Olaparib/Temozolomide Fails to Meet PFS End Point in Previously Treated Advanced Uterine Leiomyosarcoma

Gina Z. D’Amato, MD

The PARP inhibitor olaparib (Lynparza) in combination with temozolomide (Temodar) did not demonstrate superiority vs investigator’s choice of pazopanib (Votrient) or trabectedin (Yondelis) for the treatment of patients with advanced uterine leiomyosarcoma following disease progression on prior chemotherapy, according to Gina Z. D’Amato, MD.

The results of the phase 2/3 Alliance A092104 trial (NCT05432791), which were presented at the 2025 ASCO Annual Meeting, revealed that olaparib/temozolomide failed to meet its primary end point of progression-free survival (PFS) in the biomarker-unselected patient population. Of note, the study will be closed for futility on October 1, 2025. In the olaparib/temozolomide arm (n = 37), the median PFS was 3.2 months (95% CI, 2.0-7.0) vs 5.5 months (95% CI, 2.6-10.2) in the pazopanib or trabectedin arm (n = 37; stratified HR, 1.16; 95% CI, 0.67-1.99; stratified P = .703). Furthermore, the median overall survival was 19.3 months (95% CI, 15.2-not evaluable [NE]) compared with 12.9 months (95% CI, 10.4-NE), respectively (HR, 0.70; 95% CI, 0.33-1.47).

“We still don't [have a clear understanding of] which particular patients are responding [to the therapy]. 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,” D’Amato said during an interview with OncLive®. “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.”

D’Amato is 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 in Florida.

In the interview, D’Amato discussed the background and design of Alliance A092104, the efficacy data that were reported with olaparib plus temozolomide, and the safety profile of the regimen.

OncLive: What was the rationale of Alliance A092104?

D’Amato: 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. There was some synergy in the lab with the molecular process, and the combination is well tolerated in both of the oral [treatments].

What is important to note about the design, methods, and patient enrollment?

Patients had metastatic uterine leiomyosarcoma and [previously received] at least 1 line of systemic therapy, with at least an anthracycline-based regimen. They were [randomly assigned] to investigator’s choice or the combination. [Specifically,] the investigator’s choice was either trabectedin or pazopanib, and those were [administered via] the label doses. The investigator had to declare which [regimen] they would enroll patients on before they [randomly assigned] patients, [especially if] they didn't receive the [experimental] drugs.

What were the key efficacy data?

This was a randomized trial, and the idea of the trial was to have early safety measures in place after the phase 2 portion enrolled 70 patients. After that data were analyzed, and if there was a statistically significant difference with the combination, then we were going to open it up to a larger number of patients. However, 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. Trabectedin might have overperformed, as well as pazopanib.

Right now, all the reasons are theoretical. We may often underestimate the responses and results our patients [demonstrate] in the real-world [setting]. The drugs pazopanib and trabectedin were approved for [patients with] multiple sarcoma subtypes, [based on PFS]. Therefore, we don't have strong data with just pazopanib alone in uterine leiomyosarcoma. When we predict the statistics of the actual response rates and the median PFS, it's a prediction based on extrapolation from other studies. It’s the same thing with trabectedin—we don't know the full median PFS in just [patients with] uterine leiomyosarcomas. We had, for example, doxorubicin plus trabectedin vs doxorubicin alone, but we didn't have trabectedin alone. When we try to produce a statistically significant difference, those predictions are also very tricky. [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; however, I would still say that it's a potential treatment option. The study is just no longer going to move forward.

What was the safety profile of olaparib plus temozolomide?

There weren’t any surprises with the safety; [the findings] were standard. I don't believe the trial ended because of safety issues, and, therefore, there weren’t any surprises there. There were some gastrointestinal toxicities, but nothing unexpected, and there were no signals that this wouldn’t be a good combination. We just need to figure out which patients would benefit most from this combination.

Reference

Van Tine BA, Allred JB, Hensley ML, et al. Alliance A092104: a randomized phase 2/3 study of olaparib plus temozolomide versus investigator’s choice for the treatment of patients with advanced uterine leiomyosarcoma after progression on prior chemotherapy. J Clin Oncol. 2025; 43(suppl 16):11507. doi: 10.1200/JCO.2025.43.16_suppl.11507