AbstractBackgroundBased on a high incidence of genomic alteration in the cell cycle and DNA damage and response (DDR)‐related pathways in small cell lung cancer (SCLC), the clinical efficacy of the DDR‐targeting agent olaparib (PARP inhibitor) as monotherapy and in combination with ceralasertib (ATR inhibitor) in relapsed or refractory SCLC was evaluated.MethodsAs part of a phase 2 biomarker driven umbrella study, patients with SCLC and predefined DDR gene alterations who failed to benefit from prior platinum‐based regimens were allocated to the olaparib monotherapy arm and nonbiomarker‐selected patients were allocated to the olaparib and ceralasertib combination arm.ResultsIn the olaparib monotherapy arm (n = 15), the objective response rate was 6.7% (one partial response), and the disease control rate was 33.3%, including three patients with stable disease. The median progression‐free survival was 1.3 months (95% CI, 1.2–NA). In the combination arm (n = 26), the objective response rate and disease control rate were 3.8% and 42.3%, respectively, with one partial response and 10 patients with stable disease. The median progression‐free survival was 2.8 months (95% CI, 1.8–5.4). Treatment was generally well tolerated except for one fatal case of neutropenic fever in the combination arm.ConclusionsTargeting DDR pathways with olaparib as a single agent or in combination with ceralasertib did not meet the predefined efficacy end point. However, disease stabilization was more evident in the combination arm. Further investigation of the combination of olaparib in SCLC should be performed with diverse combinations and patient selection strategies to maximize efficacy.