Adding capivasertib to fulvestrant improves PFS in patients with advanced hormone receptor-positive breast cancer

Results of the phase III CAPItello-291 trial demonstrated that in patients with HR+/HER2- tumours resistant to aromatase inhibitors, the addition of the investigational AKT inhibitor capivasertib to fulvestrant doubled the median progression-free survival as compared to fulvestrant alone. In addition, the adverse event profile was manageable and consistent with data from previous studies.

AKT pathway activation has been implicated in the development of endocrine therapy resistance in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) advanced breast cancer (ABC). In the Phase II, placebo-controlled FAKTION trial, the addition of the pan-AKT inhibitor capivasertib to fulvestrant significantly improved progression-free survival (PFS) and overall survival (OS) in postmenopausal women with aromatase inhibitor (AI)-resistant HR+/HER2– ABC. The phase III, randomised, double-blind, placebo-controlled CAPItello-291 trial investigated the efficacy and safety of capivasertib plus fulvestrant in patients with AI-resistant HR+/HER2– ABC.

Study design

Eligible pre/peri- or postmenopausal women or men with HR+/HER2– ABC that had recurred or progressed on or after AI therapy with or without a cyclin-dependent kinase 4 and 6  (CDK4/6) inhibitor were randomised 1:1 to receive fulvestrant (per standard dosing schedule) with either placebo or capivasertib (400 mg twice daily; 4 days on, 3 days off). Randomisation was stratified by the presence of liver metastases, prior use of CDK4/6 inhibitors, and geographic location. AKT pathway alteration status (at least one qualifying PIK3CA, AKT1, or PTEN alteration) was determined using next-generation sequencing in tumour tissue. The dual primary endpoint was investigator-assessed PFS in the overall population and in patients with AKT pathway-altered tumours.

Results

In total, 708 patients were randomised to capivasertib plus fulvestrant (N= 355) or placebo plus fulvestrant (N= 353). Of them, 41% had AKT pathway altered tumours, 22% were pre- or perimenopausal and 1% was male. Prior therapy for advanced disease included: 87% of patients with ≥1 line of prior treatment, 69% with a prior CDK4/6 inhibitor, and 18% with prior chemotherapy. Demographic and baseline characteristics were broadly balanced between the overall and altered populations and by treatment groups. Patients treated with capivasertib plus fulvestrant had a median PFS of 7.2 months, compared to 3.6 months in patients treated with placebo plus fulvestrant. This amounted to a 40 percent lower risk of progression among patients who received capivasertib plus fulvestrant (HR[95%CI]: 0.60[0.51-0.71], p< 0.001). The benefit from capivasertib was consistent across clinically relevant subgroups, including in patients previously treated with a CDK4/6 inhibitor and in patients with liver metastases. The objective response rate (ORR) was 22.9% among patients treated with capivasertib plus fulvestrant, compared with 12.2% for patients treated with placebo plus fulvestrant. Among patients with AKT pathway mutations treated with capivasertib plus fulvestrant, the median PFS was 7.3 months, as compared to 3.1 months for patients in the placebo arm (HR[95%CI]: 0.50[0.38-0.65], p< 0.001). Corresponding ORR were 28.8% and 9.7%, respectively. Overall survival data only had a 28% maturity overall but were in favour of capivasertib in both the overall population (HR[95%CI]: 0.74[0.56-0.98]) and the AKT pathway-altered population (HR[95%CI]: 0.69[0.45-1.05]).

The most common adverse events of grade 3 or higher among patients treated with capivasertib plus fulvestrant were rash (12.1%), diarrhoea (9.3%), and hyperglycaemia (2.3%). The rate of discontinuation due to adverse events was 13% among patients who received capivasertib plus fulvestrant and 2.3% among patients who received placebo plus fulvestrant. The adverse event profile was manageable and consistent with data from previous studies.

Conclusion

Capivasertib plus fulvestrant provides a statistically significant and clinically meaningful improvement in PFS in the overall and the AKT pathway-altered population. The benefit from capivasertib was consistent across clinically relevant subgroups, including in patients previously treated with a CDK4/6 inhibitor and in patients with liver metastases. In addition, the safety profile of capivasertib plus fulvestrant appears consistent with that previously reported, with a relatively low discontinuation rate due to adverse events. As such, capivasertib plus fulvestrant has the potential to be a future treatment option for patients with HR+ ABC who have progressed on an endocrine-based regimen.

Reference

Turner N, 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. Presented at SABCS 2022; Abstract GS3-04.