Background: Uterine leiomyosarcoma (uLMS) is an aggressive sarcoma subtype with frequent metastatic relapse. Advanced uLMS is treated with gemcitabine/docetaxel or anthracycline-based regimens. After failure of initial chemotherapy, remaining options provide limited benefit (trabectedin: objective response rate (ORR) 11%, median progression-free survival (mPFS) 4.0 months (mo); pazopanib: ORR 11%, mPFS 3.0 mo; dacarbazine: ORR 9%, mPFS 1.5 mo). 18-23% of uLMS harbor deleterious alterations in homologous recombination (HR) DNA repair genes. HR-deficient cancers are unable to effectively repair double-stranded DNA breaks and may be sensitive to poly ADP-ribose polymerase (PARP) inhibitor-based strategies. In preclinical studies, the combination of temozolomide (T), an alkylating agent, and olaparib (O), a PARP inhibitor, markedly suppressed proliferation of uLMS models. Among 22 uLMS patients with median 3 prior lines, O+T demonstrated mPFS 6.9 mo and ORR 27% (Ingham M. et al. ASCO 2021: #11506). In correlative analysis, alterations in HR genes including PALB2 and RAD51B or absence of RAD51 foci formation by a functional assay were observed in patients with prolonged PFS (Bose S. et al. ASCO 2022: #11509). Based on these results, we designed a randomized phase 2/3 study to further evaluate O+T in advanced, pretreated uLMS. Methods: Alliance for Clinical Trials in Oncology A092104 is a randomized, open-label phase 2/3 clinical trial of O+T versus investigator’s choice in advanced uLMS. Eligible patients have ECOG performance status ≤2, progression on ≥ 2 prior treatment lines and measurable disease. Patients are randomized 1:1 to receive T 75 mg/m2 orally daily + O 200 mg orally twice daily on days 1-7 in 21-day cycles (Arm 1) or investigator’s choice of trabectedin 1.5 mg/m2 over 24 hours every 21 days or pazopanib 400-600 mg orally daily (Arm 2). For phase 2, the primary endpoint is PFS. The design evaluates for an improvement in PFS from 4 mo to 8 mo, requires 70 patients, and yields 90% power and 1-sided alpha 0.10. If phase 2 is positive, phase 3 will enroll. For phase 3, the primary endpoint is overall survival (OS). The design evaluates for an improvement in OS from 13 mo to 23 mo, requires 165 patients (including 70 from phase 2) and yields 90% power with 1-sided alpha 0.025. Secondary endpoints include ORR, duration of response, safety and patient-reported outcomes. Archival tissue will be collected and evaluated with a RAD51 foci formation assay. Genomic sequencing results will be obtained where available. The study opened to accrual in 1/2023. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org. Clinical trial information: NCT05633381.