Treatment-emergent neuroendocrine prostate cancer with a germline <i>BRCA2</i> mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance

Abstract

Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen receptor-targeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as <i>BRCA1/2</i>, are also being increasingly detected in individuals with advanced prostate cancer. We present the case of a 65-yr-old man with a germline <i>BRCA2</i> mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. He achieved a complete response to platinum-containing chemotherapy, but a limited remission duration with the use of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy. Upon relapse, tumor genomic profiling revealed a novel 228-bp deletion in exon 11 of the <i>BRCA2</i> gene. The addition of the anti-PD1 drug pembrolizumab to olaparib was ineffective. This case highlights the ongoing challenges in treating neuroendocrine prostate cancer, even in the setting of homologous recombination repair deficiency.