Phase II study of olaparib in malignant mesothelioma (MM) to correlate efficacy with germline and somatic mutations in DNA repair genes.

Abstract

9054 Background: BRCA1 associated protein 1 ( BAP1), a nuclear deubiquitinase involved in DNA double-strand break repair is frequently mutated in MM. Because poly(ADP-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we sought to evaluate efficacy of olaparib in patients with MM and correlate it with pathogenic germline and somatic mutations in DNA repair genes. Methods: Phase II single-center study (NCT03531840) enrolled patients with advanced pleural or peritoneal mesothelioma who had progressed on prior therapies, age >18 years, ECOG performance status <1, adequate organ and bone marrow function. Olaparib 300mg was given twice daily orally in 3 week cycles until disease progression or toxicity. Efficacy was assessed by CT scan every 6 weeks using RECIST criteria. Whole exome sequencing (WES) was performed on blood and tumor samples to identify pathogenic germline and somatic mutations in DNA repair genes. Primary objective was to determine response rate based on germline or somatic mutation status of DNA repair genes. Results: Between July 2018 to May 2019, 23 patients were enrolled, 15 pleural and 8 peritoneal MM [14 male; median age 63 (range 41-75 years); median number of prior treatments 3 (range 1-5)]. Median olaparib cycles received was 4 (2-21). WES to identify pathogenic mutations in the germline and tumor was performed in 23 and 17 patients respectively. Four patients had germline BAP1, 1 germline MRE11A, and 5 had somatic BAP1 mutations. Of 22 evaluable patients, 1(4%) had partial response (PR), 17 (77%) had stable disease at 6 weeks and 4 (18%) had progressive disease. Patient with PR had a germline mutation in MRE11A. Median progression free survival (PFS) and overall survival (OS) for all patients was 3.4 months (95% CI: 2.7 – 4.8 months) and 8.1 months (95% CI: 4.5 months – not estimable) respectively. Median PFS of germline BAP1 mutant patients (n = 4) was 2.3 months (95% CI: 1.3 – 3.6 months) compared to 4.1 months (95% CI: 2.7 – 5.5 months) for BAP1wild type patients (n = 18;P = 0.026). Median OS was 4.6 months (95% CI: 3.1 – 4.9 months) for patients with germline BAP1 mutation versus not reached for those without germline BAP1 mutation (P = 0.0058). The most common side effects of olaparib were anemia (16%), lymphopenia (24%), nausea (14%), and increased creatinine (9%). Conclusions: Olaparib has limited anti-tumor activity in previously treated MM patients including those with germline or somatic BAP1 mutations. Presence of germline BAP1 mutations was associated with decreased PFS and OS. Clinical trial information: NCT03531840.