FDA Approves Capivasertib Plus Fulvestrant in Advanced HR+, HER2– Breast Cancer

Patients with locally advanced or metastatic breast cancer that is hormone receptor–positive, HER2-negative breast cancer with 1 or more PIK3CA, AKT1, or PTEN alterations may now receive capivasertib plus fulvestrant.

The FDA has approved capivasertib plus fulvestrant (Faslodex) for patients with locally advanced or metastatic breast cancer that is hormone receptor (HR)–positive, HER2-negative with 1 or more PIK3CA, AKT1, or PTEN alterations, and has progressed on or after 1 endocrine-based regimen in the metastatic setting, or recurrence on or within 12 months of completing adjuvant treatment.¹

The approval is based on results from the phase 3 CAPItello-291 trial (NCT04305496), in which the efficacy of the combination was evaluated.² Initial results were reported at the 2022 San Antonio Breast Cancer Symposium.

The FDA simultaneously approved the FoundationOne®CDx assay as a companion diagnostic device, which will be used to identify patients with breast cancer who can receive capivasertib plus fulvestrant.

“We do need novel drugs in the second-line setting and beyond, for hormone receptor–positive metastatic breast cancer. The CAPItello-291 phase 3 trial showed that we could potentially have the first agent targeting AKT that is potentially approved and may help to treat certain patients with HR-positive, HER2-negative metastatic breast cancer with activity that is very intriguing, that promises also to have an impact on the quality of life of these patients,” said Paolo Tarantino, MD, a medical oncologist from Dana-Farber Cancer Institute, in an interview with CancerNetwork.

A total of 708 patients were enrolled and were randomly assigned to either the capivasertib plus fulvestrant group (n = 355) or the placebo plus fulvestrant group (n = 353). Most notable was those 289 patients who harbored PIK3CA/AKT1/PTEN alterations.

The median age was 58 years, and 77.3% were postmenopausal. The entire study population had HER2–negative disease, with 69.1% of patients previously receiving a CDK4/6 inhibitor, and 18.2% receiving chemotherapy for advanced cancer.

At the data cutoff, 17.7% of patients were still receiving the combination treatment, and 12.3% received the placebo. For patients on capivasertib, the median duration of treatment was 5.4 months, vs 3.6 months in the placebo group. For those receiving fulvestrant in the combination group, the median duration of treatment was 5.8 months vs 3.7 months in the placebo group.

A total of 82.3% of patients discontinued capivasertib vs 87.7% who discontinued fulvestrant. The main reasons for discontinuation were disease progression (58.9% vs 78.0%) between both treatment groups, respectively.

The median progression-free survival (PFS) in the combination group was 7.2 months vs 3.6 months in the placebo group (HR, 0.60; 95% CI, 0.51-0.71; P <.001). For patients who had an AKT pathway alteration, the median PFS in the combination group was 7.3 months (95% CI, 5.5-9.0) vs 3.1 months (95% CI, 2.0-3.7) in the placebo group (HR, 0.50; 95% CI, 0.38-0.65; P <.0001).

An exploratory analysis was conducted regarding patients with AKT pathway-non-altered tumors. This included patients who had unknown results on next-generation sequencing (NGS) (n = 419; HR, 0.79; 95% CI, 0.56-0.88); those with AKT pathway–non-altered tumors, excluding patients with unknown results on NGS (n = 313; HR, 0.79; 95% CI, 0.61-1.02); and those with an unknown result on NGS (n = 106; HR in the post-hoc analysis, 0.52; 95% CI, 0.32-0.83).

A PFS analysis on blinded independent central review was determined to be similar to the investigator-assessed analyses in the overall population (HR, 0.61; 95% CI, 0.50-0.73) and the AKT pathway population (HR, 0.51; 95% CI, 0.38-0.68).

Overall, 27.5% of patients had died at the time of the analysis. At 18 months, the estimated overall survival (OS) was 73.9% (95% CI, 68.3%-78.7%) in the combination group and 65.0% (95% CI, 58.7%-70.6%) in the placebo group (HR, 0.74; 95% CI, 0.56-0.98) in the overall population. For the AKT pathway population, the OS at 18 months was 73.2% (95% CI, 64.8%-80.0%) in the combination group and 62.9% (95% CI, 53.1%-71.2%) in the placebo group (HR, 0.69; 95% CI, 0.45-1.05).

Regarding safety, the most common adverse effects (AEs) occurred in 72.4% of patients in the combination arm and 20.0% in the placebo arm. These included rash (38.0% vs 7.1%), and nausea (34,6% vs 15.4%) in both groups, respectively. Grade 3 or higher AEs that were most common included rash (12.1% vs 0.3%), diarrhea (9.3% vs 0.3%), and hyperglycemia (2.3% vs 0.3%) between both groups, respectively.

In the combination arm, serious AEs occurred in 16.1% of patients in the combination arm and 8.0% in the placebo arm. A total of 4 patients died due to AEs in the combination arm vs 1 in the placebo arm. No deaths were in relation to the treatment of capivasertib plus fulvestrant.

A dose interruption due to AEs occurred in 34.9% of patients receiving capivasertib vs 10.3% receiving placebo, a dose reduction occurred in 19.7% vs 1.7%, and discontinuation due to AEs occurred in 13.0% vs 2.3% of patients.

References

1. FDA approves capivasertib with fulvestrant for breast cancer. News release. FDA. November 16, 2023. Accessed November 16, 2023. https://shorturl.at/abtH8
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