Preliminary Results of a Phase Ib Study of Olaparib with Concomitant Radiotherapy in Locally Advanced/Unresectable Soft-Tissue Sarcoma from the French Sarcoma Group

Abstract

The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (O) has radiosensitizing properties in several tumor models including sarcomas. We studied pharmacokinetics (PK), safety and toxicity of O with external beam radiation therapy (EBRT) in patients with soft-tissue sarcomas (STS). Patients with locally advanced STS (with or without distant metastases) were eligible for the study. In this phase I study based on a time-to-event continual reassessment method (TITE-CRM) design, patients were treated with escalating doses of O administered in combination with EBRT (59.4 Gy in 33 fractions of 1.8 Gy). Four dose levels of O were explored: DL1:25 mg, DL2:50 mg, DL3:100 mg, DL4:150 mg BID. Tumor response was assessed by investigators according to RECIST 1.1. 26 pts were enrolled (10 males, 16 females). Eleven patients had undifferentiated pleomorphic sarcoma, six patients had liposarcoma, 2 myxofibrosarcoma, 2 synovial sarcoma, 1 myxo-inflammatory fibroblastic sarcoma, 1 MPNST, 1 leiomyosarcoma, 1 phyllode sarcoma, 1 undifferentiated round-cell sarcoma. There were 1 DLT on at DL 1 (n = 5), 1 DLT at DL2 (n = 7), 0 DLT at DL3 (n = 11) and 1 DLT at DL4 (n = 3). RP2D was 100 mg BID. Most common adverse events related to O and/or EBRT were acute dermatitis (100%, G3/4 50%), fatigue (42%, G3/4 0%), nausea (38.5%, G3/4 0%), anorexia (19.2%, G3/4 0%) and anemia (15.3%, G3/4 0%). Surgery of the primary tumor was done in 7 patients; 3 of them presented grade 5 post-operative toxicity. Of 20 evaluable patients, 10 had tumor shrinkage resulting in partial response in 3 patients (one liposarcoma, one phyllode sarcoma and one undifferentiated pleomorphic sarcoma). 13 patients had stable disease, 3 patients had progressive disease and 1 NE. The median PFS and OS were 17.9 and 15.9 months, respectively. This study shows that the combination of O with EBRT is well tolerated and lead to encouraging downstaging and survival rates in patients with locally advanced STS. Currently we are enrolling 15 additional pts at the recommended dose of O to further evaluate efficacy and safety.