ESMO Congress 2023 | OncologyPRO

Abstract 888P

Background

PARP-inhibitors have potent radiosensitising properties in pre-clinical models; their use as radiation response modifiers in the clinic, however, are less well characterised. To identify the maximum tolerated dose (MTD) of the PARP inhibitor olaparib in combination with radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC), a single institutional phase I dose escalation trial was conducted.

Methods

Twelve patients with HNSCC (laryngeal cancer (cT2N0M0 or cT1-2N1-2bM0), HPV-negative oropharyngeal cancer or HPV-positive oropharyngeal cancer associated with a history of smoking ≥ 10 pack-years (cT1-2N1-2bM0 or cT3N0-2bM0) or locally-advanced disease from both tumour sites), scheduled for radiotherapy, were entered in the study; nine were eligible for analysis. The starting dose of olaparib was 25 mg BID, combined with radiotherapy to a total dose of 70 Gy in 35 fractions of 2 Gy. The MTD was defined as the highest dose level at which not more than 20% of patients experience dose-limiting toxicities (DLT) or as the highest reached dose in the absence of DLT.

Results

Olaparib administration started 1 week prior to radiotherapy. In dose level I, this was followed by accelerated radiotherapy (70 Gy in 6 weeks) in combination with olaparib (25 mg BID). Because of DLT in 3 of 4 patients (acute tracheotomy in 2 patients at 5 and 7 months after treatment and osteoradionecrosis in 1 patient at 7 months after treatment), the olaparib dose was de-escalated to 25 mg QD, and combined with conventional radiotherapy (70 Gy in 7 weeks; dose level II). No DLT was observed in 5 patients in dose level II. After a median follow-up of 60 months, the 4-year local-regional control and overall survival rates were 77.8% and 88.9%, respectively.

Conclusions

Olaparib 25 mg QD combined with conventionally fractionated radiotherapy was well tolerated and identified as the MTD. This combination might be further explored in future olaparib dose escalation studies in patients with locally advanced HNSCC unfit for concurrent chemo- or bio-radiotherapy.