PCa Commentary | Volume 204 – August 2025

Posted by Edward Weber | August 2025

Management of Transformed Neuroendocrine Prostate Cancer “tNEPC” — An Unmet Challenge.

Background:

Neuroendocrine cells are normal constituents of the prostate. They perform a regulatory role, influencing growth and differentiation. Spread throughout the body, they receive signals from the nervous system to secrete hormones that govern other systems.

Mutations in regular prostate adenocarcinoma cells can transform themselves and their neighbors into malignant neuroendocrine cancer cells (tNEPC). While there are rare cases (1%) wherein the entire prostate gland is overwhelmed by malignant NEPC cells, the usual situation is that, later in disease progression, due to mutations resulting from sequential therapies, 20% to 30% of adenocarcinoma cells are transformed into aggressive tNEPC. These cells do not secrete PSA, nor do they express the cell-surface prostate-specific membrane antigen (PSMA). They are unaffected by androgen suppression and escape Pluvicto therapy, which requires the expression of the PSMA antigen to guide 177Lutetium to its target.

Identifying tNEPC:

In late disease, an indication that portions or most of the regular adenocarcinoma metastases have been transformed into tNEPC might be suspected by noting an unusual pattern of metastases on scans (to liver, lung, or adrenal glands) along with an inappropriately low PSA to tumor burden. Unfortunately, this is a rather non-specific determination.

Pylarify and Axumin PET-CT scans identify lesions expressing PSMA, but do not image tNEPC lesions, which are only imaged by the CT portion of the scan. Hence, the mismatch of lesions that are CT-positive, but PSMA-negative, suggests that some lesions contain tNEPC. Another scan, the

18F-FDG PETCT images the aggressive lesions of tNEPC, whereas the PSMA PET-CT images only PSMA-positive lesions. This is termed FDG/PSMA mismatch. A prominent Pluvicto researcher, Dr. Hoffman in Australia, excluded men showing this mismatch from his Pluvicto trial, knowing that men whose lesions were FDG-positive, but PSMA-negative, would not completely respond to Pluvicto.

Biopsies of metastatic lesions searching for NEPC can be unreliable. NEPC is heterogeneously distributed within and among metastatic lesions. Biopsies can miss the cancer, and bone-directed biopsies can have adverse consequences. Elevation of the serum biomarker Chromogranan A (normal levels 100-120 ng/mL) to, say, ~300 ng/mL is highly suggestive of tNEPC.

Himisha Beltran (Dana Farber) developed “a targeted DNA methylation assay to detect CRPC-NE cancer using plasma cell-free circulating DNA (cfDNA): “Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation” (Cancer Discovery. 2024).

She pointed out, “The current diagnosis of CRPC-NE is challenging and relies on [unreliable] metastatic biopsy.”  Her assay is termed NEMO (NEuroendocrine detection and MOnitoring) and can “quantify tumor fraction and identify patients with neuroendocrine cancer non-invasively.” It will be useful in patient selection for treatment. Unfortunately, NEMO is currently only available to patients in Massachusetts.

New Imaging and Treatment Combinations Under Development for tNEPC.

tNEPC cells express the biomarker protein DLL-3 on their outer membrane. DLL-3 is overexpressed in NEPC (~77% of cases), promotes tumor progression, and is minimally expressed in healthy tissues. The intravenously administered anti-DLL3 antibody, [89]Zirconium Zr-DFO-SC16.56 is under study for imaging this cancer at Memorial Sloan Kettering Cancer Center. (NCT04199741).

When and How to Treat tNEPC:

Since tNEPC can be involved to a variable extent of the total tumor burden, the challenging question is when to intervene with new therapies, considering that if tNEPC is present in only a small portion of the tumor burden, then a change of therapy might not be warranted. The currently used regimens for treating tNEPC include platinum-based chemotherapy (carbazataxel and carboplatin) combined with an anti-PDL1 immune checkpoint inhibitor. However, these all carry increased adverse effects compared to standard hormone suppression and might well be withheld until tNEPC comprises a substantial extent of the total tumor burden.

The NEMO analysis would be helpful to indicate the extent of the tNEPC involvement and guide the treatment decision. Since NEMO has limited availability, other measures discussed above will have to serve.

New Treatments Under Development:

Regimens targeting the DLL-3 protein expressed on NEPC cells are being studied. They combine the DLL-3 targeting antibody SC16.56 with the radioisotopes, [89] Zirconium, [177] Lutetium, or [225] Actinium. Clinical trial NCT04199741 is ongoing at Memorial Sloan Kettering for neuroendocrine prostate cancer. It combines the SC16.56 antibody with the radioisotope 89Zirconium.

BOTTOM LINE: The imaging and treatment of tNEPC remains challenging. Radioisotope therapies targeting DLL-3 on tNEPC cells are promising.

“We appreciate the unfailing assistance of the librarians at Providence/Swedish.”