Dr D’Amato on the Rationale for Studying Olaparib/Temozolomide in Leiomyosarcoma

"Uterine leiomyosarcomas are a rare group of cancers, and there were a lot of preliminary data involved, both preclinical and clinical, with the combination of olaparib and temozolomide. We were quite hopeful about the results."

Gina Z. D’Amato, MD, a professor of clinical medicine, assistant director of clinical research, medical director of the Nurse Practitioner Oncology Fellowship Program, and medical director of patient education at the Sylvester Comprehensive Cancer Center and the Miller School of Medicine at the University of Miami, discussed the rationale for and design of the phase 2/3 Alliance A092104 trial (NCT05432791) investigating olaparib (Lynparza) plus temozolomide (Temodar) in patients with advanced uterine leiomyosarcoma who had disease progression on prior chemotherapy.

Uterine leiomyosarcomas represent a rare subset of malignancies, D’Amato began. Substantial preclinical and early clinical data have supported investigation of the combination of olaparib and temozolomide in this disease setting, she noted. Preclinical studies demonstrated mechanistic synergy between these agents at the molecular level, and early-phase data suggested that the regimen is both orally administered and generally well tolerated, she explained.

Patients enrolled in the Alliance A092104 trial had metastatic uterine leiomyosarcoma with prior exposure to at least 1 line of systemic therapy, including an anthracycline-based regimen. Patients were randomly assigned to receive either the investigational combination of olaparib plus temozolomide or treatment according to investigator’s choice. The investigator’s choice arm included either trabectedin (Yondelis) or pazopanib (Votrient), administered at their respective standard, label-approved doses. Importantly, investigators were required to prospectively declare which comparator regimen they would use for their patients prior to randomization. This ensured transparency and consistency in treatment assignment for patients who did not receive the experimental combination, D’Amato added.

Notably, findings from the trial demonstrated that olaparib/temozolomide failed to provide a progression-free survival benefit in the biomarker-unselected patient population. The study will be closed for futility on October 1, 2025.