The addition of capivasertib to fulvestrant improves time to second progression (PFS2) and time to first subsequent chemotherapy or death (TSFC) in PIK3CA/AKT1/PTEN-altered patients with HR+/HER2- advanced breast cancer and the overall population, suggesting a clinically meaningful benefit when compared with placebo plus fulvestrant, as shown in the phase III CAPItello-291 trial.
Furthermore, the combination of capivasertib and fulvestrant confers a numerically higher overall survival (OS) than placebo plus fulvestrant, albeit statistically nonsignificant.
In the primary analysis of CAPItello-291, capivasertib plus fulvestrant provided a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in the PIK3CA/AKT1/PTEN-altered and overall populations relative to fulvestrant alone, according to lead study author Dr Hope S Rugo, City of Hope Medical Center, Los Angeles, US.
In this trial, Rugo and her team randomized 708 patients to capivasertib (400 mg BID; 4 days on, 3 days off; n=355) plus fulvestrant (500 mg IM on days 1 and 15 of cycle 1, and day 1 of each subsequent 28-day cycle; n=353) or to placebo plus fulvestrant.
OS in the PIK3CA/AKT1/PTEN-altered and overall populations was a key secondary endpoint. Other endpoints included PFS2, defined as time from randomization to second progression (earliest of either death or a progression event following subsequent treatment after first progression), and TFSC.
Rugo and colleagues used a Cox proportional hazard model to examine all endpoints and log-rank test to assess OS. They also stratified analyses by liver metastases, region (overall only), and prior CDK4/6i.
Survival benefit
In the final OS analysis, a numerical trend in hazard ratio (HR) favoured capivasertib vs placebo plus fulvestrant in the PIK3CA/AKT1/PTEN-altered population, but this did not reach statistical significance (median OS, 28.5 vs 30.4 months; HR, 0.83, 95 percent confidence interval [CI], 0.63‒1.10; p=0.201). [ESMO Breast Cancer 2026, abstract 4170]
OS in the overall population was no longer formally explored since no statistical significance was reached in the altered population. No numerical between-group difference was seen in the risk of death (median OS, 29.4 vs 28.6 months; HR, 1.00, 95 percent CI, 0.83‒1.19).
“Extensive post-progression therapy likely confounded OS, with a high burden of subsequent treatment lines and greater use of targeted therapies in the placebo–fulvestrant arm vs the capivasertib–fulvestrant arm, potentially diluting the treatment effect,” Rugo said.
The combination of capivasertib and fulvestrant also retained treatment benefits through PFS2, which was numerically improved in both overall and PIK3CA/AKT1/PTEN-altered populations (median PFS2, 15.4 vs 12.7 months; HR, 0.85, 95 percent CI, 0.72‒1.00).
Similarly, capivasertib‒fulvestrant prolonged TFSC in both populations when compared with placebo‒fulvestrant (median TFSC, 11.0 vs 7.0 months; HR, 0.74, 95 percent CI, 0.87).
“At final analysis, the combination showed sustained, meaningful benefit beyond PFS, evidenced by improvements in PFS2 and delayed TTFSC across both the PIK3CA/AKT1/PTEN-altered and overall populations,” Rugo said.
The safety profile of capivasertib plus fulvestrant remained consistent with the primary analysis, with no new safety signals identified.
“Capivasertib–fulvestrant provides lasting treatment benefit versus placebo–fulvestrant, with manageable safety,” Rugo said. “OS interpretation is limited by study power and post-progression treatment confounding.”