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

Our plain-English summary of Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene, by A. Ghafoor, I. Mian, C. Wagner, et al (JTO Clinical and Research Reports, 2021).

The study

• Authors: A. Ghafoor, I. Mian, C. Wagner, Y. Mallory, M.G. Agra, B. Morrow, J.S. Wei, J. Khan, A. Thomas, M. Sengupta, S.M. Steinberg, R. Hassan
• Journal: JTO Clinical and Research Reports
• Published: 2021;2(10):100231
• Cited by: 59 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This single-arm, open-label phase 2 trial gave olaparib, a PARP inhibitor, 300 mg twice daily, to 23 previously treated mesothelioma patients (16 pleural, seven peritoneal). Four of 23 patients carried inherited (germline) BAP1 mutations; 8 of 19 tested tumors had somatic BAP1 mutations. One patient (4%) had a partial response, 18 (78%) had stable disease at 6 weeks and four (17%) had progressive disease. Median progression-free survival was 3.6 months (95% confidence interval 2.7 to 4.2) and median overall survival 8.7 months (95% CI 4.7 to not estimable). In exploratory analysis, the four germline BAP1 carriers had shorter median progression-free survival (2.3 months, CI 1.3 to 3.6, versus 4.1, CI 2.7 to 5.5) and overall survival (4.6, CI 3.1 to 4.9, versus 9.6, CI 5.5 to not estimable) than the 19 non-carriers. Progression-free and overall survival showed no statistical difference between patients with and without somatic BAP1 mutations. The sole responder had a germline MRE11A and a somatic BAP1 mutation. The authors concluded olaparib had limited activity, noting the germline BAP1 comparison involved a limited number of patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-center, nonrandomized, single-arm, open-label phase 2 clinical trial
• Who was studied: 23 patients with previously treated, progressive mesothelioma (16 pleural, 7 peritoneal), enrolled July 2018 to May 2019. Median age was 63 and 60% were men. All had prior platinum and pemetrexed chemotherapy.
• Exposure: Treatment with the PARP inhibitor olaparib, 300 mg tablets twice daily in 3-week cycles, until progression or intolerable toxicity. Outcomes were compared by germline and somatic BAP1 mutation status. Asbestos exposure was not studied.
• Main results:
  • Mutation status: 4 of 23 patients (17%) had pathogenic germline BAP1 mutations. 8 of the 19 patients whose tumors were sequenced (42%) had somatic BAP1 mutations.
  • All 23 patients: 1 partial response (4%), 18 with stable disease at 6 weeks (78%), and 4 with progressive disease (17%). The objective response rate was 4%.
  • All 23 patients: median progression-free survival was 3.6 months (95% CI: 2.7 to 4.2 months). Median overall survival was 8.7 months (95% CI: 4.7 months to not estimable).
  • In a prespecified exploratory analysis, median progression-free survival was 2.3 months (95% CI: 1.3 to 3.6) for patients with germline BAP1 mutation (n = 4). It was 4.1 months (95% CI: 2.7 to 5.5) for those with wild-type germline BAP1 (n = 19); p = 0.019.
  • Median overall survival was 4.6 months (95% CI: 3.1 to 4.9) for patients with germline BAP1 mutation. It was 9.6 months (CI: 5.5 to not estimable) for wild-type BAP1; p = 0.004.
  • There was no statistical difference in progression-free or overall survival between patients with somatic BAP1 mutations and the wild-type group. Median progression-free survival was 3.3 months (95% CI: 1.4 to 4.1) with somatic BAP1 mutation versus 3.6 months (95% CI: 1.5 to 8.2) without (p = 0.28). Median overall survival was 8.8 versus 9.6 months (p = 0.98).
  • The only responder was a 63-year-old woman with pleural mesothelioma who carried a germline MRE11A mutation and a somatic BAP1 mutation. Her radiologic response lasted 30 weeks, and her progression-free survival was 6.9 months.
  • Safety (23 patients): the most common non-blood side effects were nausea (70%), renal toxicity (48%) and fatigue (48%). The most common blood-related effects were decreased lymphocyte count (78%) and anemia (52%). No grade 4 or higher toxicities were reported. 12 patients (52%) needed dose reductions, and two left the study because of intolerable toxicity.
• The authors' conclusion: The authors concluded that olaparib alone has limited antitumor activity in previously treated mesothelioma, including in patients with BAP1 mutations. They found germline BAP1 mutations were associated with decreased progression-free and overall survival. They suggested the response in the patient with a germline MRE11A mutation may reflect a possible synthetic lethality that warrants further study.
• Limitations the authors state:
  • The difference in survival between germline BAP1 mutation carriers and others was based on a limited number of patients.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Somatic Mutation, BAP1, Disease Progression, Germline Mutation, Progression-Free Survival, Overall Survival, Peritoneal Mesothelioma.

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