Dr D'Amato on Efficacy Data With Olaparib Plus Temozolomide in Advanced Uterine Leiomyosarcoma

"Unfortunately, [the study] did not meet its primary end point, and the study was closed after 70 patients. That was difficult because it was very promising in the phase 2 portion, [although] it’s hard to go against other drugs."

Gina Z. D’Amato, MD, a professor of clinical medicine and assistant director of clinical research at Sylvester Comprehensive Cancer Center and the Miller School of Medicine at the University of Miami, shared findings from the phase 2/3 Alliance A092104 trial (NCT05432791), which evaluated olaparib (Lynparza) plus temozolomide (Temodar) in patients with advanced uterine leiomyosarcoma. The combination failed to meet the trial’s primary progression-free survival (PFS) end point in a biomarker-unselected population, prompting trial closure due to futility.

Data presented at the 2025 ASCO Annual Meeting showed that among the 74 patients enrolled, the median PFS was 3.2 months (95% CI, 2.0-7.0) in the olaparib plus temozolomide arm (n = 37) vs 5.5 months (95% CI, 2.6-10.2) with investigator’s choice of pazopanib (Votrient) or trabectedin (Yondelis; n = 37; stratified HR, 1.16; 95% CI, 0.67-1.99; P = .703). Although the median overall survival (OS) was longer with the investigational regimen at 19.3 months (95% CI, 15.2-not evaluable [NE]) vs 12.9 months (95% CI, 10.4-NE), this finding was not statistically significant (HR, 0.70; 95% CI, 0.33-1.47).

According to D’Amato, this randomized trial incorporated predefined safety assessments after the initial phase 2 cohort of 70 patients. The trial design allowed for expansion if efficacy criteria were met, but the lack of PFS benefit halted further enrollment. D’Amato noted that although the phase 1 and early phase 2 data were promising, the comparator agents may have overperformed, making it challenging for the investigational regimen to demonstrate superiority.

No new safety signals were identified with olaparib plus temozolomide, D’Amato continued Gastrointestinal toxicities were observed but remained within expected ranges, and overall, the combination was well tolerated. D’Amato emphasized that the negative outcome was not due to safety concerns, but rather the need to better define which molecularly selected patients might benefit most from this therapeutic approach. As a result, the trial will be closed on October 1, 2025.