), aspartate aminotransferase (13.6.4 percent), and alanine aminotransferase (5.3 percent).

Eighty percent of participants on the experimental regimen permanently discontinued alpelisib primarily due to progressive disease (40.1 percent) and AEs (27.2 percent).

Dose reductions were more frequent in the alpelisib vs the placebo arm (56.5 percent vs 3.2 percent), as were dose interruptions (70.7 percent vs 19.1 percent).

There were no new safety signals compared with the established safety profile of alpelisib, de Laurentiis noted. “The safety profile is consistent with what is already known. AEs were usually manageable and reversible. No unexpected safety issues emerged.”

Drug resistance inevitable

The National Comprehensive Cancer Network Guidelines recommend endocrine therapy combined with a CDK4/6i as standard first-line treatment for HR+, HER2– ABC, de Laurentiis noted. “However, resistance to these agents inevitably develops,” he said. [Cancers (Basel) 2021;13:5397]

In the SOLAR-1 study, alpelisib plus fulvestrant has shown benefit in patients with HR+, HER2– ABC with a PIK3CA mutation (median PFS 11 vs 5.7 months; HR, 0.65; p=0.00065). [N Engl J Med 2019;380:1929-1940] However, the study included only a few participants who had previously received CDK4/6i treatment, mainly due to the limited availability of CDK4/6is at that time, de Laurentiis noted.

“To fill this gap, we conducted EPIK-B5, which was specifically designed to investigate the efficacy of alpelisib plus fulvestrant in this patient population,” he said. EPIK-B5 included adult postmenopausal women and men with HR+, HER2− ABC with PIK3CA mutation who have progressed or relapsed on or after CDK4/6i and AI and had ≥1 measurable lesion per RECIST v1.1 as assessed by investigator, ≤1 line of prior chemotherapy (except neoadjuvant/adjuvant chemo), and adequate tumour tissue for PIK3CA mutation status by central laboratory.

A total of 188 participants (median age 62 years) from 66 centres across 17 countries were randomized 1:1 to fulvestrant 500 mg plus either alpelisib 300 mg or placebo. Crossover from placebo to alpelisib was permitted upon confirmation of disease progression by the blinded independent review committee.

Approximately 71 percent of the participants had liver and/or lung metastasis. All participants had previously received a CDK4/6i in any setting.

“The current data confirm and extend the SOLAR-1 findings and support the use of alpelisib plus fulvestrant as an effective treatment option for patients with HR+, HER– ABC who harbour a PIK3CA mutation with a favourable benefit-risk assessment,” de Laurentiis said.