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: BAP1; MRE11A; Mesothelioma; Olaparib; PARPI.

Figure 1

Progression-free survival and mutation status in the intention-to-treat population. Progression-free survival of patients in days is plotted from the start of therapy until the progression of the disease. Germline and somatic BAP1 status and germline MRE11A mutation are indicated. Light blue bars indicate patients with somatic BAP1 mutation, dark blue with germline BAP1 mutation, yellow with no somatic or germline BAP1 mutations, and yellow hashed bar with no germline BAP1 mutation. However, in these patients (yellow hashed bar) tumor sequencing was not performed owing to insufficient tissues; hence, somatic BAP1 status was not assessed. Pink bar shows the only patient with germline MRE11A and somatic BAP1 mutations. y axis: Patient identification number (N = 1–23). ID, identification document.

Figure 2

A partial response seen in a patient with germline MRE11A mutation. A 63-year-old woman with heavily pretreated pleural mesothelioma harboring germline MRE11A and somatic BAP1 mutations achieved a durable (>6 mo) partial response. (A) Pretreatment and posttreatment PET scans and (B) CT scans revealed tumor regression. The response was achieved approximately after 12 weeks of treatment, with immediate clinical improvement of disease-related dyspnea and cough. The duration of the radiologic response lasted 30 weeks. CT, computed tomography; PET, positron emission tomography.

Figure 3

Kaplan-Meier curves for PFS and OS in the overall intention-to-treat population and the germline BAP1 cohort. PFS and OS were measured in months from the start of olaparib treatment. The median potential follow-up was 14.5 months. (A) In the overall cohort (N = 23), the median PFS was 3.6 months (95% CI: 2.7–4.2 mo) and the 6-month PFS was 17.4% (95% CI: 5.4%–35.0%). (B) The median OS was 8.7 months (95% CI: 4.7 mo–not estimable), the 6-month OS was 60.9% (95% CI: 38.7%–77.4%), and the 9-month OS was 43.5% (95% CI: 23.3%–62.1%). (C) In the germline BAP1 cohort (n = 4), the median PFS was 2.3 months (95% CI: 1.3–3.6 mo) and the 6-month PFS was not reached. In the cohort with wild-type germline BAP1 (n = 19), the median PFS was 4.1 months (95% CI: 2.7–5.5 mo) and the 6-month PFS was 21.1% (95% CI: 6.6%–41.0%) (p = 0.019). (D) In the germline BAP1 cohort (n = 4), the median OS was 4.6 months (95% CI: 3.1–4.9 mo) and the 6-month OS was not reached. In the cohort with wild-type BAP1 (n = 19), the median OS was 9.6 months (95% CI: 5.5 mo–not estimable) and the 6-month OS was 73.7% (95% CI: 47.9%–88.1%) (∗∗p = 0.0040). CI, confidence interval; OS, overall survival; PFS, progression-free survival.