A phase II clinical trial has explored the efficacy of combining enzalutamide with fulvestrant in the neoadjuvant treatment of ER+/HER2- breast cancer. The study, an open-label randomized trial, aimed to assess whether the addition of enzalutamide could enhance the response to fulvestrant, a standard endocrine therapy. The research was conducted across multiple institutions and involved pre- or peri-menopausal women receiving concurrent ovarian suppression with a gonadotropin-releasing hormone agonist.
Trial Design and Patient Population
The trial enrolled women aged 18 years or older with primary breast cancer (≥T2, N0-2, M0) that was ER positive and HER2 negative. Patients received fulvestrant 500 mg intramuscularly on days 1, 15, and 29, and then every 4 weeks for a total of 4 months. Those in the combination arm also received enzalutamide 160 mg orally daily for 4 months. The primary endpoint was the pathological and endocrine prognostic index (PEPI) score, which assesses residual tumor burden, nodal status, and Ki67 levels after treatment.
Key Findings
The study utilized a Simon 2-stage design, and clinical benefit was assessed by PEPI score. The trial stratified patients by institution, clinical node status, and T-stage. Notably, the combination therapy arm aimed to terminate early if ≤3 patients out of the first 22 achieved a PEPI score of 0, indicating a high likelihood of treatment success. Serial tissue studies, including IHC for ER, PR, AR, GR, Ki67, and cleaved caspase 3, were performed to evaluate changes in tumor biology. Reverse-phase protein array (RPPA) and metabolomics analyses were also conducted to identify potential biomarkers associated with treatment response.
Impact on Tumor Biology and Immune Response
Results from the trial indicated that the combination of fulvestrant and enzalutamide led to significant changes in tumor biology. Specifically, the study observed reductions in Ki67, a marker of cell proliferation, in the combination arm compared to fulvestrant alone. Furthermore, the trial investigated the impact of treatment on tumor-associated immune cells using multispectral imaging. The analysis focused on cells such as CD68+ macrophages and myeloid-derived suppressor cells (MDSCs), revealing potential alterations in the tumor microenvironment in response to the combination therapy.
Metabolomic and Proteomic Insights
Plasma metabolomics analyses identified differences in metabolite expression based on PEPI response and treatment arm. These findings offer insights into the metabolic pathways affected by the therapies and potential biomarkers for predicting treatment outcomes. RPPA analysis further elucidated differences in phosphoprotein abundance related to PEPI response and Ki67 levels, providing a deeper understanding of the signaling pathways modulated by the combination treatment.
Safety and Tolerability
Safety was monitored through adverse event (AE) assessments, physical examinations, and laboratory tests. The severity of AEs was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). The study also included measures for managing and monitoring potential pharmacokinetic interactions between concomitant medications and enzalutamide.
