Tracking Response and Resistance to Lu-177 Plus Immunotherapy

A new analysis of the PRINCE clinical trial suggests that combining blood-based ctDNA testing with PSMA PET could help identify which men with metastatic castration-resistant prostate cancer (mCRPC) are most likely to respond to Lu-177 PSMA plus immunotherapy.

PRINCE was a multicentre Phase 1/2 trial involving 37 men with mCRPC. Patients received up to six cycles of 177Lu-PSMA-617 (Pluvicto) every six weeks together with pembrolizumab every three weeks. In the original trial, 28 of 37 patients, or 76%, achieved a PSA decline of at least 50%.

The new study does not test another treatment. Instead, researchers analysed blood samples and PET scans collected from PRINCE participants to understand why some patients responded better than others and how resistance developed. ctDNA, circulating tumour cells, PSMA PET and FDG PET were examined before treatment, at 12 weeks and when the cancer progressed.

Patients with a low amount of ctDNA before treatment and strongly PSMA-positive metastases tended to have better responses. This suggests that combining information from a liquid biopsy with PSMA PET could eventually provide a more precise way of identifying patients most likely to benefit from this type of treatment.

The 12-week measurements were also informative. Detectable ctDNA and changes seen on PSMA PET were strongly associated with how deep and durable the treatment response would be. This raises the possibility that blood tests and imaging could identify relatively early whether treatment is effectively controlling the cancer.

Genetics also mattered. Alterations involving the tumour-suppressor genes TP53, RB1 or PTEN were associated with greater FDG uptake, a larger metabolically active tumour burden and poorer prognosis.

Researchers also found evidence of how the cancer changed under treatment pressure. At progression, PSMA expression on PET was lower than it had been before treatment. At the same time, ctDNA and circulating tumour-cell analyses showed changes in the cancer’s genetic composition, including expansion of tumour clones carrying alterations in tumour-suppressor genes.

This suggests that resistance may involve both loss of the target recognised by Lu-177 PSMA and selection of more aggressive cancer populations. Following ctDNA and molecular imaging together could therefore provide information not only about whether treatment is working, but also about how the cancer is evolving.

The findings remain preliminary. PRINCE included only 37 patients and had no Lu-177 PSMA-only control group, so the analysis cannot establish which biomarkers specifically predict benefit from adding pembrolizumab. The results instead provide a framework for testing these biomarkers in larger trials.

Combining ctDNA, PSMA PET and FDG PET could potentially show both the biological characteristics of the cancer before treatment and how those characteristics change as resistance develops.

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