Capivasertib/Fulvestrant Yields Numerical OS Advantage in PIK3CA/AKT1/PTEN–Altered Breast Cancer

The addition of the AKT inhibitor capivasertib (Truqap) to fulvestrant (Faslodex) demonstrated a numerical trend toward improved overall survival (OS) compared with placebo plus fulvestrant in patients with PIK3CA/AKT1/PTEN–altered, hormone receptor–positive, HER2-negative advanced breast cancer, according to final results from the phase 3 CAPItello-291 trial (NCT04305496) presented at the 2026 ESMO Breast Cancer Congress.¹

In the PIK3CA/AKT1/PTEN–altered patient population (n = 289), the median OS was 28.5 months with capivasertib plus fulvestrant compared with 30.4 months with placebo plus fulvestrant (HR, 0.83; 95% CI, 0.63-1.10; P = .201). Although this trend numerically favored the investigational combination, the trial was underpowered (at 53%) to detect a statistically significant OS difference in this patient subgroup. In the overall population (n = 708), no meaningful numerical difference in the risk of death was observed; the median OS was 29.4 months vs 28.6 months, respectively (HR, 1.00; 95% CI, 0.83-1.19).

“The combination at final analysis showed a sustained benefit beyond progression-free survival [PFS], with an improvement in [time to second progression] and time to first subsequent chemotherapy [TTFSC] across both the altered and overall populations,” Hope S. Rugo, MD, FASCO, stated in the presentation of the data.

Rugo is director of the Women’s Cancers Program; division chief of breast medical oncology; and a professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center in Duarte, California.

What was the design of the phase 3 CAPItello-291 trial?

The double-blind, placebo-controlled trial randomly assigned 708 patients with hormone receptor–positive, HER2-negative advanced breast cancer 1:1 to receive either:

• Capivasertib (400 mg twice daily; 4 days on, 3 days off) plus fulvestrant (500 mg every 4 weeks with a loading dose)
• Placebo plus fulvestrant

Eligible patients had progressed on or within 12 months of completing adjuvant aromatase inhibitor therapy, or during aromatase inhibitor therapy for advanced disease. Prior treatment with a CDK4/6 inhibitor was allowed and required for at least 51% of patients in the cohort.

The study had dual primary end points of PFS in the PIK3CA/AKT1/PTEN–altered and overall populations, both of which were met at the primary analysis. OS served as a key secondary end point.

What data from CAPItello-291 have been previously reported?

At the primary analysis, the addition of capivasertib to fulvestrant generated a statistically significant and clinically meaningful PFS improvement across both the altered and overall populations.² In the altered population, the median PFS was 7.3 months (95% CI, 5.5-9.0) in the capivasertib arm vs 3.1 months (95% CI, 2.0-3.7) in the control arm (HR, 0.50; 95% CI, 0.38-0.65; P < .001). In the overall population, these respective values were 7.2 months (95% CI, 5.5-7.4) and 3.6 months (95% CI, 2.8-3.7; HR, 0.60; 95% CI, 0.51-0.71; P < .001). The PFS benefit in the overall population was observed regardless of ESR1 mutation status in circulating tumor DNA, including in patients who had received first-line aromatase inhibition plus a CDK4/6 inhibitor.

What additional efficacy signals were observed in the final analysis?

In the final OS analysis, investigators noted a clinically relevant subgroup signal among patients in the altered population who had received prior CDK4/6 inhibitor therapy.¹ In these patients, capivasertib plus fulvestrant extended the median OS by 6.9 months compared with the control arm (28.1 months vs 21.2 months; HR, 0.78; 95% CI, 0.57-1.07).

Regarding subsequent treatment patterns in the overall population, in the capivasertib arm (n = 355), the rates of patients receiving 3 or 4 or more subsequent lines of treatment were 17.5% and 24.2%, respectively. In the control arm (n = 353), these respective rates were 15.6% and 26.6%. Additionally, a higher rate of targeted therapy use following CAPItello-291 discontinuation was seen in the control arm (36.0%) vs the capivasertib arm (29.6%).

Furthermore, capivasertib delayed the TTFSC across both populations. In the altered population, the median TTFSC was 11.0 months with capivasertib vs 6.0 months with placebo (HR, 0.62; 95% CI, 0.48-0.80). In the overall population, these values were 11.0 months and 7.0 months, respectively (HR, 0.74; 95% CI, 0.63-0.87).

What was the safety profile of the capivasertib combination?

The safety profile at the final analysis remained consistent with that seen in the primary analysis, with no new safety signals identified. In the altered population, the most common adverse effects (AEs) of any grade in the capivasertib arm included:

• Diarrhea (77%)
• Rash (41%)
• Nausea (35%)
• Fatigue (23%)
• Vomiting (22%)

Dose reductions were required for 21.9% of patients in the capivasertib arm compared with 0.8% of those in the placebo arm. Treatment discontinuation due to AEs occurred in 6.5% and 0.8% of patients, respectively.

“Capivasertib/fulvestrant still provides lasting treatment benefit vs placebo/fulvestrant with manageable safety,” Rugo concluded. “OS interpretation is limited by study power and post-progression treatment confounding, an increasing issue in our phase 3 trials.”

Disclosures: Rugo reported receiving grants to her prior institution (the University of California San Francisco) from AstraZeneca, Gilead Sciences, Lilly, Merck & Co., Daiichi Sankyo, Novartis Pharmaceuticals, Pfizer, F. Hoffman-La Roche/AG/Genentech, Stemline Therapeutics, and Ambryx; as well as receiving grants to City of Hope Comprehensive Cancer Center from Bicycle Therapeutics, F. Hoffman-La Roche/AG/Genentech, PhoenixMD, Merck, Relay Therapeutics, ALX Oncology, Pfizer, and Stemline Therapeutics. She also reported performing consulting or advisory roles with Napo, Bristol Myers Squibb, Helsinn, and BioNTech.

References

1. Rugo HS, Oliveira M, Howell S, et al. Capivasertib (C) and fulvestrant (F) for patients (pts) with HR+/HER2_ advanced breast cancer (ABC): final overall survival (OS) results from the phase 3 CAPItello-291 trial. Presented at: 2025 ESMO Breast Cancer Congress. May 6-8, 2026; Berlin, Germany. Abstract 417O.
2. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131