Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene

Abstract

Introduction: PARP inhibition may enhance antitumor responses in BAP1-associated mesothelioma by inducing synthetic lethality. Methods: A single-center, nonrandomized, phase 2 trial was conducted, in which patients with refractory mesothelioma were given olaparib 300 mg twice daily in a 21-day cycle until disease progression or intolerable toxicity. The primary objective was to determine the objective response rate on the basis of somatic or germline mutation status of DNA repair genes. The secondary objectives were to assess safety and tolerability and to determine progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing was performed on blood and tumor. Results: A total of 23 previously treated patients with pleural and peritoneal mesothelioma were enrolled and treated (germline BAP1, n = 4; germline MRE11A, n = 1; somatic BAP1, n = 8 mutations). There was one (4%) partial response, 18 (78%) with stable disease at 6 weeks, and four (17%) with progressive disease. The median overall PFS and OS were 3.6 months (95% confidence interval [CI]: 2.7–4.2 mo) and 8.7 months (95% CI: 4.7 mo–not estimable), respectively. The median PFS of germline BAP1 mutants (n = 4) was 2.3 months (95% CI: 1.3–3.6 mo) versus 4.1 months (95% CI: 2.7–5.5 mo) for wild-type (n = 19; p = 0.019). The median OS was 4.6 months (95% CI: 3.1–4.9 mo) for germline BAP1 mutation versus 9.6 months (95% CI: 5.5 mo–not estimable) in no germline mutation (p = 0.0040). Olaparib was safe with no new safety concerns. Conclusions: Olaparib has limited activity in previously treated mesothelioma including patients with BAP1 mutations. Germline BAP1 mutations were associated with decreased PFS and OS.

Keywords

• Mesothelioma
• PARPI
• Olaparib
• BAP1
• MRE11A