Background Immunotherapy has made breakthroughs in a variety of malignant tumors, but the effect of monotherapy is not good. PARP inhibitors can up-regulate the expression of PD-L1 in patients with DNA mismatch repair defects such as BRCA pathogenic/suspected pathogenic mutations, and the combination therapy of the two has a synergistic effect. However, there are fewer relevant clinical studies.
Objective To investigate the efficacy and safety of PARP inhibitors in combination with immunotherapy for advanced malignancies in clinical practice, and conduct a preliminary exploration of biomarkers.
Methods Clinical data about patients with advanced malignant tumors treated with PARP inhibitors combined with immune checkpoint inhibitors from January 2014 to December 2022 at the First Medical Center of Chinese PLA General Hospital were collected, and their efficacy and safety were analyzed. The efficacy indexes included objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Kaplan-Meier method for plotting survival curves was performed, and the relationship between different factors and prognosis was analyzed using unifactorial and multifactorial COX regression.
Results A total of 136 patients with advanced malignant tumors were included in this study, including 83 (61.0%) males and 53 (39.0%) females, there were 72 cases (52.9%) with age <60 years and 64 cases (47.1%) with age ≥60 years. Twenty-nine (21.3%) cases had non-small-cell lung cancer, 26 (19.1%) cases of small-cell lung cancer, 21 (15.4%) cases of ovarian cancer, 9 cases (6.6%) of pancreatic cancer, 6 cases (4.4%) of cholangiocarcinoma, 6 cases (4.4%) of uroepithelial carcinoma, and 39 cases (28.7%) of other tumors; 66 patients (48.5%) with the number of lines of treatment for three or more; no patient reached CR, 21 cases (15.4%) of PR, 73 cases (53.7%) of SD, and 42 cases (30.9%) of PD. The overall ORR was 15.4% and the DCR was 69.1%. As of the final follow-up time of October 1, 2023, the median follow-up time was 31.0 months. The median PFS was 3.65 months (95% CI: 3.0-4.5) and the median OS was 10.0 months (95% CI: 9.0-12.0). Multivariate COX regression analyses showed that front-line treatment (HR=1.466, 95% CI: 1.032-2.102, P=0.037), de-chemotherapy (HR=0.593, 95% CI: 0.404-0.871, P=0.008) and efficacy up to DCR (HR=7.414, 95% CI: 4.496-12.227, P＜0.001) were positively correlated with PFS; and good physical status (HR=2.182, 95% CI: 1.411-3.375, P＜0.001), efficacy to DCR (HR=4.659, 95% CI: 2.909-7.463, P＜0.001) and NLR ＜ 4 (HR=2.343, 95% CI: 1.256-4.367, P=0.007) were positively correlated with OS. A total of 85 (62.5%) patients in this study experienced treatment-related adverse events, of which 73 (53.7%) were in grade 1-2, mainly presented as nausea, vomiting, anemia, and immune-associated pneumonia, and there were no treatment-related deaths, resulting in a good and controllable overall safety profile.
Conclusion The combination of PARP inhibitors and immune checkpoint inhibitors in the treatment of advanced malignancies has considerable efficacy, safety and controllability, and provides patients with advanced tumors with a choice of late-line treatment options, which is worthy of further expansion of sample studies and effective biomarker exploration.
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