Aggarwal R, et al. - In a multi-institutional prospective study, authors assessed the clinical and genomic features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC). In nearly one-fifth of patients with metastatic castration-resistant prostate cancer (mCRPC), t-SCNC is present and it is correlated with reduced survival. It is possible that t-SCNC could be a distinct subset of mCRPC, as suggested by the near-mutual exclusivity with DNA repair alterations. The identification of t-SCNC and novel therapeutic targets were facilitated by transcriptional profiling.

Methods

• Researchers included patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) who had metastatic tumor biopsy and followed them for survival.
• Along with RNA/DNA sequencing, metastatic biopsy specimens underwent independent, blinded pathology review.

Results

• A total of 202 consecutive patients were enrolled; 148 (73%) had prior disease progression on abiraterone and/or enzalutamide.
• Results demonstrated that 79% was the biopsy evaluable rate.
• Researchers noted that 17% was overall incidence of t-SCNC detection.
• They noted the presence of AR amplification and protein expression in 67% and 75 of t-SCNC biopsy specimens%, respectively.
• At similar proportions in bone, node, and visceral organ biopsy specimens, t-SCNC was detected.
• In the DNA repair pathway, genomic alterations were nearly mutually exclusive with t-SCNC differentiation (P=.035).
• They noted a correlation of detection of t-SCNC with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82).
• In multiple external data sets, a t-SCNC transcriptional signature was developed and validated with > 90% accuracy.
• As per the findings, they identified multiple transcriptional regulators of t-SCNC, including the pancreatic neuroendocrine marker PDX1.