A comparison of fulvestrant plus a targeted agent with fulvestrant alone in hormone receptor-positive advanced breast cancer that progressed on prior endocrine therapy: a meta-analysis

Liang Xu,1,* Ningning Yan,2,* Zhihua Li,1 Lihua Luo,3 Xiaobo Wu,1 Qiuming Liu,1 Yingchun Xu,4 Yali Cao1 1The First Department of Prevention and Cure Centre of Breast Disease, The Third Hospital of Nanchang City, Key Laboratory of Breast Disease in Jiangxi Province, Nanchang, JiangXi 330009, China; 2Department of Oncology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; 3Medical Department, Graduate School of Nanchang University, Nanchang, Jiangxi 330006, China; 4Department of Oncology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China *These authors contributed equally to this work Abstract: Fulvestrant is recommended for the hormone receptor-positive metastatic breast cancer (MBC) patients progressed during or after prior endocrine therapy. Notably, recent evidence has also demonstrated that adding a targeted agent to fulvestrant conferred a significantly clinical benefit in these patients. Since these results were inconsistent among the studies, this meta-analysis herein was conducted to compare the efficacy and toxicities of the fulvestrant-based combination therapy with fulvestrant monotherapy. Thus, a systemic research was performed in PubMed, Embase, and Cochrane library to identify relevant Phase II or Phase III randomized controlled trials. The progression-free survival (PFS), overall response rate (ORR), and toxicities were evaluated. And HR, risk ratio (RR), and their 95% CIs were employed to complete the pooled analyses. In total, 13 studies with 3,910-hour positive MBC patients progressed on prior endocrine therapy were included in our meta-analysis. Improvements of doublet-agents group were proven in terms of PFS (HR 0.73, 95% CI =0.63–0.86, P=0.000) and ORR (RR 2.07, 95% CI =1.67–2.58, P=0.000). And the further subgroup analysis also demonstrated that fulvestrant in combination with a cyclin-dependent kinase (CDK4/6) inhibitor or a PI3K/mTOR inhibitor was associated with a superior efficacy (RR 2.72, 95% CI =1.93–3.83, P=0.000 and RR 1.60, 95% CI =1.15–2.23, P=0.005, respectively). However, the efficacy was comparable between the other combination strategies and fulvestrant alone. With respect to the adverse effects, adding a targeted agent to fulvestrant also produced more frequent grade 3/4 toxicities (RR 3.86, 95% CI =2.66–5.61, P=0.000). Taken together, combination of fulvestrant with a targeted agent, especially inhibitors targeting CDK4/6 or PI3K/mTOR pathway, may open a new avenue for more effective therapies in relapse or metastatic hormone receptor-positive breast cancer after prior aromatase inhibitors or tamoxifen treatment. In addition, identifying reliable biomarkers to delineate which subgroup of patients will specially benefit from fulvestrant-based combination therapy is warranted. Keywords: fulvestrant, breast cancer, combination therapy, endocrine resistanc