Capivasertib/Fulvestrant Improves PFS2 in Pretreated PIK3CA/AKT1/PTEN+ HR+/HER2– Breast Cancer

Hope S. Rugo, MD

The addition of capivasertib (Truqap) to fulvestrant (Faslodex) led to an improvement in time to second progression (PFS2) compared with fulvestrant alone in patients with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer, including in patients harboring at least 1 PIK3CA, AKT1, or PTEN alteration, according to data from the phase 3 CAPItello-291 trial (NCT04305496) presented during the 2024 ESMO Breast Cancer Congress.¹

Findings showed that in the overall population, patients treated with capivasertib plus fulvestrant (n = 355) experienced a median PFS2 of 14.7 months (95% CI, 13.6-16.4) compared with 12.5 months (95% CI, 11.3-13.4) for those given placebo plus fulvestrant (n = 353; adjusted HR, 0.70; 95% CI, 0.57-0.86).

In the PIK3CA/AKT1/PTEN-altered population, the median PFS2 was 15.5 months (95% CI, 13.2-17.6) in the capivasertib arm (n = 155) compared with 10.8 months (95% CI, 8.1-12.7) for the placebo arm (n = 134; adjusted HR, 0.52; 95% CI, 0.38-0.71).

Furthermore, capivasertib plus fulvestrant delayed time to first subsequent chemotherapy (TFSC) in the overall and PIK3CA/AKT1/PTEN-altered populations. In the overall population, the median TFSC was 11.0 months (95% CI, 9.4-13.0) for the capivasertib plus fulvestrant arm compared with 6.8 months (95% CI, 5.7-8.0) for the placebo plus fulvestrant arm (adjusted HR, 0.63; 95% CI, 0.52-0.75). In the PIK3CA/AKT1/PTEN-altered populations, the median TFSC was 11.0 months (95% CI, 9.1-13.6) in the capivasertib group compared with 6.0 months (95% CI, 4.4-8.0) in the placebo group (adjusted HR, 0.56; 95% CI, 0.42-0.74).

“[These]data demonstrates that capivasertib with fulvestrant provided long-lasting benefits retained through PFS2 in patients with hormone receptor–positive, HER2-negative advanced disease who progressed on or after an endocrine-based regimen,” Hope S. Rugo, MD, stated in a presentation of the data.

Rugo serves as a professor in the Department of Medicine, Hematology/Oncology, director of Breast Oncology and Clinical Trials Education, and the medical director of Cancer Infusion Services at the University of California, San Francisco, Helen Diller Comprehensive Cancer Center.

In November 2023, the FDA approved capivasertib in combination with fulvestrant for the treatment of patients with HR-positive/HER2-negative, locally advanced or metastatic breast cancer harboring 1 or more PIK3CA/AKT1/PTEN alterations following progression on at least 1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.²

This regulatory approval was based on previously reported data from CAPItello-291, which showed that capivasertib plus fulvestrant generated a statistically significant and clinically meaningful improvement in PFS compared with fulvestrant alone in the overall population and the PIK3CA/AKT1/PTEN-altered population. In the overall population, patients in the capivasertib arm achieved a median progression-free survival (PFS) of 7.2 months (95% CI, 5.5-7.4) compared with 3.6 months (95% CI, 2.8-3.7) for patients receiving placebo plus fulvestrant (HR, 0.60; 95% CI, 0.51-0.71; P <.001). In patients harboring alterations in the AKT pathway, the median PFS was 7.3 months (95% CI, 5.5-9.0) for the capivasertib regimen vs 3.1 months (95% CI, 2.0-3.7) for the placebo regimen (HR, 0.50; 95% CI, 0.38-0.65; P <.001).³

The randomized, double-blind, placebo-controlled CAPItello-291 trial enrolled men and pre- or post-menopausal women with locally advanced or metastatic, hormone receptor–positive, HER2-negative breast cancer who experienced recurrence or progression during or within 12 months of completing adjuvant treatment with an aromatase inhibitor (AI), or during prior AI therapy for advanced breast cancer. Additionally, eligible patients must have undergone no more than 2 lines of prior endocrine therapy for advanced disease; no more than 1 line of chemotherapy; and no prior treatment with selective estrogen receptor degraders (SERDs), mTOR inhibitors, PI3K inhibitors, or AKT inhibitors. However, prior treatment with CDK4/6 inhibitors was permitted. Notably, patients with HbA1c levels below 8.0% (63.9 mmol/mol) and diabetes not requiring insulin were eligible for enrollment.

