Early Evidence of Activity of Trabectedin and Olaparib in Sarcoma

Bone and soft tissue sarcomas comprise a group of biologically diverse tumors that are associated with poor prognosis, despite an increasing number of treatment options that include chemotherapy and targeted therapy. Trabectedin is a safe and effective second-line therapy approved for treatment of advanced soft tissue sarcoma (STS). Poly(ADP ribose) polymerase (PARP) inhibitors are a highly effective treatment in ovarian cancer and other solid tumors. These agents function to prevent DNA damage repair. Thus, combination with DNA damaging agents such as trabectedin, which is well tolerated with low rate of overlapping toxicities, is considered rational to enhance activity. Indeed, in preclinical models of bone and STS, combination of PARP inhibitors with trabectedin resulted in synergistic activity.

In the phase Ib TOMAS study carried out by the Italian sarcoma group, the combination of trabectedin and olaparib was evaluated in 50 patients with bone or STS who had progressed on standard treatments. The trial included a 3 + 3 dose escalation cohort (28 patients) and a dose expansion cohort (22 patients).

The most common grade 3/4 adverse events (AEs) across all dose levels were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and increased alanine aminotransferase (18%). Thrombocytopenia, neutropenia for more than 7 days, and febrile neutropenia were identified as dose-limiting toxicities. There were no deaths or life-threatening toxicities due to treatment. A dose of 1.1 mg/m2 trabectedin every 3 weeks and 150 mg olaparib twice daily was selected for future studies.

The overall response rate (ORR) across all dose levels was 14% (7 of 50 patients), with all responses occurring in patients with STS. The 6-month progression-free survival (PFS) was 26%, and the median overall survival (OS) for all treated patients was 11 months. There was no correlation between BRCA expression or BRCAness and response. However, patients with high PARP1 expression had improved outcomes compared to patients with low PARP1 expression, suggesting a potential role for PARP1 expression as a biomarker. The 6-month PFS in patients with high PARP1 expression was 59%, compared to 8% in patients with low PARP1 expression (HR 0.37, P = .01).

Based on these results, the investigators concluded that the combination of trabectedin and olaparib is active in advanced STS, but not bone sarcoma, with a manageable toxicity profile. In an accompanying commentary, the authors commended the investigators of the TOMAS trial for their efforts in translating preclinical work into the clinical setting and stressed the importance of further investigation of olaparib and trabectedin combination in a randomized trial stratified according to potential predictive biomarkers and histological subtypes. Given the activity seen in the phase Ib trial, further studies of this combination are planned, including a randomized phase II trial in advanced, unresectable STS that will stratify patients according to PARPi expression and a phase II trial in platinum-resistant ovarian cancer.

Lancet Oncol. 2018 Sept 11 [Epub ahead of print].

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