Alpelisib plus fulvestrant meets primary PFS endpoint in CDK4/6 inhibitor-pretreated patients with PIK3CA mutant HR+/HER2 breast cancer

Alpelisib(Alpelisib) compared with fulvestrant alone in CDK4/6 inhibitor-pretreated, PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer patients - Piqra y plus fulvestrant (Fulvestrant; Falsodex; AstraZeneca) ) significantly improved progression-free survival (PFS), meeting the primary endpoint of the Phase 3 EIK-B5 study (NCT05038735).

Results from the study published in2025 show that, as of the data cutoff point of October 15, 2024, patients who receivedapelliris plus fulvestrant(n=94) were 10% of the total according to RECIST Median PFS for 1.1 standard was 7.4 months (95% CI, 5.52-9.10), compared with 2.8 months (95% CI, 1.94-3.84) for placebo plus fulvestrant (n=1994; HR, 0.52; 95% CI, 0.37-0.72; log-rank P<.0001). The overall response rates (ORR) for each 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 endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS in patients with hormone receptor-positive, HER2-negative PIK3CA-mutated [disease] who had progressed on prior treatment with a CDK4/6 inhibitor. In May 2019, the U.S. Food and Drug Administration approved apelvis plus fulvestrant for the treatment of postmenopausal women and men with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced or metastatic breast cancer detected by an FDA-approved test during or after an endocrine-based regimen. 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 = 0.001).

How was this study designed?

EPIK-B5 enrolls patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancerAdult postmenopausal women and men with cancer who experience disease progression or recurrence during or after treatment with CDK4/6 inhibitors and aromatase inhibitors. According to the RECIST 1.1 criteria assessed by the investigators, patients were required to have at least 1 measurable lesion, have received no more than 1 previous line of chemotherapy (excluding neoadjuvant/adjuvant chemotherapy), and have sufficient tumor tissue for assessment of PIK3CA mutation status by a central laboratory.

Patients were randomly assigned in a 1:1 ratio to receive 300 mg of apelvis combined with 500 mg of fulvestrant or placebo plus fulvestrant. Crossover to the combination arm was allowed at disease progression according to BICR's RECIST 1.1 criteria. According to BICR, the primary endpoint is PFS. Secondary endpoints 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 are also secondary endpoints.

At baseline, the median age was 62.0 years in the combination group and 61.5 years in the placebo group. The majority of patients in both groups had an ECOG performance status of 0 (56.4% vs. 63.8%), had visceral metastases (71.3% vs. 71.3%), and had received CDK4/6 inhibitor therapy for at least 6 months (86.2% vs. 89.4%). Patients in both groups received prior adjuvant chemotherapy (28.7% vs. 31.9%) and metastatic chemotherapy (12.8% vs. 18.1%).

What are the additional efficacy and safety data for the combination?

At the data cutoff date of May 26, 2025, updated OS data showed that the median OS of patients receiving the combination (n=105) and placebo (n=107) were 29.5 months and 23.8 months, respectively. The HR for OS was 0.64 (95%CI, 0.41-0.99; P=0.021).

For safety, the most common adverse reactions (AEs) of any grade occurring in at least 10% of patients in the combination treatment group (n=92) were hyperglycemia (72.8%), diarrhea (51.1%), nausea (44.6%), decreased appetite (30.4%), and rash (30.5%). In the placebo group (n=94), the most common adverse events of any grade were fatigue (16.0%), arthralgia (16%), increased alanine aminotransferase levels (14.9%), and increased gamma-glutamyltransferase levels (1 4.9%. The rates of adverse events of any grade were 100% and 86.2% in the combination group and placebo group, respectively; the incidence rates of grade 3 or higher AEs were 70.7% and 33.0%, respectively.

There are no new safety signals and the safety profile is consistent with what is already known (for Apelvis). These data confirm and extend the SOALR-1 findings and support the use of apelvis plus fulvestrant after progression on CDK4/6 inhibitorsAs an effective treatment option for patients with hormone receptor-positive,HER2-negative PIK3CA-mutated [breast cancer].

References: Updated onDecember 12, 2025, https://www.onclive.com/view/alpelisib-plus-fulvestrant-hits-primary-pfs-end-point-in-cdk4-6-inhibitor-pretreated-pik3ca-mutant-hr-her2-breast-cancer