Dr Van Tine on Olaparib Plus Temozolomide in Advanced Uterine Leiomyosarcoma

"We need to figure out [which patients] with uterine leiomyosarcoma [are] going to benefit from this, and I think this work will continue."

Brian A. Van Tine, MD, PhD, a professor of medicine in the John T. Milliken Department of Medicine Division of Oncology at the Washington University School of Medicine, discussed efficacy data from the phase 2/3 Alliance A092104 trial (NCT05432791) investigating olaparib (Lynparza) plus temozolomide (Temodar) vs investigator's choice of therapy in patients with advanced uterine leiomyosarcoma who had progressed on prior chemotherapy.

The investigator’s choice arm demonstrated superiority over the experimental arm, Van Tine began. There was a 2-month progression-free survival advantage for patients receiving either trabectedin (Yondelis) or pazopanib (Votrient), with the most pronounced benefit observed among those treated with trabectedin who had experienced prior disease progression, he said. This subgroup analysis suggested a clear therapeutic signal for trabectedin as an active agent in this setting, he explained.

The trial also highlighted challenges in translating earlier promising results into a larger cooperative group setting, according to Van Tine. In a preceding smaller trial led by highly experienced phase 1 investigators, hematologic toxicity associated with the PARP inhibitor/temozolomide combination had been manageable, he stated. However, in the Alliance A092104 trial, a high rate of hematologic adverse effects necessitated substantial dose modifications, he noted. In total, 44.2% of treatment cycles in the experimental arm required dose modifications. These modifications likely affected the overall efficacy signal of the investigational combination, contributing to the underperformance of that regimen relative to standard therapies, he reported.

Another critical issue with this trial pertained to biomarker selection, Van Tine emphasized. Previously, investigators found that homologous recombination deficiency (HRD), as identified by the RAD51 foci assay, correlated strongly with therapeutic response, he said. However, the rate of patients with HRD alterations in the A092104 trial was relatively low, he explained. Moreover, the lack of a CLIA-certified RAD51 foci assay limited the ability to appropriately stratify patients, which may have further diluted the efficacy signal, he continued. Despite this, responses to the olaparib/temozolomide combination were observed, reinforcing the possibility that a biologically defined subgroup of patients may still derive durable benefit with this regimen, he elaborated.

These findings demonstrate the ongoing need to refine patient selection strategies in uterine leiomyosarcoma, Van Tine underscored. The sarcoma community continues to observe durable responses in individual patients treated with PARP inhibitors, some extending 3 to 4 years, he stated. Therefore, the olaparib/temozolomide regimen should not be dismissed as ineffective but rather approached with a renewed focus on biomarker-driven trial design and the development of CLIA-certified assays for HRD detection, he noted. Furthermore, emerging selective agents with reduced hematologic toxicity hold promise for future investigations, he reported. The field must continue to pursue studies that define the subset of patients with uterine leiomyosarcoma who are most likely to benefit from this therapeutic strategy, he concluded.