Fulvestrant in the treatment of luminal HER-2-negative metastatic breast cancer

Hormonal therapy is an effective treatment for luminal HER2-negative metastatic breast cancer (mBC). Aromatase inhibitors and fulvestrant are the mainstays of hormone therapy. Fulvestrant is both a competitive antagonist and a selective estrogen receptor degrader (SERD), this mechanism of action provides complete blocking of the estrogen signaling pathway. In the FALCON phase III study (n = 462), which included postmenopausal MBC patients who had not previously received any endocrine therapy, fulvestrant 500 mg was compared with the aromatase inhibitor anastrozole. Significant improvement in PFS was achieved with fulvestrant therapy compared to anastrozole: 16.6 months in the fulvestrant group versus 13.8 months with anastrozole [OR = 0.797; 95% CI 0.637–0.999; P = 0.0486]. A subgroup analysis showed that patients without visceral metastases can benefit most from taking fulvestrant. In all studies fulvestrant 500 mg has demonstrated a good toxicity profile, so it is being studied as a component of combined endocrine therapy. In the PALOMA-3 study the combination of fulvestrant with palbociclib (CDK4/6 inhibitor) demonstrated a median PFS 9.5 months, compared with monotherapy with fulvestrant – 4.6 months (HR = 0.46, p < 0.0001). In the MONALEESA-3 study, the median PFS in patients receiving ribociclib with fulvestrant was significantly higher compared to those taking placebo with fulvestrant: 20.5 months and 12.8 months, respectively (HR = 0.593; 95% CI: 0.480–0.732; p < 0.001). In the MONARCH-2 study the combination of fulvestrant and abemaciclib was studied in the second line of therapy, the median PFS was 16.4 months in the group of fulvestrant and abemaciclib, and 9.3 months in the group of fulvestrant and placebo (HR = 0.553; 95% CI 0.449–0.681; p < 0.0001). The SOLAR-1 study demonstrated the efficacy of the combination of fulvestrant + alpelisib (PI3K inhibitor) in luminal HER2-negative mBC associated with PIK3CA mutation in the first and second lines of therapy. The median PFS in the fulvestrant + alpelisib group was 11 months compared with 5.7 months in the fulvestrant group (HR = 0.65; 95% CI 0.50–0.85; p < 0.001). Based on clinical research data, the combination of aromatase inhibitors with CDK4/6 inhibitors is the optimal first-line treatment in patients with hormone-sensitive tumors, i.e. with progression more than 1 year after the end of adjuvant hormone therapy. While fulvestrant ± CDK4/6 inhibitors is used for disease progression on the background of adjuvant hormone therapy in the first line or as a second line for progression on aromatase inhibitor therapy for metastatic cancer. The combination fulvestrant + alpelisib is highly effective in the second-line treatment of luminal HER2negative breast cancer in the presence of a PIK3CA mutation.