Background: Poly (ADP-ribose) polymerase (PARP) inhibition in combination with TMZ is a promising treatment strategy for ES-SCLC. In SCLC models, TALA, a potent PARP inhibitor, exhibits cytotoxic effects by impairing PARP proteins 1/2 and trapping PARP on DNA while TMZ potentiates antitumor response by contributing to genomic instability (Wainberg 2016). A prior analysis of ctDNA in 15 pts treated on trial with TALA and TMZ suggested that mutations in DNA damage repair (DDR) genes occurred with this combination and may associate with response (Mulroy ASCO 2021). Methods: Pts with relapsed or refractory ES-SCLC were treated with TALA 0.75 mg po daily with TMZ 37.5 mg/m2 po on days 1-5 of 28-day cycles in a phase 2 clinical trial (UCLA/TRIO-US L-07, NCT03672773). ctDNA was collected and assessed based on allele frequency and plasma copy number at baseline and every 8 weeks during treatment with the Guardant360 assay (Redwood City, CA). DDR status was defined as a mutation known or likely to result in aberrant expression of ATM or BRCA1/2 (other DDR genes not detected by assay) (Pearl 2015). Germline DDR mutations were evaluated with matched-normal (PBMC) whole exome sequencing (WES) with archival specimens by Tempus (Chicago, IL). Response to treatment was defined by RECIST 1.1 criteria. Fisher?s exact tests were used to compare proportions of patients, with P-values <0.05 considered statistically significant (www.r-project.org, Vienna, AU). Results: For 27 pts with evaluable response, 78 ctDNA samples were collected. The most common baseline somatic alterations were mutations in TP53 (23 pts), RB1 (8 pts), ATM (5 pts), and BRCA2 (5 pts). There were no patients with germline DDR mutations. Overall, 22/27 (81.5%) had disease control (DC), including 11 with confirmed partial responses (PR) and 11 with stable disease while 5 had progressive disease. All those with PRs and ctDNA burden >0.2% at baseline experienced a ctDNA decrease at 8 weeks of treatment. DDR mutations were found in 18/27 (66.7%) pts. Of those with ≥ 1 follow-up ctDNA time point collected, 13/17 (76.4%) pts had at least one new mutation detected while on treatment, most commonly in ATM (6 pts). The appearance of new mutations associated with DC (P=0.042) and with a trend towards improved progression free survival (PFS, 5.9 m vs 3.6 m, P=0.099). All 5 pts with DDR mutations present at baseline had DC with TALA and TMZ, and 9/11 (81.8%) of those with PR had DDR mutations detected at some point during the trial, although the trend toward DC enrichment with DDR mutations did not maintain statistical significance (P=0.24). Conclusions: Mutations in DDR genes occur on treatment with TALA and TMZ and may associate with disease control. Validation in a larger cohort will be pursued.