The combination of olaparib and temozolomide failed to demonstrate superiority over standard therapies in patients with advanced uterine leiomyosarcoma, according to results from the phase 2/3 Alliance A092104 trial presented at the 2025 ASCO Annual Meeting. The study, which enrolled 74 patients with previously treated disease, will be closed for futility on October 1, 2025.
Trial Results Show No PFS Benefit
The randomized trial evaluated olaparib (Lynparza) plus temozolomide (Temodar) against investigator's choice of pazopanib (Votrient) or trabectedin (Yondelis) in patients with advanced uterine leiomyosarcoma following disease progression on prior chemotherapy. The primary endpoint of progression-free survival was not met in the biomarker-unselected population.
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) compared to 5.5 months (95% CI, 2.6-10.2) with investigator's choice of pazopanib or trabectedin (n = 37; stratified HR, 1.16; 95% CI, 0.67-1.99; P = .703).
While the median overall survival was numerically longer with the investigational regimen at 19.3 months (95% CI, 15.2-not evaluable) versus 12.9 months (95% CI, 10.4-NE), this finding was not statistically significant (HR, 0.70; 95% CI, 0.33-1.47).
Early Closure Despite Promising Preclinical Data
"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," said Gina Z. D'Amato, MD, 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.
The trial incorporated predefined safety assessments after the initial phase 2 cohort of 70 patients, with design allowing for expansion if efficacy criteria were met. However, the lack of PFS benefit halted further enrollment.
Comparator Performance May Have Exceeded Expectations
D'Amato noted that the comparator agents may have overperformed relative to historical expectations. "Trabectedin might have overperformed, as well as pazopanib," she explained. "We may often underestimate the responses and results our patients [demonstrate] in the real-world [setting]."
The challenge stems from limited data on these agents specifically in uterine leiomyosarcoma. "We don't have strong data with just pazopanib alone in uterine leiomyosarcoma," D'Amato said. "It's the same thing with trabectedin—we don't know the full median PFS in just [patients with] uterine leiomyosarcomas."
Safety Profile Remains Acceptable
No new safety signals were identified with the olaparib plus temozolomide combination. Gastrointestinal toxicities were observed but remained within expected ranges, and the combination was well tolerated overall. D'Amato emphasized that the negative outcome was not due to safety concerns.
"I don't believe the trial ended because of safety issues, and, therefore, there weren't any surprises there," she noted. "There were some gastrointestinal toxicities, but nothing unexpected, and there were no signals that this wouldn't be a good combination."
Need for Better Patient Selection
The trial's failure highlights the ongoing challenge of identifying which patients with uterine leiomyosarcoma might benefit from specific therapeutic approaches. "We still don't [have a clear understanding of] which particular patients are responding [to the therapy]," D'Amato said.
"We [inferred that we] would understand, on a molecular basis, that a PARP inhibitor in combination with temozolomide could be selected for certain patients who are going to respond better. At this point, we still don't know what the prediction can be, and we don't know which patients are going to respond better to pazopanib as well as trabectedin."
Despite the trial's failure to meet its primary endpoint, D'Amato suggested the combination might still represent a potential treatment option. "Although the study didn't meet its end point, it doesn't mean the combination isn't effective. It's just might not be better than what we have," she said. "We just need to figure out which patients would benefit most from this combination."
