Background: Poly(ADP-ribose) polymerase (PARP) inhibitors drive increased DNA damage and tumor cell death, particularly in tumors with existing defects in DNA repair. Furthermore,they promote immune priming, through a range of molecular mechanisms. Foremost, among candidate intracellular pathways is STING (stimulator of interferon genes), an innate immune response activated by cytosolic DNA (perhaps a consequence of DNA damage) that can lead to enhanced interferon (IFN) production. PARP inhibitor-induced DNA damage also leads to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. To this end, there is increasing rationale for testing PARP inhibitors alone or in combination with chemotherapy or PD1 checkpoint inhibitors in HNSCC. Methods: 39 patients were enrolled in OPHELIA phase II trial in which pts were randomized 3:3:3:1 to Cisplatin (C) 60 mg/m2 on d1 followed by Olaparib (O) 75mg d 1-5 (Arm A), O 300 mg bid for 21-28 days (Arm B), no treatment (ARM C) orD 1500 mg on d1 followed by O 600 mg daily for 21-28 days (Arm D). Response was defined as tumor reduction noted on exam, imaging or pathology. Pretreatment biopsies were subjected to 310 gene OncoDNA NGS panel. Double Stranded Brakes/Repair (DSB/R) was measured by evaluating phosphorylation of histone H2AX by immunochistochemistry (IHC). In addition, IHC for PD-L1 (CPS) and STING was performed in paired pre- and post-treatment biopsies. Results: 17/36 pts in (O) treatment arms (6/11 evaluable pts Arm A, 9/11 evaluable pts Arm B, 2/11evaluable\ pts arm D) developed a response. One patient in D+O arm developed path CR. Low γH2AX staining at pretreatment biopsies was associated with progression (p=0.029). Higher PD-L1 expression (CPS≥1) was associated with disease progression (p=0.014). CPS PD-L1 was upregulated following (O) treatment. STING expression was not significantly upregulated post treatment in (O) treatment arms. Alterations in genes that have been previously reported to be associated with (O) sensitivity, namely DNA damage Response/Repair (DDR) genes and genes involved in chromatin remodeling (CHK2, KMT2D, KMT2C, ARID2 and AJUBA), were identified in responders. Conclusions: This window study demonstrated promising signs of activity of (O) in HNSCC, particularly in tumors with high expression of γH2AX and alterations in DDR or chromatin remodeling genes. Clinical trial information: NCT02882308.