Sapanisertib plus Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive/HER2-Negative Advanced Breast Cancer after Progression on Aromatase Inhibitor

Purpose: This phase II study investigated daily or weekly sapanisertib (a selective dual inhibitor of mTOR complexes 1 and 2) in combination with fulvestrant. Patients and Methods: Postmenopausal women with estrogen receptor-positive (ER+)/HER2-negative (HER2-) advanced or aromatase inhibitor treatment were randomized to receive fulvestrant 500 mg (28-day treatment cycles), fulvestrant plus sapanisertib 4 mg daily, or fulvestrant plus sapanisertib 30 mg weekly, until progressive disease, unacceptable toxicity, consent withdrawal, or study completion. Results: Among 141 enrolled patients, baseline characteristics were balanced among treatment arms, including prior cyclindependent kinase-4/6 (CDK4/6) inhibitor treatment in 33% to 35% of patients. Median progression-free survival (PFS; primary endpoint) was 3.5 months in the single-agent fulvestrant arm, compared with 7.2 months for fulvestrant plus sapanisertib daily [HR, 0.77; 95% confidence interval (CI), 0.47-1.26] and 5.6 months for fulvestrant plus sapanisertib weekly (HR, 0.88; 95% CI, 0.53- 1.45). The greatest PFS benefits were seen in patients who had previously received CDK4/6 inhibitors. The most common adverse events were nausea, vomiting, and hyperglycemia, all occurring more frequently in the combination therapy arms. Treatment discontinuation due to adverse events occurred more frequently in the two combination therapy arms than with single-agent fulvestrant (32% and 36% vs. 4%, respectively). Conclusions: Fulvestrant plus sapanisertib daily/weekly resulted in numerically longer PFS in patients with ER+/HER2-advanced or metastatic breast cancer, compared with single-agent fulvestrant. The combination was associated with increased toxicity. Further development of sapanisertib using these dosing schedules in this setting is not supported by these data.

Automated summary

This phase II study examined the efficacy and toxicity of daily or weekly combination treatment of sapanisertib with fulvestrant in postmenopausal women with estrogen receptor-positive/HER2-negative advanced or metastatic breast cancer. The study found that the combination treatment resulted in a numerically longer progression-free survival compared to single-agent fulvestrant, but was associated with increased toxicity.