OBJECTIVES: For patients with HR-positive, HER2-negative, PIK3CA-altered advanced breast cancer (aBC) with disease progression following endocrine-based therapy, FDA approved treatments include alpelisib-fulvestrant (PIK3CA-altered only) and capivasertib-fulvestrant (PIK3CA/AKT1/PTEN-altered). In the SOLAR-1 (NCT02437318) and CAPItello-291 (NCT04305496) phase 3 studies, these regimens demonstrated significantly improved progression-free survival (PFS) versus placebo-fulvestrant. As there are no head-to-head studies between regimens, we assessed the relative efficacy and safety of capivasertib-fulvestrant versus alpelisib-fulvestrant for PIK3CA-altered aBC via indirect treatment comparison (ITC).

METHODS: Anchored Bayesian ITCs were performed on investigator-assessed PFS, any grade adverse event (AE) leading to treatment discontinuation, any grade 3 or 4 AE, and relevant individual AEs. The efficacy ITC was conducted using (log) hazard ratio scale using published data from PIK3CA-altered subgroups of SOLAR-1 and CAPItello-291. Safety ITCs were conducted on a risk difference (RD) scale using aggregate data from the safety analysis set of each study. Hazard ratio/RD estimates were calculated alongside 95% credible intervals (95%CrI).

RESULTS: For PFS, the hazard ratio for capivasertib-fulvestrant versus alpelisib-fulvestrant was 0.79 (95%CrI 0.52 to 1.18). The Bayesian probability of capivasertib-fulvestrant being more efficacious (HR<1) than alpelisib-fulvestrant was 87%. The safety RD (95%CrI) ITC results suggest nominally significant risk reductions (RD<0.00) for capivasertib-fulvestrant in any AE leading to discontinuation (–0.10: –0.17 to –0.03), any grade 4 AE (–0.07: –0.12 to –0.01) and any grade of hyperglycaemia (–0.43: –0.50 to –0.35), weight decreased (–0.24: –0.30 to –0.18), alopecia (–0.16: –0.22 to –0.11) and stomatitis (–0.08: –0.15 to –0.01), and an increased risk of any grade diarrhoea (0.09: –0.00 to 0.19) versus alpelisib-fulvestrant.

CONCLUSIONS: Results indicate that for patients with HR-positive, HER2-negative, PIK3CA-altered aBC capivasertib-fulvestrant has numerically improved PFS and a high probability of being more efficacious than alpelisib-fulvestrant with an overall more favourable safety profile. Results are exploratory and subject to limitations.