BACKGROUND: Radiotherapy is essential for locoregional control in resectable soft-tissue sarcoma (STS) and remains a key strategy for unresectable STS. PARP inhibitors, such as olaparib, may enhance radiosensitivity by targeting DNA damage repair pathways. PATIENTS AND METHODS: This multicenter phase 1b trial evaluated the combination of olaparib and radiotherapy in STS of the limbs or trunk wall. Olaparib was administered twice daily at doses of 25, 50, 100, or 150 mg during the dose-escalation phase. Radiotherapy consisted of 50 Gy (25 fractions) for resectable tumors or 59.4 Gy (33 fractions) for unresectable tumors. Radiotherapy was exclusively preoperative for operable patients. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Dose escalation was conducted using the Time-to-Event Continual Reassessment Method (TITE-CRM). Histological response was assessed in surgical cases, and RECIST 1.1 criteria were applied for non-surgical cases. RESULTS: Between October 2016 and April 2021, 41 patients were recruited across five French centers. The RP2D was identified as 100 mg olaparib twice daily. For operable patients, a favorable histological response was observed in 33% of patients, with a local relapse-free survival rate of 90.5% at one year. In contrast, among patients with inoperable tumors, the median progression-free survival was 7.7 months (95% CI: 2.6-28.4), with partial responses achieved in 20% of cases and stable disease in 60%. Grade 3 radiation dermatitis was the most frequent adverse event (34.1%), and two patients experienced grade 5 toxicity (4.8%). CONCLUSION: The combination of olaparib and radiotherapy is feasible for STS patients but requires stringent selection, avoiding patients with tumors involving critical vascular structures or those at high surgical risk, to minimize severe complications. Further randomized trials are warranted to validate efficacy and safety compared to radiotherapy alone.Read less <