Dr Van Tine on Investigating Olaparib Plus Temozolomide vs Investigator’s Choice of Therapy in Advanced Uterine Leiomyosarcoma

"There is a subset [of patients] that has a problem with DNA recombination and the ability to fix that when it’s happening. Because of that, this is a hot area where many people are still trying to figure out which patients we should be treating with PARP inhibitors in the uterine leiomyosarcoma setting, and beyond that, within the HRD sarcoma [population].”

Brian A. Van Tine, MD, PhD, a professor of medicine in the John T. Milliken Department of Medicine in the Division of Oncology at the Washington University School of Medicine, outlined the scientific rationale for 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 have progressed after chemotherapy.

The trial builds on earlier data that demonstrated potential synergy between PARP inhibition and temozolomide in homologous recombination–deficient (HRD) tumors, Van Tine began. Foundational work from Gary Schwartz, MD, of the Columbia University Irving Medical Center, and colleagues provided the initial rationale for investigating this combination through the phase 2 ETCTN 10250 study (NCT03880019), a single-arm trial evaluating olaparib plus temozolomide in patients with advanced uterine leiomyosarcoma, he said. In that study, the overall response rate was 27% in a small patient cohort (n = 22). Importantly, correlative analyses revealed that patients with HRD tumors achieved a median progression-free survival (PFS) of 11.2 months, whereas those without HRD derived substantially less benefit, with a median PFS of 5.4 months.

Van Tine emphasized that these findings supported the hypothesis that HRD represents a biologically relevant vulnerability in a subset of uterine leiomyosarcomas. Mechanistically, temozolomide induces DNA damage that becomes more cytotoxic when DNA repair mechanisms are impaired, he explained. Concurrent inhibition of PARP activity through olaparib further compromises DNA repair capacity, leading to synthetic lethality in tumors with defective homologous recombination pathways, he added. This biological rationale underpins the combination’s potential utility in uterine leiomyosarcoma, where HRD appears to define a clinically meaningful subset of patients, he noted.

The Alliance A092104 study was designed to prospectively test this hypothesis in a randomized setting. Patients with advanced uterine leiomyosarcoma who had progressed on prior chemotherapy were randomly assigned to receive olaparib plus temozolomide or investigator’s choice of therapy. The trial aimed to determine whether the combination improved outcomes compared with standard treatment, with efficacy and biomarker analyses expected to clarify the role of HRD as a predictive marker. According to Van Tine, beyond this trial, the broader question remains how best to identify and treat subsets of patients with HRD sarcomas who may benefit from PARP-based strategies.