Advancing metastatic prostate cancer care: best practices and future directions in molecular testing

To review the current state of molecular testing in metastatic prostate cancer (mPC), including testing modalities, approaches and strategies, and practical ways to implement testing into patient care of candidates for treatment with poly-adenosine diphosphate-ribose polymerase inhibitors (PARPi). We performed a narrative review of publications, over a 15-year period, reporting on the use of testing modalities for biomarker identification in patients with homologous recombination repair (HRR) gene-altered mPC, with a focus on next-generation sequencing (NGS), variability among NGS assays, and their ability to detect certain types of genomic alterations. While NGS has become the most common modality for HRR gene testing, substantial variability among assays to detect certain types of genomic alterations exists. Tumor tissue remains the gold standard for somatic alteration evaluation, however, circulating tumor DNA (ctDNA)–based testing is minimally invasive and an alternative when tissue is unavailable. Nevertheless, both tissue- and ctDNA-based testing modalities face challenges pertaining to disease characteristics, sample acquisition, processing, storage, and the influence of treatment status, which may affect success rates, as well as the likelihood of false-negative and false-positive results. Additionally, choices surrounding germline and somatic testing have important implications for the utility and interpretation of biomarker test results. The adoption of HRR gene mutation testing in mPC remains suboptimal, highlighting a need to identify patients who may benefit from targeted PARPi therapy. The benefits and challenges of various molecular testing approaches using tissue or ctDNA and strategies in patients with mPC must be fully understood to employ a practical approach to the integration of molecular biomarker testing.