Molecular Testing Identifies Determinants of Exceptional Response and Guides Precision Therapy in a Patient with Lethal, Treatment-emergent Neuroendocrine Prostate Cancer

Nearly all prostate cancers start out as adenocarcinomas driven by the androgen receptor (AR). Neuroendocrine prostate cancer (NEPC) is a rare, AR-independent subtype with a poor prognosis and limited treatment options. Importantly, because of the widespread use of novel AR-targeting agents, the incidence of treatment-emergent (t)-NEPC is increasing in frequency. Molecular features commonly found in prostate adenocarcinomas are now well-recognized, including defects in homologous recombination (HR) genes, like breast cancer type 2 susceptibility protein (BRCA2), leading to increased sensitivity to deoxyribonucleic acid (DNA)-damaging agents (e.g., platinum chemotherapy or poly adenosine diphosphate-ribose polymerase (PARP) inhibitors). However, our own prior work demonstrates that HR gene defects are uncommon in t-NEPC. Herein, we describe a patient who originally presented with adenocarcinoma but who subsequently developed t-NEPC. Molecular testing determined that his t-NEPC tumor (but not his original adenocarcinoma) harbored complete copy number loss of BRCA2, as well as copy number loss of another HR gene - ataxia telangiectasia, mutated (ATM). Uncharacteristically for t-NEPC, the patient achieved a complete response to platinum chemotherapy. Based on emerging data for the role of maintenance PARP inhibitor therapy in ovarian cancer patients whose tumors harbor BRCA1/2 defects, we treated him with PARP inhibitor maintenance after chemotherapy. At nine months follow-up, the patient was still in complete remission. This report demonstrates the importance of molecular testing to clarify the biology of exceptional responders and to direct treatment. Our results also suggest that clinical trials of PARP inhibitor maintenance may be warranted in select patients with advanced prostate cancer, including those with t-NEPC, whose tumors harbor HR defects.