Neuroendocrine Prostate Cancer May Not Mean the End of PSMA

Prostate cancer that develops neuroendocrine features is commonly associated with loss of androgen-receptor dependence and reduced PSMA expression, potentially making PSMA-targeted treatments less useful. A new dual-tracer imaging study suggests that the reality may be considerably more complicated.

Researchers retrospectively examined eight men with metastatic castration-resistant prostate cancer who were suspected of developing treatment-emergent neuroendocrine differentiation. Each underwent both 68Ga-PSMA PET/CT and 68Ga-DOTATATE PET/CT on consecutive days, allowing the distribution of PSMA and somatostatin-receptor expression to be compared directly within the same patient.

Surprisingly, PSMA did not disappear. PSMA uptake was equal to or greater than DOTATATE uptake in all eight patients. Several metastases were PSMA-positive but DOTATATE-negative, including lesions in the liver and lungs as well as lymph nodes and bone. Conversely, the investigators found no documented lesions that were DOTATATE-positive while being PSMA-negative.

One particularly informative patient had biopsy-confirmed adenocarcinoma with neuroendocrine differentiation. PSMA PET detected 128 lesions compared with 67 using DOTATATE. Maximum uptake was also substantially higher with PSMA, with an SUVmax of 42.6 versus 11.0, while total tumour volume detected by PSMA was approximately 1,439 mL compared with 347 mL using DOTATATE.

This could have practical implications. Neuroendocrine differentiation is sometimes assumed to imply loss of PSMA and therefore reduced suitability for PSMA-targeted radioligand therapy. These results suggest that such an assumption may be premature: a tumour becoming clinically more neuroendocrine does not necessarily mean that its PSMA target has disappeared.

The study also illustrates how heterogeneous advanced prostate cancer can become. Different metastases within the same patient may evolve along different biological paths, meaning labels such as “adenocarcinoma” or “neuroendocrine prostate cancer” may not fully describe the molecular targets present across every tumour site.

There is, however, an important limitation. Only eight patients were studied and histological confirmation of neuroendocrine differentiation was available in just one. The remaining seven were considered suspicious for treatment-emergent neuroendocrine disease on clinical grounds. The results therefore cannot establish how frequently confirmed neuroendocrine prostate cancer retains PSMA, but they raise an important clinical question. Rather than automatically excluding PSMA-targeted approaches when neuroendocrine differentiation is suspected, imaging the patient’s actual disease may reveal whether the target remains present.

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