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Clinical Trial
. 2023 Dec;8(6):102041.
doi: 10.1016/j.esmoop.2023.102041. Epub 2023 Oct 16.

Efficacy of olaparib in advanced cancers with germline or somatic mutations in BRCA1, BRCA2, CHEK2 and ATM, a Belgian Precision tumor-agnostic phase II study

S Joris  1 , H Denys  2 , J Collignon  3 , M Rasschaert  4 , D T'Kint de Roodenbeke  5 , F P Duhoux  6 , J-L Canon  7 , S Tejpar  8 , J Mebis  9 , L Decoster  10 , P Aftimos  5 , J De Grève  11
Affiliations
Clinical Trial

Efficacy of olaparib in advanced cancers with germline or somatic mutations in BRCA1, BRCA2, CHEK2 and ATM, a Belgian Precision tumor-agnostic phase II study

S Joris et al. ESMO Open. 2023 Dec.

Abstract

Background: The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic next-generation sequencing in patients with advanced cancer and enhance access to molecularly guided treatment options. Academic tumor-agnostic basket phase II studies are part of this initiative. The current investigator-driven trial aimed to investigate the efficacy of olaparib in advanced cancers with a (likely) pathogenic mutation (germline or somatic) in a gene that plays a role in homologous recombination (HR).

Patients and methods: This open-label, multi-cohort, phase II study examines the efficacy of olaparib in patients with an HR gene mutation in their tumor and disease progression on standard of care. Patients with a somatic or germline mutation in the same gene define a cohort. For each cohort, a Simon minimax two-stage design was used. If a response was observed in the first 13 patients, 14 additional patients were included. Here, we report the results on four completed cohorts: patients with a BRCA1, BRCA2, CHEK2 or ATM mutation.

Results: The overall objective response rate across different tumor types was 11% in the BRCA1-mutated (n = 27) and 21% in the BRCA2-mutated (n = 27) cohorts. Partial responses were seen in pancreatic cancer, gallbladder cancer, endocrine carcinoma of the pancreas and parathyroid cancer. One patient with a BRCA2 germline-mutated colon cancer has an ongoing complete response with 19+ months on treatment. Median progression-free survival in responding patients was 14+ months (5-34+ months). The clinical benefit rate was 63% in the BRCA1-mutated and 46% in the BRCA2-mutated cohorts. No clinical activity was observed in the ATM (n = 13) and CHEK2 (n = 14) cohorts.

Conclusion: Olaparib showed efficacy in different cancer types harboring somatic or germline mutations in the BRCA1/2 genes but not in ATM and CHEK2. Patients with any cancer type harboring BRCA1/2 mutations should have access to olaparib.

Keywords: ATM; BRCA1; BRCA2; CHEK2; agnostic NGS; biliary tract cancer; colorectal cancer; olaparib; parathyroid cancer.

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Conflict of interest statement

The authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Swimmer plot shows the response to treatment with olaparib in the BRCA1 cohort.x-axis: time in months, y-axis: patient identification number. The events in time are displayed on the bar with each patient: complete response (filled black square), partial response (filled black triangle), stable disease (filled black circle) and progressive disease (empty circle). If an arrow is shown at the end of a bar, the response is still ongoing at the time of analysis.
Figure 2
Figure 2
Swimmer plot shows the response to treatment with olaparib in the BRCA2 cohort.x-axis: time in months, y-axis: patient identification number. The events in time are displayed on the bar with each patient: complete response (filled black square), partial response (filled black triangle), stable disease (filled black circle) and progressive disease (empty circle). If an arrow is shown at the end of a bar, the response is still ongoing at the time of analysis.
Supplementary Figure 1
Supplementary Figure 1
Supplementary Figure 2
Supplementary Figure 2
See this image and copyright information in PMC

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