Background: The molecular profiling of small cell lung cancer (SCLC) has demonstrated a high incidence of genomic alterations in cell cycle-related genes and DNA damage and response (DDR) pathways, which correlates with devastating clinical outcomes of SCLC. Using two small molecules targeting the DNA repair pathway, olaparib (PARP inhibitor) and ceralasertib (ATR inhibitor), we evaluated their clinical efficacy in monotherapy or in combination, in relapsed SCLC. Methods: As part of the phase II biomarker-driven umbrella study in SCLC (SUKSES), patients who failed prior platinum-based regimen were enrolled and allocated based on their genomic alterations. Patients with mutations harboring HR pathway gene mutation not limited to BRCA 1 or 2, ATM deficiency or MRE11A mutations were allocated to the olaparib monotherapy (SUKSES-B, NCT03009682). As an biomarker non-matched arm, biomarker unselected patients were also allowed to receive olaparib and ceralasertib arm (SUKSES-N2, NCT0328607). The primary endpoint was objective response rate (ORR), and two-stage Simon’s design was used. Results: Based on pre-defined protocol criteria, both arms terminated at stage 1. In the olaparib monotherapy arm (SUKSES-B, n = 15), ORR was 6.7%, and disease control rate (DCR) was 26.7%, 1 partial response (PR), and 3 stable diseases (SD). Median progression-free survival (PFS) was 1.25 months (95% confidential interval [CI] 1.18–NA), and median overall survival (OS) was 8.56 months (95% CI, 6.62–NA). Adverse events that led to treatment discontinuation (n = 2 total, 13.3%) were drug related grade 3 renal impairment, thrombocytopenia, and grade 2 anemia. A patient with confirmed PR showed a tumor volume decrease of 37% compared to the baseline, and a splicing site mutation in BRCA2 was identified from deep target sequencing. In the olaparib and ceralasertib treatment arm (SUKSES-N2, n = 26), ORR was 3.8% (n = 1) and DCR was 42.3% (n = 11). Median PFS was 2.75 months (95% CI 1.77–5.44), and OS was 7.18 months (95% CI 5.97-10.79). Three patients discontinued treatment due to drug related grade 5 pneumonia, grade 3 drug-induced pneumonitis and grade 2 anemia. The most common adverse events for the combination were anemia (n = 11, 42.3%), followed by thrombocytopenia (n = 6, 23.1%). A patient with confirmed PR with a 43% decreases in tumor volume compared with baseline had a mutation in TP53. Conclusions: Targeting the DDR pathways with olaparib as single agent or in combination with ceralasertib demonstrated early signal of efficacy in relapsed SCLC patients with a tolerable safety profile. Clinical trial information: NCT03009682, NCT0328607