Reference Detail

Ref Type

Journal Article

PMID

(37467452)

Authors

Ingham M, Allred JB, Chen L, Das B, Kochupurakkal B, Gano K, George S, Attia S, Burgess MA, Seetharam M, Boikos SA, Bui N, Chen JL, Close JL, Cote GM, Thaker PH, Ivy SP, Bose S, D'Andrea A, Marino-Enriquez A, Shapiro GI, Schwartz GK

Title

Phase II Study of Olaparib and Temozolomide for Advanced Uterine Leiomyosarcoma (NCI Protocol 10250).

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology			2023 Jul 19	JCO2300402	J Clin Oncol

URL

Abstract Text

Uterine leiomyosarcoma (uLMS) is an aggressive subtype of soft-tissue sarcoma with frequent metastatic relapse after curative surgery. Chemotherapy provides limited benefit for advanced disease. Multiomics profiling studies have identified homologous recombination deficiency in uLMS. In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor growth.NCI Protocol 10250 is a single-arm, open-label, multicenter, phase II study evaluating olaparib and temozolomide in advanced uLMS. Patients with progression on ≥1 prior line received temozolomide 75 mg/m2 orally once daily with olaparib 200 mg orally twice a day both on days 1-7 in 21-day cycles. The primary end point was the best objective response rate (ORR) within 6 months. A one-stage binomial design was used. If ≥5 of 22 responded, the treatment would be considered promising (93% power; α = .06). All patients underwent paired biopsies that were evaluated with whole-exome sequencing (WES)/RNAseq and a RAD51 foci formation assay.Twenty-two patients were evaluable. The median age was 55 years, and 59% had received three or more prior lines. Best ORR within 6 months was 23% (5 of 22). The overall ORR was 27% (6 of 22). The median progression-free survival (mPFS) was 6.9 months (95% CI, 5.4 months to not estimable). Hematologic toxicity was common (grade 3/4 neutropenia: 75%; thrombocytopenia: 32%) but manageable with dose modification. Five of 16 (31%) of tumors contained a deleterious homologous recombination gene alteration by WES, and 9 of 18 (50%) were homologous recombination-deficient by the RAD51 assay. In an exploratory analysis, mPFS was prolonged for patients with homologous recombination-deficient versus homologous recombination-proficient tumors (11.2 v 5.4 months, P = .05) by RAD51.Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PALB2 del	uterus leiomyosarcoma	predicted - sensitive	Olaparib + Temozolomide	Case Reports/Case Series	Actionable	In a clinical case study, Lynparza (olaparib) and Temodar (temozolomide) combination treatment resulted in stable disease and progression-free survival lasting 381 days in a patient with advanced uterine leiomyosarcoma harboring a homozygous deletion of PALB2 (PMID: 37467452).	37467452
RAD51B del	uterus leiomyosarcoma	predicted - sensitive	Olaparib + Temozolomide	Case Reports/Case Series	Actionable	In a clinical case study, Lynparza (olaparib) and Temodar (temozolomide) combination treatment resulted in stable disease and progression-free survival lasting 980 days in a patient with advanced uterine leiomyosarcoma harboring a homozygous deletion of RAD51B (PMID: 37467452).	37467452