This is a multicenter, prospective, phase II, one-arm, three-cohort, open-label study of pembrolizumab in combination with olaparib in patients with advanced HER2 negative breast cancer who have either~a deleterious germline mutation in BRCA1/2 irrespective of tumor HRD status (Cohort 1),~or a deleterious germline mutation in ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2 irrespective of tumor HRD status (Cohort 2),~or a centrally confirmed high tumor HRD status, but no deleterious germline mutation in BRCA1/2, ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2 (Cohort 3). HRD assessment needs to be performed on a tumor biopsy not more than 12 months before study entry.~All eligible participants according to the definition of cohorts 1-3 will receive pembrolizumab i.v. 200 mg q3w in combination with olaparib tablets 300 mg twice daily (total dose 600 mg per day).~Study medication will be withdrawn/ended in case of onset of unacceptable toxicities, progression, withdrawal of consent, death, or end of study, whichever occurs first. Safety follow-up is planned for 90 days after the last application of study medication. Participants will be followed for survival for a maximum of 18 months after therapy start.
This study will examine the combination of pembrolizumab and olaparib in three populations.~Cohort 1: aBC patients with a germline mutation in BRCA1 or BRCA2,~cohort 2: aBC patients with a germline mutation in one of the moderate penetrance homologous repair genes (ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2), and~cohort 3: aBC patients with a HRD as assessed by whole genome sequencing.