Background: In unselected patients (pts) with extensive-stage small cell lung cancer (ES-SCLC), the addition of immune checkpoint inhibitors (ICI) to chemotherapy resulted in a modest improvement in OS. In a retrospective analysis of a study with veliparib (PARP inhibitor [PARPi]) and temozolomide in patients with SCLC, Schlafen-11 (SLFN11) predicted PFS and OS benefit for the addition of PARPi. We evaluated whether the addition of PARPi (talazoparib) to standard-of-care maintenance ICI (atezolizumab) following frontline chemoimmunotherapy improved outcomes in pts with SLFN11-positive ES-SCLC. Methods: Participants with ES-SCLC expressing SLFN11 (H-score ≥ 1, evaluated centrally at MDACC) were randomized to maintenance atezolizumab (A) versus atezolizumab plus talazoparib (AT) following frontline chemotherapy and A. Randomization was stratified by Zebrod PS (0-1 vs 2) and use of consolidation thoracic radiation. The primary endpoint was PFS, and secondary endpoints included ORR, OS, and toxicity. The primary analysis was done using a 1-sided 10% level stratified log-rank test. Target sample size was 94 pts. Results: From June 2020 to December 2022, 309 pts were screened, of which 204 of 259 (79%) with evaluable tissue were SLFN11 positive, and 106 were randomized (52 A, 54 AT). Median follow up time is 5 months. Median age was 67 (45-84); 51 (48%) were females; 94 (89%) were white,102 (96%) were PS 0-1, and 26 (25%) had radiation prior to randomization. With 80 PFS events reported, PFS was significantly improved with AT (hazard ratio [80% CI]: 0.70 [0.52-0.94]; p = 0.056). Median PFS was 2.8 months (80% CI 2.0-2.9) for A and 4.2 months (80% CI 2.8-4.7) for AT. OS was not different (hazard ratio [80% CI]: 1.17 [0.80-1.71]; p = 0.30). Median OS was 8.5 months (80 % CI 7.4-12.7) for A and 9.4 months (80% CI 8.1-14.2) for AT. ORR was 16% (5/32, 80% CI 8-27%) for A and 12% (4/34, 80% CI 5-22%) for AT. Grade 3 or greater treatment related non-hematological adverse events (AEs) occurred in 13% pts in A and 15% in AT. Hematological AEs occurred 4% in A compared to 50% pts in AT (Expected for T) (p < 0.001). There were no treatment related grade 5 events. One participant on AT experienced grade 3 febrile neutropenia. The majority of grade 3 AEs were due to anemia (2% in A and 37% in AT). Only three pts discontinued treatment due to toxicity (2 in A and 1 in AT). Conclusions: This study met its primary endpoint demonstrating that maintenance AT improved PFS in SLFN11-selected patients with ES-SCLC. Hematologic toxicity was increased with AT as expected, with majority being grade 3 anemia. This study demonstrates the feasibility of conducting biomarker selected trials in SCLC, paving the way for future evaluation of novel therapies in selected SCLC populations. Clinical trial information: NCT04334941.