Background: Given that trabectedin (T) causes single- and double-strand breaks along DNA, we hypothesized to combine trabectedin with the selective PARP1-inhibitor olaparib (O) to induce irreparable DNA damage (Pignochino Y abs 10066 2012 ASCO). We report the results from a trial of T + O combination in advanced BSTS pts (Clinical trial information: NCT02398058). Methods: Pts with radiographic progression after first or further-line therapy received T (24-hour infusion on day 1) and O (tablets BID) in 21-day cycles across 6 dose levels (T: 0.675-1.3 mg/m²; O: 100-300 mg BID), to determine safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and recommended phase 2 dose (RP2D) using a standard 3+3 dosing schema. Other objectives included tumor response assessment (RECIST 1.1 + Choi criteria) every 2 cycles and biomarkers correlation with response. Biomarkers were studied on archival tumor samples; PK and PD were evaluated on peripheral blood at predefined time points. Results: 24 pts, median age 51(19-73), median previous lines 2 (1-8) were enrolled in ISG centers and received a median of 2 cycles (range 1-13) of T + O. In 2/3 patients at dose level 5 (T: 1.3 mg/m² / O: 200 mg BID), the dose-limiting toxicities were grade 4 neutropenia for ≥ 7 days and thrombocytopenia which precluded further dose escalation. Treatment-related adverse events included anemia, leukopenia, neutropenia, febrile neutropenia (≤3 days), thrombocytopenia, macrocytosis, fatigue, nausea, elevated liver enzymes, mucositis, asymptomatic amylase/lipase increase. No pts interrupted treatment or died for toxicity. PD data demonstrated DNA damage and PARP1 inhibition. In 22 pts evaluable for response we observed 4 (18%) partial responses (synovial sarcoma, LMS) and 5 (23%) stable diseases (LPS, Ewing sarcoma, SFT, MPNST). Data on biomarkers and RP2D will be presented at the meeting. Conclusions: The combination of trabectedin + olaparib was overall well tolerated without marked PK drug-drug interactions. Finally, the preliminary evidences of activity in different histotypes warrant further studies of this combination in BSTS pts. Clinical trial information: NCT02398058