The combination of capivasertib, an AKT pathway inhibitor, plus fulvestrant, an estrogen receptor antagonist, significantly improved progression-free survival compared with fulvestrant alone in patients with hormone receptor–positive, HER2-negative advanced breast cancer, according to results of the phase III CAPItello-291 trial presented at the 2022 San Antonio Breast Cancer Symposium. This benefit was seen in the overall study population, including patients with tumors harboring genetic alterations in the AKT pathway. The data were reported by lead author Nicholas C. Turner, MD, PhD, of the Royal Marsden Hospital and Institute of Cancer Research, London.¹

“This is a statistically significant and clinically meaningful improvement in progression-free survival in the overall population and the AKT pathway–altered population.”

— NICHOLAS C. TURNER, MD, PhD

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Median progression-free survival in the capivasertib-plus-fulvestrant arm was double that of the fulvestrant-plus-placebo arm—7.2 months vs 3.6 months—representing a 40% reduction in risk of disease progression or death that was statistically significant (P < .001). In patients who had AKT pathway–mutated tumors, median progression-free survival was 7.3 months in the capivasertib arm vs 3.1 months in the placebo arm, with a 50% reduction in risk of disease progression or death (P < .001).

“This is a statistically significant and clinically meaningful improvement in progression-free survival in the overall population and the AKT pathway–altered population [the dual primary endpoint]. The benefit of capivasertib was consistent across clinically relevant subgroups. The improvement in progression-free survival with relatively well-tolerated [adverse] effects is extremely encouraging,” said Dr. Turner. “We are hopeful that capivasertib will become a new treatment option for patients with hormone receptor–positive advanced breast cancer [whose disease has] progressed on an endocrine-based regimen.”

The objective response rate was 22.9% in the capivasertib-plus-fulvestrant arm vs 12.2% in the fulvestrant-plus-placebo arm. In patients with AKT pathway–mutated breast cancer, the objective response rate was 28.8% vs 9.7% in the capivasertib and placebo arms, respectively.

Study Details

A total of 708 patients were randomly assigned 1:1 to treatment with either capivasertib plus fulvestrant (n = 355) or placebo plus fulvestrant (n = 353). Patients with AKT pathway–altered tumors were also randomly assigned to either the capivasertib arm (n = 155) or the placebo arm (n = 134). Patients received 400 mg twice daily of capivasertib for 4 days on and 3 days off plus 500 mg of fulvestrant during cycle 1 on days 1 and 15, then every 4 weeks. Patients in the control arm received a matching placebo plus fulvestrant.

Patients enrolled in the trial had hormone receptor–positive, HER2-negative advanced breast cancer. Both menopausal and premenopausal women were enrolled who had experienced disease recurrence or progression within 12 months from the end of adjuvant aromatase inhibitor therapy or had disease progression while on an aromatase inhibitor in the metastatic setting. Up to two lines of prior endocrine therapy and up to one line of prior chemotherapy, with or without prior CDK4/6 inhibitor therapy, were permitted. Tumor tissue from the primary or recurrent tumor was available for molecular testing.

The dual primary endpoints were progression-free survival according to investigator assessment both in the overall population and in those with AKT pathway–altered tumors. Secondary endpoints included overall survival and objective response rates.

In the overall population, a majority of patients had received one prior line of endocrine therapy (80.6% in the capivasertib plus fulvestrant arm vs 71.4% in the placebo plus fulvestrant arm, respectively); the percentages were similar in the patients with AKT pathway–altered tumors (83.9% vs 71.6%, respectively). Prior CDK4/6 inhibitors were given to 69.0% vs 69.1%, respectively, in the overall population and to 72.9% vs 67.9%, respectively, in the AKT pathway–altered population.

Previous adjuvant/neoadjuvant therapy in the overall population was used by 50.7% vs 48.2%, respectively, and by about 50% in the groups with AKT alterations.

In the overall population, the investigator-assessed progression-free survival was 7.2 months in the capivasertib arm vs 3.7 months in the placebo arm, reflecting a 40% reduction in risk of disease progression or death (P < .001). In the AKT-altered population, median progression-free survival was 7.3 months and 3.1 months, respectively, a 50% reduction in risk when capivasertib was given. In a prespecified subgroup analysis, a consistent benefit of capivasertib was observed in all subgroups, including those previously treated with a CDK4/6 inhibitor and in those with liver metastases.

The planned survival analysis showed a 26% reduction in the risk of death in the overall population and a 31% risk reduction in the AKT pathway–altered group in the capivasertib-plus-fulvestrant arms. Overall survival follow-up is ongoing.

Grade 3 or greater adverse events that were more common in the capivasertib group were diarrhea (9.3% vs 0.3%, respectively), maculopapular rash (6.2% vs 0%), rash (5.4% vs 0.6%), hyperglycemia (2.3% vs 0.3%), and stomatitis (2.0% vs 0%). Discontinuation of therapy due to adverse events was reported in 2.3% of patients in both the capivasertib and placebo arms. 

DISCLOSURE: CAPItello-291 is sponsored by AstraZeneca. Dr. Turner has served as a consultant or advisor to Arvinas, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Inivata, Eli Lilly, Merck Sharpe & Dohme, Novartis, Pfizer, Repare Therapeutics, Roche/Genentech, and Zentalis Pharmaceuticals; and has conducted contracted research for AstraZeneca, Bio-Rad, Guardant Health, Inivata, Invitae, Merck Sharpe & Dohme, Natera, Personalis, Pfizer, and Roche/Genentech.

REFERENCE

1. Turner N, Oliveria M, Howell SJ, et al: Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the Phase III CAPItello-291 trial. 2022 San Antonio Breast Cancer Symposium. Abstract GS3-04. Presented December 8, 2022.