Background: Poly (ADP-ribose) polymerase (PARP) inhibition in combination with TMZ is a promising treatment strategy for ES-SCLC. In SCLC models, talazoparib, a potent PARP inhibitor, exhibits cytotoxic effects by inhibiting PARP proteins 1/2 and trapping PARP on DNA while TMZ potentiates antitumor response by contributing to genomic instability (Wainberg 2016). Prior ctDNA studies in SCLC have suggested that treatment precipitates the appearance of DNA repair alterations (Nong 2018), but it is unknown whether homologous recombination deficiency (HRD) predicts for treatment response with this combination. Methods: Patients (pts) with relapsed or refractory ES-SCLC were treated with oral talazoparib 0.75 mg daily on 28-day cycles and oral TMZ 37.5 mg/m2 on days 1-5 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). HRD was defined as a deletion or missense mutation known or likely to result in aberrant expression of ATM or BRCA1/2 (other HRD genes not detected by assay). 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 15 evaluable pts in the first Simon stage of this trial, 45 ctDNA samples were collected. The most common baseline genetic alterations were mutations in TP53 (14 pts), BRCA2 (5 pts), ATM (4 pts), and RB1 (3 pts). Of those with > 1 ctDNA timepoint collected, 10/11 (90.9%) pts had ≥1 new mutation (range 1-19) detected after receiving treatment (range 8-35 weeks), most commonly in ATM (5 pts). Overall, 5 pts had confirmed partial responses (PR), 7 had stable disease, and 3 had progressive disease. Disease control (DC) was associated with the presence of new mutations (P = 0.022) and was more common in those with HRD, with DC in 9/10 (90.0%) HRD pts vs 3/5 (60.0%) pts without HRD. All those with PRs experienced a ctDNA nadir at 8 weeks of treatment with nearly all (4/5, 80.0%) exhibiting HRD, 2 at baseline and 2 at 8 weeks of treatment. Conclusions: Mutations in DNA repair genes occur on treatment with talazoparib and TMZ and may associate with disease control. With a response rate of 33% in the first Simon stage of this trial, the TRIO-US L-07 trial exploring the combination of talazoparib and TMZ will be assessed in 13 additional patients, after which additional ctDNA analyses will be performed on the cohort as a whole. Clinical trial information: NCT03672773