Endocrine-based targeted combination versus endocrine therapy alone as first-line treatment in elderly patients with hormone receptor-positive advanced breast cancer: Meta-analysis of phase II and III randomized clinical trials.

Background: Combined endocrine approaches have been widely investigated as 1st-line treatment in hormone receptors positive metastatic breast cancer. In particular, multiple randomized trials showed that the addiction of CDK (cyclindependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged ≥ 65 years) are under represented in most of the clinical studies. Moreover, due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present metaanalysis aimed to understand the role of the new endocrine approaches in women aged ≥65 years. Methods: This metaanalysis included first line phase II/III randomized published trials comparing (ET) to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged ≥ 65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Results: 8 studies were included in the analysis. 4 trials (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found in elderly population subgroup. Conclusions: The novel experimental combo-strategies in the first line setting showed an improvement in PFS in the subgroup of elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone. The magnitude of PFS benefit due to addition of CDK4/6 inhibitors to ET is age-independent.