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In patients with taxane-naive metastatic castration-resistant prostate cancer (mCRPC), circulating tumor DNA (ctDNA) has both prognostic and predictive value, results from an exploratory analysis of phase 3 PSMAfore trial suggest.

PSMAfore (NCT04689828) is a phase 3 randomized trial recently demonstrating ¹⁷⁷LU-PSMA-617 therapy to prolong radiographic progression-free survival (rPFS) versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive mCPCP¹. The prognostic and predictive value of (changes) in ctDNA were evaluated in an exploratory analysis. Prof. Johan de Bono, PhD, of Royal Marsden Hospital, in the UK, presented the results².

In PSMAfore, 468 patients were 1:1 randomly assigned to ¹⁷⁷LU-PSMA-617 therapy or ARPI change. CtDNA samples were obtained at baseline before therapy and day 1 of course 2 of treatment. CtDNA fraction (relative amount of tumor DNA in the sample) and alteration in key prostate cancer drivers were assessed.

Baseline ctDNA fraction proved to have prognostic value: participants with baseline ctDNA fraction over 0.5% had shorter rPFS compared with participants with ctDNA fraction under or equal to 0.5%, regardless of treatment received: 13.6 months versus 2.55 months. Early clearance of ctDNA was associated with longer rPFS.

Lower baseline ctDNA fractions were observed in responders than in non-responders regardless of therapy, suggesting a predictive value for ctDNA fraction. In addition, genomic analysis of ctDNA showed that known prognostic genetic biomarkers, e.g. AR amplification, chromosome 8q and MYC amplification, and TP53 deleterious alterations, have predictive value. For example, in the ¹⁷⁷Lu-PSMA arm, median rPFS was improved in participants without 8q amplification compared to participants with 8q amplification (11.0 months vs 8.6 months in case of low ctDNA fraction; 9.2 months vs 2.5 months in case of high ctDNA fraction). The presence of AR amplification and the presence of TP53 deleterious alterations were associated with poorer median rPFS in the ¹⁷⁷Lu-PSMA arm.

“Baseline ctDNA in patients with taxane-naive mCRPS has both prognostic and predictive value. Early ctDNA fraction dynamics inform of rPFS and tumor response. In addition, the presence of genomic alterations in ctDNA have predictive value,” summarized Prof. De Bono.

Medical writing support was provided by Marten Dooper, PhD.

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