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

Abstract

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.

Treatment With Antitumor Agents Recommended by Cancer Genome Panel for Uterine Leiomyosarcoma

“…This result may be because of the absence of biomarkers for ICI, including microsatellite instability-high (Supplementary Ma- Cancer Genome Medicine for Advanced Leiomyosarcoma J Clin Med Res. 2023;15 (10)(11):461-468 terial 4, www.jocmr.org) and TMB-high, in the uterine leiomyosarcoma of the participants enrolled in the clinical trial [23]. Furthermore, in previous clinical trials, the completed efficacy of serine-threonine kinase inhibitors against uterine leiomyosarcomas has not been confirmed [24].…”

“…To date, in cancer genomic medicine in Japan, in several cases, combination therapy with multiple antitumor agents has not been performed for patients with PVs in multiple molecules. In the future, cancer genomic medicine, such as in advanced or recurrent uterine leiomyosarcomas wherein PV in the breast cancer 1 (BRCA1) or BRCA2 gene and an active PV in AKT are detected using cancer genomic testing, combination therapy with a poly (ADP-ribose) polymerase (PARP) inhibitor (e.g., olaparib or niraparib) (Supplementary Material 5, www.jocmr.org) and a tyrosine kinase inhibitor should be considered [11,26]. In Japan, prescriptions of the combination therapy of a PARP inhibitor with tyrosine kinase inhibitor for advanced and recurrent uterine leiomyosarcomas are not covered by health insurance.…”

“…Furthermore, owing to the high prevalence of uterine leiomyomas, the diagnosis of uterine leiomyosarcoma, particularly before surgery, is extremely challenging [8,9]. To date, clinical trials conducted by various medical teams have investigated the effectiveness of antitumor agents on uterine smooth muscle tumors; however, the effectiveness of various antitumor agents against uterine leiomyosarcomas is limited [10,11]. Unfortunately, no common treatment has been established for uterine leiomyosarcomas.…”

Synthetic lethality from the combination of a histone methyltransferase, SUV39H2 inhibitor and a poly (ADP-ribose) polymerase inhibitor for uterine leiomyosarcoma

“…Recently, PARP inhibitors have become increasingly important for the treatment of gynecological tumors with HRD as 25% of the patients with uLMS have HRD [13]. Case reports have used PARP inhibitors for uLMS, and phase II clinical trials of PARP inhibitors for uLMS have begun [11,12,42]. Although PARP inhibitors have become widely used, the acquisition of resistance to PARP inhibitors has become a critical issue in cancer treatment.…”

The Future of Targeted Therapy for Leiomyosarcoma

“…The mPFS was 3.9 vs. 2.9 months, though not statistically significantly different, 20% treated with the combination were treated for over a year. Another example is the NCI protocol 10250, a recent phase 2 trial of olaparib in combination with temozolomide in advanced ULMS, which enrolled 22 pre-treated patients and showed an ORR of 27% and mPFS of 6.9 months [ 80 ]. The benefit appeared to be greater for patients with tumors harboring deleterious HR gene alterations.…”