Background: While prior studies have shown robust efficacy leading to FDA approval of PARP inhibitors (PARPi) in BRCA-associated cancers, data in NSCLC are much less clear. S1900A, a LUNG-MAP substudy, evaluated the PARPi rucaparib in advanced stage NSCLC harboring BRCA1/2 mutations or genomic loss of heterozygosity (LOH) as a phenotypic marker of homologous recombination deficiency (HRD). Methods: Eligible patients (pts) were required to have a deleterious mutation in BRCA1/BRCA2 and/or high (≥21%) genomic LOH. Key eligibility criteria: advanced NSCLC patients (pts) with progression on or after platinum based chemotherapy and/or PD-(L)1 antibody and progressed on most recent line of systemic therapy, a Zubrod performance status of 0-1, adequate organ function, no ≥ grade 3 hypercholesterolemia, no previous PARPi exposure and no systemic therapy within 21 days of registration. Pts stratified by histology into two cohorts (squamous [sq] and non-squamous/mixed histology [nsq]). With 40 eligible pts per cohort, the design had 91% power to rule out an ORR of 15% if the true ORR was at least 35% at the 1-sided 5% level. A planned interim analysis on the first 20 pts evaluable for response per cohort required ≥ 3 responses to proceed to full enrollment. Results: 64 pts enrolled (27 sq cohort; 37 nsq cohort) of whom 59 are eligible. Median age 65.7 yrs; M/F 33/26 (56/44%); 98% of the pts received at least 1 prior line of treatment for stage IV disease. Biomarker selection included 36 pts (61%) LOH only, 4 pts (7%) BRCA1 only, 11 pts (19%) BRCA2 only, 4 pts (7%) BRCA1 + LOH high and 4 pts (7%) BRCA2 + LOH high. Both cohorts were closed for futility with insufficient responses in the interim analysis populations. In the full study, 4 responses (3 nsq/1 sq) were reported. ORR was 7% (95% CI: 0-13) (9% nsq/4% sq) and DCR was 62% (95% CI: 50-75) (62% nsq/64% sq); 3 of the 4 responders harbored BRCA1/2 mutations and 1 of 4 high LOH; ORR in BRCA1/2+ pts 3/23 (13%). Median PFS was 3.2 months (95% CI: 1.6-4.6) in nsq cohort and 2.9 months (95% CI 1.6-6.2) in sq cohort. Median OS was 7.8 months in nsq cohort and 7.9 months in sq cohort. The most frequent grade ≥3 adverse events were anemia (22%), lymphopenia (8%), fatigue (8%) and transaminitis (5%). Conclusions: S1900A failed to show the requisite level of efficacy for rucaparib in advanced NSCLC pts with high genomic LOH and/or a BRCA1/2 mutation. There were no new safety signals and hematologic toxicities were the most frequent adverse events. Genomic LOH as a phenotypic marker of HRD does not predict sufficient activity of rucaparib in NSCLC. These results stand in contrast to the high level of efficacy of PARPi in patients with BRCA-associated or high LOH cancers of other tumor types. Underlying biologic differences in the genomic characteristics of these cancers vs. NSCLC may be responsible. Studies examining this premise are ongoing. (NCT03845296). Clinical trial information: NCT03845296