Immunotherapy and PARP inhibitors as first-line treatment in endometrial cancer: A systematic review and network meta-analysis

Background: Several first-line therapeutic strategies have been evaluated alongside platinum-based chemotherapy in advanced or recurrent endometrial cancer (a/rEC). However, the optimal approach remains unclear. Methods: A systematic review was conducted to identify randomized control trials (RCTs) that evaluate first-line therapeutic strategies in a/rEC involving immune checkpoint inhibitors (ICI) and PARP inhibitors (PARPi). A network meta-analysis with a frequentist framework using random-effects and an extracted individual patient data meta-analysis were performed. The primary endpoint was progression-free survival (PFS) by MMR status, p53 status within the MMRp population and PD-L1 status. Results: A total of 3210 patients with EC were included. In the MMRp population, the combination (ICI and PARPi) showed a not statistically significant PFS benefit compared with each agent alone. In MMRp p53abnormal patients (n = 590), combining PARPi and ICI statistically improved PFS compared to ICI alone (HR=0.47, 95 %CI 0.40-0.94) with a numerically better outcome compared to PARPi alone (HR=0.63, 95 %CI 0.26-1.57). No benefit from PARPi was observed in the p53 wild-type MMRp population. PD-L1-positivity (n = 1121) appears to predict more benefit from the addition of ICI and PARPi, with a larger benefit of combination therapy. In the MMRd population (n = 769), the best outcomes were observed with ICI alone, with no additional benefit of PARPi. Grade 3 or greater treatment-related adverse events were seen in 75.1 % patients treated with the combination. Conclusions: The addition of the combination of ICI and PARPi to platinum-based chemotherapy provides greatest benefit to p53-abnormal MMRp patients. PD-L1 is a potentially useful biomarker with PD-L1-positive tumors more likely to respond to ICI. Implementation of biomarkers is crucial to redefine the treatment paradigm in a/ rEC.