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.

Trial registration: ClinicalTrials.gov NCT03880019.

FIG 1.

Waterfall plot showing maximum reduction in the sum of longest diameters of target tumor lesions per RECIST version 1.1. Three patients who ended treatment for toxicity before the first imaging assessment was performed are not shown on the waterfall plot. ^aPatients progressed because of nonmeasureable lesions. PD, progressive disease; PR, partial response; SD, stable disease.

FIG 2.

Spider plot showing the change in the sum of target tumor measurements over time per patient. PD, progressive disease; PR, partial response; SD, stable disease.

FIG 3.

(A) Kaplan-Meir plot of PFS per RECIST criteria. All 22 patients are shown. (B) Co-Mut plot showing the correlation between genomic mutations in homologous recombination pathway and other genes by WES, HRD scores (HRD), RAD51 foci formation (RAD51), and clinical outcomes: BOR and PFS. Patients who did not undergo WES because of lack of available tumor tissue are not shown in the Co-Mut plot. BOR, best overall response; HRD, homologous recombination deficiency; NA, not available; NE, not estimable; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; WES, whole-exome sequencing.

FIG 4.

Swimmer plot showing treatment duration for each patient coded by RAD51 foci result (bar color) and annotated by whole-exome sequencing result (text appearing to the right of each patient bar). PFS, progression-free survival.

FIG A1.

Representative homologous recombination-proficient (left) and homologous recombination-deficient (right) tumors from patients treated on this study as assessed by a RAD51 foci formation assay. RAD51 foci in the homologous recombination-proficient biopsy are identified with red circles.

FIG A2.

Kaplan-Meir estimates of PFS subset by homologous recombination pathway status as determined by the RAD51 foci formation assay. Three patients who ended the study because of adverse events are included in this analysis. The median PFS for homologous recombination-deficient patients was 342 days and for homologous recombination-proficient patients was 86 days (log-rank P = .077). PFS, progression-free survival.

FIG A3.

Kaplan-Meir estimates of PFS subset by homologous recombination pathway status as determined by the RAD51 foci formation assay. Three patients who ended the study for adverse events were excluded from this analysis. The median PFS for homologous recombination-deficient patients was 342 days and for homologous recombination-proficient patients was 164 days (log-rank P = .05). PFS, progression-free survival.

FIG A4.

Correlation of (A) pre-treatment SLFN11 and (B) MGMT RNA expression with PFS. Using a Cox proportional hazards model, no association was observed between either SLFN11 (HR, 0.98 [95% CI, 0.52 to 1.83]; P = .90) or MGMT (HR, 1.12 [95% CI, 0.65 to 1.92]; P = .70) RNA expression at the pretreatment time point and PFS. The 15 patients with RNAseq results from the pretreatment time point are included. Three patients who ended treatment for toxicity were censored at the time of treatment discontinuation and one patient who remains on active treatment was censored at the time of last follow-up. HR, hazard ratio; MGMT, O⁶-methylguanine-DNA methyltransferase; PFS, progression-free survival; SLFN11, Schlafen family member number 11.