Multicenter randomized phase 2 trial of trabectedin with or without olaparib for advanced soft tisuse sarcomas after anthracycline-based treatment

The phase 2 TOMAS2 study at 13 centers in Italy randomized 130 patients with metastatic soft tissue sarcomas (mSTS) after failure of anthracyclin-based regimens 1:1 to trabectedin plus olaparib or trabectedin monotherapy. The primary endpoint was progression-free survival rate at 6 months (PFS6). The median follow-up was 37.4 months. PFS6 and median PFS were 32% and 3.9 months,respectively, with the combination and 28% and 2.9 months with trabectedin monotherapy (HR 0.722; p=0.081). Among 126 evaluable patients, objective response rate was 12.7% versus 7.9% (OR 1.60; p=0.43). In the uterine leiomyosarcoma subgroup (n=28), 12-months PFS rate was 42.9% with the combination versus 0% with trabectedin monotherapy. PARP1 expression significantly correlated with improved PFS in the combination group. Grade ≥3 hematological toxicities were significantly more frequent with trabectedin-olaparib. The authors conclude that the benefit of addition of olaparib to trabectedin was marginal in the all-comers aSTS population, but patients affected by PARP1-expressing aSTS and uterine leiomyosarcoma derived substantial benefit from the combination.