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

Background: Advanced/metastatic soft tissue sarcomas (STSs) 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 II randomized trial, adult patients with advanced STS progressing after one or more prior lines of therapy, including at least one anthracycline-based regimen, were randomly assigned 1 : 1 to trabectedin 1.1 mg/m(2 )every 21 days (q21d) intravenous (i.v.) plus olaparib tablets 150 mg twice a day, or trabectedin 1.5 mg/m(2) q21d i.v. Randomization stratified patients by histology (L-sarcoma, i.e. leiomyosarcoma and liposarcoma versus non-L-sarcoma) and number of prior therapies (one versus two or more). The primary endpoint was progression-free survival (PFS) rate at 6 months (PFS6m) per RECIST1.1. Secondary endpoints included PFS, overall survival (OS), RECIST1.1 overall response rate (ORR), and safety. Exploratory endpoints encompassed biomarker/molecular analyses. Results: Between 25 May 2020 and 2 November 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% [95% confidence interval (CI) 22% to 46%] and 3.9 months (95% CI 2.7-5.2 months) with trabectedin-olaparib versus 28% (95% CI 19% to 42%) and 2.9 months (95% CI 2.2-3.6 months) with trabectedin [hazard ratio (HR) 0.722, 95% CI 0.501-1.041, P = 0.081]. Among 126 assessable patients, ORR was 12.7% (95% CI 6.1% to 22.7%) versus 7.9% (95% CI 3.0% to 16.7%), respectively (odds ratio 1.60, 95% CI 0.50-5.16, P = 0.43). In the uterine leiomyosarcoma subgroup, 12-month PFS was 42.9% with trabectedin-olaparib versus 0% with trabectedin. PARP1 expression significantly correlated with improved PFS with trabectedin-olaparib (PFS6m and median PFS were 41.5% and 4.3 months versus 27.8% and 2.5 months; HR 0.537, 95% CI 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.