Final report of a phase I trial of olaparib with cetuximab and radiation for heavy smoker patients with locally advanced head and neck cancer

Purpose: Our goal was to evaluate the safety and toxicity of combining a PARP inhibitor, olaparib, with cetuximab and fractionated intensity-modulated radiotherapy for patients with locally advanced head and neck cancer and heavy smoking histories. Patients and Methods: Patients with ≥10 packs/year history of smoking were treated with olaparib at doses ranging from 25-200 μg orally twice daily beginning approximately 10 days prior to initiation of and with concurrent radiation (69.3 Gy in 33 fractions) using a time-to-event continual reassessment method model. Cetuximab was administered starting approximately 5 days prior to radiation per standard of care. Results: A total of 16 patients were entered onto the study, with 15 evaluable for acute toxicity. The most common treatment- related grade 3-4 side effects were radiation dermatitis and mucositis (38% and 69%, respectively). The MTD was determined to be 50 μg orally twice daily, but the recommended phase II dose was deemed to be 25 μg orally twice daily. At a median follow-up of 26 months, the actuarial median overall survival was 37 months, but was not reached for other endpoints. Two-year overall survival, progressionfree survival, local control, and distant control rates were 72%, 63%, 72%, and 79%, respectively. Patients who continued to smoke during therapy experienced higher recurrence rates. MYC and KMT2A were identified as potential correlatives of response on gene amplification and mutational analysis. Conclusions: Olaparib at 25 μg orally twice daily with concurrent cetuximab and radiation was well tolerated with reduced dermatitis within the radiation field. Response rates were promising for this high-risk population.