Phase 2 Trial Analysis: Liquid Biopsy May Help Identify Prostate Cancer Patients Who Benefit Most From Targeted Radiotherapy

A new study published in JAMA Network Open suggests that circulating tumour DNA (ctDNA) could help identify patients with oligoprogressive metastatic castration-resistant prostate cancer (mCRPC) who are most likely to achieve prolonged disease control following stereotactic body radiotherapy (SBRT).

The findings come from a prespecified secondary analysis of the Phase 2 TRAP trial, which investigated SBRT in patients experiencing progression at no more than two metastatic sites while continuing treatment with an androgen receptor pathway inhibitor (ARPI). Researchers analysed blood samples from 77 patients before radiotherapy, identifying detectable ctDNA in 19 patients (24.7%), while the remaining 58 (75.3%) tested negative.

The difference in outcomes was substantial. Median progression-free survival (PFS) reached 7.8 months in ctDNA-negative patients, compared with just 3.0 months in those with detectable. At six months, 58.3% of ctDNA-negative patients remained progression-free, compared with 21.1% of ctDNA-positive patients. After adjustment for age, PSA, previous chemotherapy and irradiated metastatic site, ctDNA positivity was associated with more than twice the risk of progression (HR 2.18; 95% CI, 1.21–3.94; p = 0.009).

The difference also extended to subsequent treatment requirements. Median time to initiation of a new therapy or death was 29.6 months in ctDNA-negative patients versus 15.3 months in ctDNA-positive patients. Median overall survival was 33.6 and 27.2 months, respectively, although the association between ctDNA status and overall survival did not reach statistical significance after adjustment.

These findings suggest that liquid biopsy could provide information that conventional imaging alone cannot capture. Patients with only a few visible progressing metastases may already harbour more extensive microscopic disease, potentially explaining why some experience rapid progression despite successful local treatment. Conversely, patients without detectable ctDNA may be better candidates for treating resistant lesions while maintaining their existing systemic therapy.

However, the analysis comes from a single-arm, non-randomised study involving a relatively small population. Importantly, ctDNA negativity was associated with better outcomes but has not been proven to predict a greater benefit specifically from SBRT. A negative liquid biopsy also does not exclude the presence of microscopic disease. Prospective randomised studies are needed to establish whether ctDNA-guided treatment selection improves clinical outcomes.

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