DNA hypomethylation identifying clinical benefit subgroup of small-cell lung cancer: multi-omics analysis of a phase II trial with durvalumab plus olaparib as maintenance therapy.

Long-term survival of extensive-stage small-cell lung cancer (ES-SCLC) remains rare, with most patients experiencing disease progression during maintenance therapy. Poly (ADP-ribose) polymerase (PARP) inhibitors have the potential to confer antitumor activity, modify tumor immunogenicity, and sensitize tumors to anti-programmed cell death protein 1/programmed death-ligand 1 therapy. We conducted this phase 2 trial to investigate the efficacy and safety of durvalumab plus olaparib as maintenance therapy in patients with ES-SCLC. This was a multicenter, single-arm, phase II trial that enrolled 60 patients with previously untreated ES-SCLC (NCT05245994). Patients received durvalumab (1,500 mg) combined with platinum-etoposide chemotherapy intravenously every 21 days for up to four cycles, followed by maintenance therapy with durvalumab (1,500 mg every 28 days) and oral olaparib (300 mg two times a day) until disease progression or unacceptable toxicity. Multi-omics analyses were performed to characterize molecular subtypes associated with clinical outcomes. The combination regimen demonstrated promising efficacy, with an alive and progression-free at 12 months rate of 25.0%, an objective response rate of 73.3%, a median progression-free survival of 6.8 months, and a median overall survival of 14.6 months. Multi-omics profiling identified a hypomethylation subgroup (cluster 1) that was associated with significantly improved survival outcomes. Further analysis revealed that this subtype exhibited enhanced antigen presentation machinery, a favorable cytokine profile, and suppression of DNA damage repair (DDR) pathways, potentially through elevated promoter methylation and transcriptional silencing of specific DDR genes, which together were associated with the favorable outcomes. This study presents the first prospective evidence supporting durvalumab plus olaparib as maintenance therapy in ES-SCLC. Multi-omics analysis identifies that DNA hypomethylation status may enrich for patients who benefit from PARP inhibition and immunotherapy. NCT05245994.