Cyclin-dependent kinase (CDK)4/6 inhibitors combined with endocrine therapy (ET) is the currently recommended first-line treatment for patients with hormone receptor (HR)-positive/HER2-negative advanced breast cancer (ABC). Capivasertib, an oral Akt inhibitor, in combination with fulvestrant is recommended for patients with PIK3CA/AKT1/PTEN-altered HR-positive/HER2-negative ABC who have progressed after at least 1 line of ET-based treatment. This report presents a subgroup analysis of progression-free survival (PFS) by line of ET from the phase 3 CAPItello-291 (NCT04305496) trial.

The CAPItello-291 study is a phase 3, global, randomized, double-blind, placebo-controlled study. Patients with HR-positive/HER2-negative ABC were eligible if they had disease progression within or ≤12 months of completing a neoadjuvant aromatase inhibitor (AI) treatment (first-line ET) or during prior AI-based treatment for ABC (second- or third-line ET). Tumor alteration status was centrally determined by testing tumor tissue collected prior to enrollment. Patients were randomized 1:1 to receive capivasertib (400 mg twice daily, 4 days on/3 days off) plus fulvestrant (500 mg intramuscularly on days 1 and 15 of cycle 1, and day 1 of each subsequent 28-day cycle) or placebo plus fulvestrant. PFS was analyzed using Cox proportional-hazards regression for each subgroup based on the line of ET received.

At the data cutoff of August 15, 2022, a total of 708 patients with HR-positive/HER2-negative ABC were enrolled in the study. Of the 236 patients with PIK3CA/AKT1/PTEN-altered, HR-positive/HER2-negative ABC who had not received prior chemotherapy for ABC, 32 were treated with first-line ET (n=12, capivasertib plus fulvestrant; n=20, placebo plus fulvestrant) and 185 patients were treated with second-line ET (n=106, capivasertib plus fulvestrant; n=79, placebo plus fulvestrant), which included 155 patients treated with post-CDK4/6 inhibitors plus AI (n=88, capivasertib plus fulvestrant; n=67, placebo plus fulvestrant). Baseline characteristics were generally balanced between treatment arms, except for a higher percentage of White patients (59.0% vs 47.2%) and visceral metastases (67.2% vs 55.1%) in the second-line subgroups versus the first-line subgroups. There was a benefit seen in all chemotherapy-naïve patients in the capivasertib-plus-fulvestrant group (median PFS, 7.4; 95% confidence interval [CI], 5.5-9.2) compared with the placebo-plus-fulvestrant group (median PFS, 3.5; 95% CI, 2.0-3.9). The PFS benefit of capivasertib plus fulvestrant compared with placebo plus fulvestrant was consistent across ET subgroups (first-line, second-line, and second-line post-CDK4/6 inhibitors plus AI). The safety profile of capivasertib was consistent with findings in the overall trial population, with no new safety signals identified. The incidence of adverse events (AEs) in the capivasertib-plus-fulvestrant arms (any AE, 97.0%) were generally similar in the second-line ET patient subgroup compared with the overall population of patients who had not received prior chemotherapy for ABC (any AE, 96.9%) and the overall CAPItello-291 population (any AE, 96.6). Discontinuation rates due to AEs were broadly consistent across subgroups.

This subgroup analysis from the CAPItello-291 trial demonstrates that capivasertib in combination with fulvestrant provides consistent PFS benefits across different lines of ET in patients with PIK3CA/AKT1/PTEN-altered, HR-positive/HER2-negative ABC. These findings support the efficacy of capivasertib plus fulvestrant as a treatment option in both first- and later-line ET settings, including after progression on CDK4/6 inhibitors. Further research is warranted to confirm these observations in larger first-line ET populations.

Source: Rugo HS, Loibl S, Oliveira M, et al. Capivasertib plus fulvestrant as first and second-line endocrine-based therapy in PIK3CA/AKT1/PTEN-altered hormone receptor-positive advanced breast cancer: subgroup analysis from the phase 3 CAPItello-291 trial. Presented at: ESMO Congress 2025. October 20, 2025; Berlin, Germany. Abstract 526P.