Trabectedin-olaparib combination or trabectedin in advanced soft tissue sarcomas after failure of anthracycline-based treatment (TOMAS2): a randomized phase 2 study from the Italian Sarcoma Group

Background: Advanced/metastatic soft tissue sarcomas (STS) remain an unmet clinical need. We previously reported the feasibility and preliminary activity of trabectedin-olaparib combination in patients with advanced STS progressing after anthracycline-based regimens. Patients and methods: In this investigator-initiated, open-label, phase 2 randomized trial, adult patients with advanced STS progressing after ≥1 anthracycline-based line of therapy were randomized 1:1 to trabectedin 1.1 mg/m2 q21d i.v. plus olaparib tablets 150 mg BID, or trabectedin 1.5 mg/m2 q21d i.v. Randomization stratified patients by histology (L-sarcoma, i.e. leiomyosarcoma and liposarcoma vs. non-L-sarcoma) and number of prior therapies (1 vs. ≥2). The primary endpoint was progression-free survival (PFS) rate at 6-month (PFS6m) per RECIST1.1. Secondary endpoints included PFS, overall survival (OS), RECIST1.1 overall response rate (ORR), safety. Exploratory endpoints encompassed biomarker/molecular analyses. Results: Between May 25, 2020, and November 2, 2022, 130 patients were enrolled at 13 Italian Sarcoma Group centers (81 female; 67 L-sarcoma; 93 one prior line). With a median follow-up of 37.4 months, PFS6m and median PFS were 32% (22-46%) and 3.9 months (95%CI 2.7-5.2) with trabectedin-olaparib vs. 28% (19-42%) and 2.9 months (2.2-3.6) with trabectedin (HR=0.722, 0.501-1.041, P=0.081). Among 126 evaluable patients, ORR was 12.7% (6.1-22.7%) vs. 7.9% (3.0-16.7%), respectively (OR=1.60; 0.50-5.16; P=0.43). In the uterine leiomyosarcoma subgroup, 12-month PFS was 42.9% with trabectedin-olaparib vs. 0% with trabectedin. PARP1 expression significantly correlated with improved PFS with trabectedin-olaparib (median PFS and PFS6m 4.3 months and 41.5% vs. 2.5 months and 27.8% with trabectedin; HR=0.537, 0.337-0.855, P=0.009). Grade ≥3 hematological toxicities were significantly more frequent with trabectedin-olaparib. Conclusions: Although trabectedin-olaparib combination reached the prespecified threshold for statistical significance for PFS (p<0.10), the benefit was marginal in the all-comers STS population. Nonetheless, patients affected by PARP1-expressing STS and uterine leiomyosarcoma derived substantial benefit from the combination, supporting further histology- and biomarker-driven investigation in these settings.