Efficacy of olaparib in advanced cancers with somatic or germline mutations in BAP1, BARD1, BRIP1 and PALB2

Abstract

Background: Olaparib is registered for use in ovarian, breast, pancreatic and prostate cancers with a BRCA1/2 mutation and/or mutations in other homologous recombination deficiency (HRD) genes. HRD gene mutations are also found in other cancer types, and these cancers may also benefit from olaparib therapy. We aimed to evaluate the efficacy of olaparib in advanced cancers harboring a (likely) pathogenic germline or somatic mutation in a gene involved in homologous recombination (HR). Patients and methods: This investigator-initiated, open-label, basket phase II trial evaluates the efficacy of olaparib in patients with advanced tumors harboring HR gene mutations following progression on standard-of-care therapies. Cohorts were stratified based on the presence of either somatic or germline mutations in the same HR-related gene. Although results from the completed cohorts have been previously published, this report presents a case series focusing on cohorts with rare gene alterations. Results: In patients who harbor a tumor mutation in ARID1A, ATR, ATRX, BLM, CDK12, CHEK1, DDR2, ERCC4, FANCE, GEN1, MRE11A, NBN, POLE, RAD21, RAD50, RAD51C, RAD51D, RAD52 and SLX4, no responses were observed. In the BAP1, BARD1, BRIP1 and PALB2 cohorts, objective responses were detected. Conclusion: Olaparib demonstrated meaningful clinical activity across different cancer types with somatic or germline mutations in BAP1, BARD1, BRIP1 and PALB2.