Radioligand therapy with 177Lu-PSMA-617 has transformed the treatment landscape for metastatic castration-resistant prostate cancer, a lethal stage of the disease in which roughly half of patients survive less than five years after their metastatic diagnosis. The therapy exploits prostate-specific membrane antigen, a protein abundantly displayed on the surface of prostate cancer cells and further upregulated as tumors become castration resistant. A ligand called PSMA-617 delivers the beta-emitting radioisotope lutetium-177 directly to tumor cells, irradiating metastases throughout the body while sparing much of the surrounding healthy tissue. Following the landmark phase III VISION trial, the approach gained approval from the United States Food and Drug Administration in March 2022 for PSMA-positive patients who had already received an androgen receptor pathway inhibitor and taxane chemotherapy.

Yet the therapy has an uncomfortable secret: only about half of eligible patients derive meaningful clinical benefit. Except for PSMA PET imaging criteria used to confirm that tumors carry the target molecule, clinicians currently lack validated biomarkers to identify who will respond and who will progress despite treatment. This gap matters both scientifically and economically. A recent cost-effectiveness analysis based on the VISION trial concluded that adding 177Lu-PSMA to standard care may only be cost-effective under specific clinical and economic assumptions, underscoring the urgency of better patient selection.

To address this problem, investigators at IRCCS Istituto Romagnolo per lo Studio dei Tumori in Meldola, Italy, enrolled 145 patients between April 2017 and October 2022 in a prospective observational biological study nested within a single-arm phase II trial of 177Lu-PSMA-617. Of these, 142 patients received at least one dose and were fully evaluable. Within seven days of the first infusion, the researchers collected baseline blood samples and measured a panel of routinely available laboratory markers, including hemoglobin, alkaline phosphatase, prostate-specific antigen, chromogranin A, neuron-specific enolase, and CEA, along with inflammatory ratios derived from the complete blood count. All patients received treatment in four cycles administered every eight to twelve weeks, using either a lower activity of 3.7 to 4.4 gigabecquerels or a higher activity of 5.5 gigabecquerels per cycle.

At a median follow-up of 44 months, the cohort experienced a median progression-free survival of 7.0 months and a median overall survival of 16.8 months, outcomes broadly consistent with the pivotal VISION and TheraP trials. In univariable analyses, elevated platelet-to-lymphocyte ratio, alkaline phosphatase, PSA, and CEA each predicted shorter progression-free survival, while low hemoglobin and high neutrophil-to-lymphocyte ratio, along with the same markers, predicted shorter overall survival. But when the researchers integrated all clinical characteristics and serum biomarkers into multivariable Cox regression models, only a handful of factors retained independent significance: prior docetaxel exposure, low hemoglobin, high PSA, and, critically, elevated CEA. High CEA independently predicted both shorter progression-free survival, with a p-value of 0.026, and shorter overall survival, with a p-value of 0.003.

The statistical rigor of the analysis strengthens the claim. Multicollinearity checks using variance inflation factors confirmed that no variable simply duplicated another, with all values below two. When CEA was added to a model containing established prognostic factors, the overall model fit improved significantly according to a likelihood-ratio test, and Harrell’s concordance index rose from 0.732 to 0.742. Although PSA alone discriminated outcomes better than CEA alone, with C-indices of 0.652 versus 0.598, combining the two markers pushed the C-index to 0.694, demonstrating that CEA carries prognostic information that PSA does not capture. Exploratory correlation analyses reinforced this independence: baseline CEA showed essentially no relationship with PSA levels and only a weak association with chromogranin A, while it did not correlate with bone disease burden measured on PSMA PET scans.

The biological story behind elevated CEA may be as compelling as the statistics. CEA is an oncofetal glycoprotein long used as a tumor marker in colorectal and other cancers, and previous work has linked it to aggressive disease biology in prostate cancer. In particular, elevated serum CEA in castration-resistant prostate cancer has been associated with liver metastases, markedly shorter survival, and distinctive circulating tumor DNA alterations. It has also been tied to aggressive variant prostate cancer, a molecularly distinct and treatment-resistant phenotype. Although a single-arm design without a control group prevents the authors from claiming that CEA specifically predicts benefit from 177Lu-PSMA rather than simply flagging inherently aggressive disease, the finding raises the hypothesis that high CEA identifies a biologically distinct subgroup with intrinsic resistance to PSMA-targeted radioligand therapy. Notably, baseline FDG PET was not mandatory in this cohort, so the researchers could not test whether CEA-elevated patients harbored FDG-positive, PSMA-low lesions typical of aggressive variants.

Other markers behaved as expected. Lower hemoglobin, likely reflecting chronic inflammation and extensive bone marrow involvement rather than a direct effect on treatment response, remained independently associated with shorter overall survival. Alkaline phosphatase, a proxy for skeletal tumor burden, also independently predicted overall survival, consistent with three prior studies and a recent meta-analysis. Inflammatory ratios lost much of their significance after adjustment, although platelet-to-lymphocyte ratio retained an association with progression-free survival. An intriguing exploratory interaction suggested that the prognostic impact of CEA may differ according to the administered radiation activity, but the authors caution that this post hoc finding is hypothesis-generating only, since dose was not randomly assigned and lower activities were reserved for frailer patients.

The study’s limitations temper, but do not erase, its promise. The administered activities were lower than the currently approved Pluvicto regimen of 7.4 gigabecquerels every six weeks, potentially limiting generalizability, and no metastatic biopsies were available to histologically confirm neuroendocrine differentiation among patients with elevated chromogranin A or neuron-specific enolase, markers of limited specificity that can rise in many benign and malignant conditions. External validation in cohorts treated with the approved dosing schedule will be essential before CEA enters routine risk stratification. Still, the vision is clear: if validated, a marker already present on virtually every hospital laboratory requisition could, at essentially no added cost, help clinicians identify patients facing aggressive, inherently resistant disease, guide them toward alternative or combination strategies, and reserve this costly radioligand therapy for those most likely to benefit. In the precision oncology era, the humble CEA blood draw may prove an unexpectedly powerful ally.

Subject of Research: Baseline serum carcinoembryonic antigen as an independent prognostic biomarker for survival outcomes in metastatic castration-resistant prostate cancer patients treated with 177Lu-PSMA radioligand therapy

Article Title: Baseline serum carcinoembryonic antigen (CEA) is an independent prognostic biomarker for metastatic castration-resistant prostate cancer (mCRPC) patients receiving 177Lu-PSMA therapy

Article References: Giunta, E. F., Marini, I., Grassi, I., Nicolini, S., Foca, F., Celli, M., Caroli, P., Sarnelli, A., Brighi, N., Schepisi, G., Monti, M., De Giorgi, U., Lolli, C., & Sansovini, M. (2026). Baseline serum carcinoembryonic antigen (CEA) is an independent prognostic biomarker for metastatic castration-resistant prostate cancer (mCRPC) patients receiving 177Lu-PSMA therapy. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08173-x

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08173-x

Keywords: 177Lu-PSMA, prostate cancer, radioligand therapy, CEA, biomarker, metastatic castration-resistant prostate cancer, prognostic factors, PSMA, overall survival, progression-free survival, PSMA-617, serum tumor markers