On 16 November 2023, the US Food and Drug Administration (FDA) approved capivasertib (Truqap, AstraZeneca Pharmaceuticals) with fulvestrant for adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alterations, as detected by an FDA-approved test, following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.

FDA also approved the FoundationOne®CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with capivasertib with fulvestrant. 

Efficacy was evaluated in CAPItello-291 (NCT04305496), a randomised, double-blind, placebo-controlled, multicentre study in 708 patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer, of which 289 patients had tumours with PIK3CA/AKT1/PTEN alterations. All patients were required to have progression on aromatase inhibitor-based treatment. Patients could have received up to two prior lines of endocrine therapy and up to 1 line of chemotherapy for locally advanced or metastatic disease.

Patients were randomised (1:1) to either capivasertib 400 mg or placebo administered orally twice daily for 4 days, followed by 3 days off treatment each week over a 28-day treatment cycle. Both investigational and control arm patients received fulvestrant 500 mg intramuscularly on cycle 1 days 1 and 15, and then every 28 days thereafter. Patients received therapy until disease progression or unacceptable toxicity.

The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) in the overall population and in the population of patients whose tumours had PIK3CA/AKT1/PTEN alterations evaluated according to RECIST, version 1.1. A statistically significant difference in PFS was observed in the overall population and in the population of patients whose tumours have PIK3CA/AKT1/PTEN alteration(s).

In the 289 patients with PIK3CA/AKT1/PTEN-altered tumours, the median PFS was 7.3 months (95% confidence interval [CI] 5.5, 9.0) in the capivasertib-fulvestrant group and 3.1 months (95% CI 2.0, 3.7) in the placebo-fulvestrant group (hazard ratio [HR] 0.50, 95% CI 0.38, 0.65; p-value < 0.0001).

An exploratory analysis of PFS in the 313 (44%) patients whose tumours did not have a PIK3CA/AKT1/PTEN alteration showed a HR of 0.79 (95% CI 0.61, 1.02), indicating that the difference in the overall population was primarily attributed to the results seen in the population of patients whose tumours have PIK3CA/AKT1/PTEN alteration.

The most common adverse reactions (reported in ≥20% of patients), including laboratory abnormities were diarrhoea, cutaneous adverse reactions, increased random glucose, decreased lymphocytes, decreased haemoglobin, increased fasting glucose, nausea, fatigue, decreased leukocytes, increased triglycerides, decreased neutrophils, increased creatinine, vomiting and stomatitis.   

The recommended capivasertib dose is 400 mg orally twice daily (approximately 12 hours apart), with or without food, for 4 days followed by 3 off days until disease progression or unacceptable toxicity.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE). Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, Israel’s Ministry of Health, Singapore’s Health Sciences Authority, Switzerland’s Swissmedic, and United Kingdom’s Medicines and Healthcare Products Regulatory Agency. The application reviews are ongoing at the other regulatory agencies.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 2 weeks ahead of the FDA goal date.

This application was granted priority review.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Faciliate.