Capivasertib: A New, Effective Drug for Hormone-Positive Breast Cancer

Breast cancer has become the most common cancer worldwide. Hormone receptor-positive (HR+) disease, which responds to hormonal treatments, accounts for most cases. However, treatment resistance remains a major problem. In recent years, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been introduced for advanced HR+ breast cancer. By inhibiting cancer cell growth and proliferation, these drugs can help prolong survival.

As with hormonal therapies, resistance to CDK4/6 inhibitors can develop over time. Cancer cells become unresponsive to these drugs, allowing the disease to progress. Resistance limits treatment options and adversely affects quality of life.

Developing new treatment strategies and drugs is therefore critical for advanced HR+ breast cancer. Activation of the AKT pathway is thought to be associated with hormonal therapy resistance. A study evaluating the effectiveness and safety of the AKT inhibitor capivasertib was published on June 1, 2023 in the leading medical journal NEJM. These CAPItello-291 findings represent important progress in this field.

The Effect of Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer

CAPItello-291 was a phase 3 randomized, double-blind trial involving pre-, peri- and postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Their disease had recurred or progressed during or after aromatase inhibitor therapy, with or without previous cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy.

Patients were randomly assigned 1:1 to capivasertib plus fulvestrant or placebo plus fulvestrant.

Capivasertib is a small-molecule drug developed by AstraZeneca that inhibits the AKT signaling pathway . This pathway regulates cell growth and division and becomes overactive in some cancers, causing uncontrolled growth and disease progression. By inhibiting it, capivasertib slows cancer cell growth and may help prevent progression.

The trial had dual primary endpoints: investigator-assessed progression-free survival in the overall population and among patients whose tumors had AKT pathway alterations (PIK3CA, AKT1 or PTEN).

Results

Overall, 708 patients were enrolled; 289 (40.8%) had AKT pathway alterations, and 489 (69.1%) had previously received a CDK4/6 inhibitor for advanced breast cancer.

• In the overall population, median progression-free survival was 7.2 months with capivasertib–fulvestrant and 3.6 months with placebo–fulvestrant (hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.51 to 0.71; P<0.001).
• Among patients with AKT pathway alterations, median progression-free survival was 7.3 months with capivasertib–fulvestrant and 3.1 months with placebo–fulvestrant (hazard ratio, 0.50; 95% CI, 0.38 to 0.65; P<0.001).

The most common grade 3 or higher adverse effects with capivasertib–fulvestrant were rash (12.1% versus 0.3%) and diarrhea (9.3% versus 0.3%). Treatment discontinuation due to adverse effects occurred in 13% in the capivasertib arm and 2.3% in the placebo arm.

Commentary

CAPItello-291 is an important step in demonstrating capivasertib's potential for advanced HR+ breast cancer. Results showed that, combined with fulvestrant, this AKT inhibitor can significantly prolong progression-free survival in patients whose disease has not responded to aromatase inhibitors or CDK4/6 inhibitor therapy. 

Capivasertib could receive FDA (US Food and Drug Administration) approval in the near future as a new option for these patients and offer a promising approach for treatment-resistant disease. Further information about long-term effects and overall survival is, of course, needed and will be a focus of future research.

In conclusion, this study of treatment resistance represents a new approach to advanced HR+ breast cancer and could accelerate progress in the field. Continued research of this kind may offer more options and hope for patients with resistant disease. It is always exciting to see medical science working continuously toward solutions that save lives and improve quality of life.

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Bonus Content: An infographic poster designed to help explain breast cancer treatments