TY - JOUR
T1 - Phase II Study of Olaparib and Temozolomide for Advanced Uterine Leiomyosarcoma (NCI Protocol 10250)
AU - Ingham, Matthew
AU - Allred, Jacob B.
AU - Chen, Li
AU - Das, Biswasjit
AU - Kochupurakkal, Bose
AU - Gano, Katherine
AU - George, Suzanne
AU - Attia, Steven
AU - Burgess, Melissa A.
AU - Seetharam, Mahesh
AU - Boikos, Sosipatros A.
AU - Bui, Nam
AU - Chen, James L.
AU - Close, Julia L.
AU - Cote, Gregory M.
AU - Thaker, Premal H.
AU - Ivy, S. Percy
AU - Bose, Sminu
AU - D'Andrea, Alan
AU - Marino-Enriquez, Adrian
AU - Shapiro, Geoffrey I.
AU - Schwartz, Gary K.
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - PURPOSEUterine 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.PATIENTS AND METHODSNCI 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.RESULTSTwenty-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.CONCLUSIONOlaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.
AB - PURPOSEUterine 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.PATIENTS AND METHODSNCI 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.RESULTSTwenty-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.CONCLUSIONOlaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.
UR - http://www.scopus.com/inward/record.url?scp=85169181949&partnerID=8YFLogxK
U2 - 10.1200/JCO.23.00402
DO - 10.1200/JCO.23.00402
M3 - Article
C2 - 37467452
AN - SCOPUS:85169181949
SN - 0732-183X
VL - 41
SP - 4154
EP - 4163
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 25
ER -