Purpose – Impaired homologous recombination–mediated DNA repair is common in head and neck squamous cell carcinoma (HNSCC) and in preclinical models and sensitizes HNSCC to poly (ADP-ribose) polymerase (PARP) inhibitors and platinum therapy. PARP inhibitors and anti–PD-1 antibodies have synergistic antitumor activity. The primary hypothesis of this phase II trial was that olaparib, a PARP inhibitor, given with pembrolizumab and carboplatin as first-line treatment for biomarker-unselected recurrent or metastatic (RM)-HNSCC, would result in a higher objective response rate (ORR) than that historically reported with fluorouracil, pembrolizumab, and platinum therapy.

Methods – Patients received up to six 21-day cycles of olaparib (200 mg twice daily orally on days 1-10), pembrolizumab, and carboplatin followed by 29 cycles of olaparib (300 mg twice a day on days 1-21) and pembrolizumab. The primary end point was independent radiologist-assessed confirmed objective response per RECIST v1.1. A Simon optimal two-stage design tested the null (H0: ORR ≤36%) versus the alternative hypothesis (ORR ≥62%) at a type I error rate of 10% and a power of 90%. H0 would be rejected if ≥14 responses occurred among 29 patients. Secondary end points included duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

Results – Between July 08, 2021, and October 11, 2023, 30 patients were enrolled. Among the 29 evaluable patients, the ORR was 51.7% (90% CI, 35.2 to 68.0; v H0, one-sided P = .04). The median DoR was 14.1 months (IQR, 6.8 to 21.2), and the median PFS and OS were 7.8 (95% CI, 4.1 to 15.4) and 24.5 months (95% CI, 8.8 to 25.3), respectively. The most common study drug-related grade 3 to 4 adverse events included neutropenia (50%) and anemia (23%). Febrile neutropenia and treatment-related deaths did not occur.

Conclusion – Olaparib, pembrolizumab, and carboplatin given as first-line treatment of RM-HNSCC resulted in a higher ORR than that historically reported with fluorouracil, pembrolizumab, and platinum therapy.