Trabectedin Plus Olaparib Improves PFS in Some Patients With STS

The combination of trabectedin (Yondelis; Pharma Mar, Johnson & Johnson) and olaparib (Lynparza; AstraZeneca, Merck) may be a meaningful treatment for certain patients with advanced soft tissue sarcomas, according to a new phase 2 study. The report was published in the Annals of Oncology.¹

Corresponding author Giovanni Grignani, MD, of Italy’s Candiolo Cancer Institute, and colleagues, explained that while surgery can be used to treat localized soft tissue sarcoma (STS), most patients with advanced or inoperable disease face a “dismal” prognosis.

“In this field, some improvements have been observed mainly with combination strategies, though at the price of increased toxicity,” they wrote. However, they said even with newer strategies, there is a lack of predictive biomarkers to guide therapy.

One treatment option for advanced STS is trabectedin, which binds to the minor groove of DNA and interferes with machinery related to DNA damage response and repair (DDRR). This results in “DNA single- and double-strand breaks, and exerts a selective toxicity on tumor-associated macrophages involved in tumor angiogenesis and progression,” Grignani and colleagues said.

The investigators wanted to see whether poly-ADP-ribose-polymerase-1 (PARP1) inhibitors might work synergistically with trabectedin. They noted that the type of damage caused by trabectedin leads to the activation of PARP1. Therefore, targeting PARP1 might help boost trabectedin’s ability to damage tumor cells.

In a preclinical study published in 2017, Grignani and colleagues affirmed their hypothesis and suggested that PARP1 might be a useful predictive biomarker.² In that study, the investigators found that combining trabectedin with the PARP inhibitor olaparib increased the former’s apoptotic rate in an in vitro setting and reduced tumor growth and prevented metastatic spread in in vivo models.

In the new study, a phase 2 randomized trial, the investigators tested the combination in 130 adult patients with advanced STS progressing after at least one anthracycline-based line of therapy.¹ Patients were randomized on a 1:1 basis to receive either intravenous trabectedin at a dose of 1.1 mg/m² every 21 days plus 150 mg olaparib tablets twice daily or trabectedin at a dose of 1.5 mg/m² every 21 days. The patients received care at one of 13 Italian Sarcoma Group cancer centers.

Most of the patients were female (n = 81) and 93 had received one prior line of therapy. Sixty-seven patients had either liposarcoma or leiomyosarcoma (abbreviated as L-sarcoma). The remaining patients had non-L-STS.

The primary endpoint of the study was progression-free survival rate at 6 months using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). At a median follow-up of 37.4 months, 6-month PFS was 32% in the trabectedin-olaparib group (95% CI, 22%-46%) compared to 28% in the trabectedin-alone group (95% CI, 19%-42%). Median PFS in the combination group was 3.9 months (95% CI, 2.7-5.2) and 2.9 months in the trabectedin-only group (95% CI, 2.2-3.6).

Grignani and colleagues said the combination therapy did reach its prespecified significance threshold of (P < .10), but the benefit was marginal in the all-comers population.

However, the authors also said that certain subgroups showed more substantial benefit. For instance, patients with PARP1 expression on the tissue of their tumors had significantly improved PFS with the combination therapy, and 40% of patients with uterine leiomyosarcoma (uLMS) were progression-free at 12 months, the authors said.

In terms of overall response rate (ORR), the rate was 12.7% in the combination group and 7.9% in the trabectedin-alone group. Yet, the authors said grade 3 or above hematological toxicities were more frequent in the combination group.

The data suggest that uLMS appears to be the most promising cancer type for further evaluation of PARP1 inhibition in combination with chemotherapy. They added that PARP1 expression seems to be a promising biomarker for the combination.

“Finally, improving the assessment of DDRR defects in STS could provide valuable insights and guide more effective therapeutic approaches,” they concluded.

References

1. D'Ambrosio L, Merlini A, Brunello A, et al. 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. Ann Oncol. Published online December 5, 2025. doi:10.1016/j.annonc.2025.11.019

2. Pignochino Y, Capozzi F, D'Ambrosio L, et al. PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models. Mol Cancer. 2017;16(1):86. doi:10.1186/s12943-017-0652-5