Patients were randomly assigned 1:1 to receive capivasertib at 400 mg twice daily for 4 days on and 3 days off plus fulvestrant at 500 mg on days 1 and 15 during cycle 1, then once every 4 weeks thereafter; or placebo twice daily for 4 days on, 3 days off plus the same fulvestrant regimen. Stratification factors included liver metastases (yes vs no), treatment with a prior CDK4/6 inhibitor (yes vs no), and region.

The dual primary end points of the study were PFS by investigator assessment in the overall population and in the PIK3CA/AKT1/PTEN-altered population. Key secondary end points included overall survival (OS), overall response rate (ORR), and PFS2 in both patient populations. TFSC was an exploratory end point.

In the overall population for the capivasertib plus fulvestrant arm, the median age of patients was 59 years (range, 26-84), and 80.8% were post-menopausal. Metastatic sites included bone only (14.4%) and visceral (66.8%). Primary endocrine resistance was reported at baseline in 35.8% of patients. The number of prior endocrine therapy regimens for advanced breast cancer included 0 lines (11.0%), 1 line (80.8%), and 2 lines (8.2%). Previous CDK4/6 inhibitor use was noted in 69.6% of patients, and 18.3% received previous chemotherapy for advanced breast cancer.

In the placebo/fulvestrant group, the median age was 58 years (range, 26-90), and 73.7% were post-menopausal. Metastatic sites included bone only (14.7%) and visceral (68.3%). Primary endocrine resistance was reported in 38.2% of patients at baseline. Prior endocrine therapy for advanced breast cancer included 0 lines (15.3%), 1 line (71.4%), and 2 lines (13.3%). Additionally, 70.5% of patients received a prior CDK4/6 inhibitor, and previous chemotherapy for advanced disease was given to 18.1% of patients.

Additional data showed that among patients in the overall population receiving capivasertib/fulvestrant, 70.1% of patients had disease progression, and 67.0% of patients went on to receive subsequent treatment. First subsequent treatment consisted of cytotoxic chemotherapy (43.1%), hormone therapy (22.3%), and targeted therapy (13.0%). In the placebo arm, 79.6% of patients had disease progression, and 74.8% went on to receive a first subsequent treatment, including cytotoxic chemotherapy (47.9%), hormone therapy (23.5%), or targeted therapy (18.1%).

Among patients in the PIK3CA/AKT1/PTEN-altered population treated with capivasertib/fulvestrant, 74.2% of patients had disease progression, and 69.0% went on to receive a first subsequent treatment, including cytotoxic chemotherapy (43.2%), hormone therapy (23.9%), and targeted therapy (11.6%). In the placebo group, 80.6% of patients experienced disease progression, and 78.4% received a first subsequent therapy, including cytotoxic chemotherapy (50.0%), hormone therapy (25.4%), or targeted therapy (21.6%).

Furthermore, in the overall population, treatments given in any subsequent line of therapy included cytotoxic chemotherapy (capivasertib/fulvestrant, 56.1%; placebo/fulvestrant, 61.2%), hormone therapy (27.6%; 30.3%), and targeted therapy (18.9%; 25.8%). In the PIK3CA/AKT1/PTEN-altered population, treatments given in any subsequent line of therapy, included cytotoxic chemotherapy (60.0%; 62.7%), hormone therapy (27.7%; 35.1%), and targeted therapy (16.8%; 32.1%).

References

1. Rugo HS, Oliveira M, Howell SJ, et al. Capivasertib and fulvestrant (F) for patients (pts) with aromatase inhibitor (AI)-resistant HR+/HER2- advanced breast cancer (ABC): Second progression-free survival (PFS2) and time to first subsequent chemotherapy (TFSC) in the CAPItello-291 trial. Presented at: 2024 ESMO Breast Cancer Congress; May 15-17, 2024; Berlin, Germany. Abstract 183MO.
2. FDA approves capivasertib with fulvestrant for breast cancer. FDA. November 16, 2023. Accessed May 16, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer
3. 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