1.7 million women globally will face a diagnosis of breast cancer, almost 40% of whom will develop metastatic disease. Breast cancer brain metastasis are a frequent and aggressive form of metastatic spread, with treatment options limited for each of the clinically relevant molecular subtypes. Advanced breast cancer cells display exceptional plasticity, capable of adapting to sequential bouts of therapeutic pressure, as well as the vastly changing environmental landscape. To understand potential drivers and novel targets in brain metastasis we have undertaken multi methyl-omic studies, and identified HRD as a gained vulnerability beyond the classic germline mutations in BRCA1/2 and PALB2. Preliminary pre-clinical studies suggest targeting HRD with PARPi may be an effective strategy for this extended patient population.