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

Abstract

Background: The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic NGS in patients with advanced cancer and enhance access to molecularly-guided treatment options (MGTOs). Academic tumor-agnostic basket phase 2 studies are part of this initiative. The current investigator-driven trial aimed to investigate olaparib efficacy in advanced cancers with a pathogenic or likely pathogenic mutation (germline or somatic) in a gene that plays a role in homologous recombination (HR). Methods: Open-label multi-cohort phase 2 study that examines the efficacy of ola-parib in patients with an HR gene mutation in their tumor and failed SoC. 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 (type I error rate of 5% and a power of 80% when the true response rate is 20%). 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 (N¼27) and 21% in the BRCA2 (N¼27) mutated 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 CR with 19+ months on treatment. mPFS in responding patients is 14+ months (5-34+ months). The clinical benefit rate was 63% in the BRCA1 and 46% in the BRCA2 mutated cohorts. No clinical activity was observed in the ATM (N¼13) and CHEK2 (N¼14) cohorts. Safety data were consistent with the known profile of olaparib. Conclusions: 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 with real-world documentation of efficacy in a retrospective register. Background: Within BRCA carriers, there are data suggesting that not all alterations confer the same risk of breast or ovarian cancer. In addition, the localization of the mutation as a biomarker of response to targeted therapies such as iPARP is in the process of being validated. The distribution of mutations according to the functional domain in which they are located may be a good method for establish their role in cancer risk.