Comparative efficacy and safety of novel oral selective estrogen receptor degraders in ER+/HER2– advanced breast cancer: An updated systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Endocrine therapy (ET) plus CDK4/6 inhibitors (CDK4/6i) remains first-line (1 L) standard for ER+/HER2- metastatic breast cancer (mBC). However, ESR1 mutations lead to ET resistance and subsequent disease progression (PD). Limitations of intramuscular fulvestrant have led to the development of novel oral selective estrogen receptor degraders (SERDs). We aim to evaluate efficacy and safety of novel oral SERDs for ER+/HER2- mBC. METHODS: PubMed, Embase, and Cochrane were systematically searched for randomized controlled trials (RCTs) comparing oral SERDs with standard treatment. Primary outcomes were progression-free survival (PFS) overall and by subgroups (ESR1 mutation, menopausal status, age, prior CDK4/6i use, visceral metastases), PFS comparing oral SERDs versus fulvestrant in ESR1-mutated patients, and grade ≥ 3 or discontinuation due to treatment-related adverse events (TRAEs). Hazard and risk ratios (HRs/RRs) were pooled using random-effects models (RStudio 2025.09.2 + 418). RESULTS: Eight RCTs (n = 3,978) were included. Overall, PFS did not differ significantly between groups (HR 0.80; 95 % CI 0.62-1.04; p = 0.09). Statistically significant PFS subgroups included: ESR1 mutation (HR 0.57; 95 % CI 0.45-0.73; p < 0.01); prior CDK4/6i use (HR 0.68; 95 % CI 0.49-0.95; p = 0.03); visceral metastases (HR 0.78; 95 % CI 0.63-0.97; p = 0.03); age < 65 years (HR 0.75; 95 % CI 0.60-0.92; p = 0.01); and oral SERDs versus fulvestrant (HR 0.55; 95 % CI 0.46-0.66; p < 0.01). Grade ≥ 3 TRAEs were higher with SERDs (RR 1.64; 95 % CI 1.07-2.50; p = 0.03), while treatment discontinuation was not significant. CONCLUSIONS: Novel oral SERDs may represent a paradigm shift in managing PD after 1 L therapy, showing potential to improve PFS in selected patients.