Background: The homologous recombination deficiency (HRD) phenotype is common in HNSCC and is due to mutation and promoter hypermethylation of DNA repair genes (BRCA1, BRCA2, ATR, ATM, and FANC) and PTEN. In pre-clinical models of HNSCC, HRD sensitizes tumor to PARP inhibition and to additive antitumor activity of PARP inhibition in combination with platinum agents. PARP inhibitors also activate the STING pathway and upregulate PD-L1 expression, resulting in synergistic antitumor activity when given with PD-1 inhibitors. Olaparib is a highly selective PARP inhibitor that has been safely combined with pembrolizumab and carboplatin. Methods: In this single-arm phase 2 trial, patients with RM-HNSCC, no prior therapy for RM disease, and adequate performance status and organ function received up to six 21-day cycles of olaparib (200 mg bid orally days 1-10), pembrolizumab (200 mg IV day 1), and carboplatin (AUC 5 IV day 1), followed by up to twenty-nine 21-day cycles of olaparib (oral 300 mg bid days 1-21) and pembrolizumab (200 mg day 1). Treatment continued until discontinuation criteria were met. The primary endpoint was objective response, assessed by an independent radiologist using iRECIST. The primary hypothesis was that this regimen would result in a higher objective response rate (ORR) than historically reported with 5-FU, pembrolizumab and a platinum agent in similar patients. A Simon optimal two-stage design tested the null hypothesis (H₀ : ORR≤36%) versus the alternative hypothesis (H₁ : ORR=62%) at a type I error rate of 10% and 90% power. In the first stage, up to 13 patients could be accrued. If ≥6 responses occur, 16 additional patients will be accrued. The null hypothesis will be rejected if ≥14 responses are observed in these 29 patients. At the end of the first stage, an interim analysis was be performed to assess olaparib delivery during cycles 1 and 2 with the goal of 100% delivery in ≥ 80% of patients. We report the results of the primary endpoint and olaparib delivery for the first stage of the trial. Results: Twelve patients enrolled into the first stage of the trial. Key characteristics included median age 62 years (range 59-74), tobacco history (Y-5; N-7), primary site (oropharynx-7; oral cavity-4; larynx-1), HPV status (positive: 6; negative: 6) and PD-L1 status (CPS 0: 1; 1-19: 4; ≥20: 7). Tumor response occurred in 8 patients (ORR 67%). The best tumor response to date was CR (1), PR (7), SD (3) and PD (1). Olaparib delivery during cycles 1 and 2 was 100% for all patients. Conclusions: Among patients with RM-HNSCC, first-line treatment with olaparib, pembrolizumab and carboplatin resulted in an ORR of 67% during the first stage of the trial. Olaparib delivery was 100%. Enrollment into the second stage is ongoing. Clinical trial information: NCT04643379.