Workflow for the development of an integrated predictive biomarker of response to homologous recombination (HR) defect directed therapy. The workflow begins with genomics data - either sequence or single-nucleotide polymorphism microarray data - for tumor samples that have been annotated with patient response data to a given HR targeting drug therapy. After development of a genomic scar measure and a cutoff with high negative predictive value (NPV) were shown to identify non-responders but likely poor positive predictive value (PPV) due to inclusion of patients who have developed resistance (for example, 53BP1 loss) subsequent to development of the genomic scar, two groups can be identified: those predicted not to respond and those predicted to respond accepting a poor PPV. Patients in the former group should not be treated with the drug, whereas for patients in the predicted responder group, gene expression or mutation data are collected. Within the latter group, a biomarker excluding those with acquired resistance is constructed that is highly specific for response to the drug, better dichotomizing patients into those who do and those who do not benefit. By combining the genomic scar biomarker with the resistance-refined biomarker, the resultant two-step companion diagnostic should possess both high NPV and high PPV.