Beyond PSA: Could ctDNA Become an Early Compass for Treatment in Metastatic Prostate Cancer?

For decades, PSA has been the main biomarker used to monitor prostate cancer. It is inexpensive, accessible, and clinically familiar, but it does not always reflect what is happening inside metastatic tumors. PSA production is linked to androgen-receptor signaling, meaning that treatment-resistant or neuroendocrine-like tumor clones may continue to grow without producing a corresponding PSA increase.

Circulating tumor DNA, or ctDNA, may offer a more direct and earlier view of tumor behavior. Released into the bloodstream by cancer cells, ctDNA can reflect tumor burden, clonal evolution, and emerging treatment resistance. Unlike PSA, it is not directly dependent on androgen-receptor activity and may capture DNA shed from several metastatic sites at once.

A prospective study of 114 patients with high-volume metastatic castration-sensitive prostate cancer examined ctDNA during the first six cycles of treatment with androgen-deprivation therapy combined with docetaxel or an androgen-receptor pathway inhibitor. ctDNA was detectable in approximately 70% of patients before treatment, but this fell to about 29% after six to twelve weeks, suggesting that effective therapy produces a rapid molecular response.

The most important finding involved patients whose ctDNA remained detectable. At cycles three or four, these patients had substantially worse survival than those whose ctDNA became undetectable. Twenty-four-month overall survival was approximately 50% in the ctDNA-positive group compared with 85% in the ctDNA-negative group. ctDNA also appeared to provide prognostic information earlier than PSA, potentially identifying poor responders before PSA kinetics became clearly unfavorable.

The implications are significant. Persistent ctDNA could identify patients who might benefit from closer monitoring, clinical-trial enrollment, or future treatment intensification. In contrast, sustained ctDNA clearance might eventually help identify patients suitable for treatment de-escalation studies, although this possibility remains unproven.

The key message is not that ctDNA should replace PSA. PSA remains essential because it is cheap, standardized, and widely available. Instead, ctDNA and PSA may provide complementary information: PSA reflects a familiar biochemical response, while ctDNA offers a more direct molecular view of tumor burden and resistance.

However, the study was prognostic rather than interventional. It showed that persistent ctDNA is associated with poor outcomes, but it did not prove that changing treatment because of persistent ctDNA improves survival. Before ctDNA can be used routinely to guide treatment changes, randomized trials must establish the benefit of acting on its results.

For now, ctDNA is best viewed as a promising early compass for metastatic prostate cancer—particularly for identifying inadequate treatment response and guiding molecular profiling—while PSA and imaging remain essential components of clinical decision-making.

Nature.