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PC models, reversing neuroendocrine differentiation and restoring sensitivity to AR-targeted
therapies [43,44,77] . A phase 2 study of maintenance olaparib following platinum-based chemotherapy in
aggressive variant prostate cancer is currently underway (NCT03263650). The small molecule inhibitor of
ONECUT2 CSRM617 has also shown encouraging pre-clinical activity in t-SCNC cell lines and PDX
models , and indirect targeting of ONECUT2 activity through the hypoxia-activated pro-drug TH-302 is
[54]
under current clinical investigation in a phase 1b/2 study of mCRPC (NCT00743379). Finally, several trials
of drugs targeting epigenetic pathways are underway: bromodomain inhibitors of epigenetic reader BET
proteins, such as ZEN-3694 (Zenith Epigenetics), have shown encouraging activity in aggressive variant PC
(i.e., with clinical features suggestive of t-SCNC) , while EZH2 inhibitors (e.g., tazemetostat, CPI-1205)
[78]
have generated promising pre-clinical and early clinical data [42,63,79,80] . CPI-1205 (Constellation
Pharmaceuticals) is under current investigation in combination with AR-targeted therapy in a phase 1b/2
trial of mCRPC patients (NCT03480646).

CONCLUSION
Phenotypic switch to t-SCNC is an increasingly recognized mechanism of resistance to AR-targeted
therapy. Improved molecular profiling has revealed a distinct t-SCNC transcriptional landscape
characterized by the upregulation of stem-cell-associated and neuronal programs, as well as decreased
canonical AR activity [3,11,14,31,32] . Nevertheless, despite stark differences in their transcriptional, histologic, and
clinical features, there is a surprising degree of genomic overlap between mCRPC-adenocarcinoma and t-
SCNC [3,11,14] . Furthermore, with a few notable exceptions (e.g., TP53, RB1, and AR), many gene expression
differences observed across the two histologic subtypes are not accounted for by underlying genomic
alterations. This finding supports a divergent model of evolution, whereby t-SCNC transdifferentiates from
a mCRPC-adenocarcinoma subclone. It also underscores the role of epigenetic mechanisms in driving
lineage plasticity and neuroendocrine differentiation. Thus, in addition to the observation of clear genome-
wide differences in the DNA methylation and histone modification landscapes across the two histologic
subtypes [3,47,57] , several epigenetic regulators (e.g., EZH2, SRRM4) have recently emerged as key drivers of t-
SCNC [64,65] . Improved understanding of the molecular underpinnings of t-SCNC carries important
implications for the management of this aggressive mCRPC variant: transcriptional and epigenetic
signatures have already shown promising results in the diagnosis of t-SCNC and in the development of
non-invasive biomarkers. Therapeutic strategies targeting the unique genomic and epigenetic features of t-
SCNC are similarly underway, with encouraging pre-clinical and early clinical activity.

DECLARATIONS
Authors’ contributions
Reviewed literature and wrote the manuscript: de Kouchkovsky I
Provided critical review and editing of the manuscript: Small EJ, Quigley DA, Aggarwal R

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
Small EJ reports consulting fees from Janssen, Fortis, Teon Therapeutics, Ulragenyx, Beigene, Tolero,
honoraria for speaking enagements from Janssen, Johnson and Johnson, and stock in Fortis Therapeutics
and Harpoon Therapeutics. Quigley DA reports consulting fees from Varian and Circle Pharma. de
Kouchkovsky I and Aggarwal R declared that there are no conflicts of interest.