Baseline ctDNA has both prognostic and predictive value in mCRPC

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

PSMAfore (NCT04689828) is a randomised, phase 3 trial which recently demonstrated that ¹⁷⁷LU-PSMA-617 therapy prolongs radiographic progression-free survival (PFS) compared with an androgen receptor pathway inhibitor (ARPI) change in taxane-naïve mCRPC [1]. Prof. Johann de Bono (Royal Marsden Hospital, UK) presented an exploratory analysis that evaulated the prognostic and predictive value and dynamics of ctDNA levels [2].

PSMAfore randomised 468 participants to ¹⁷⁷LU-PSMA-617 therapy (7.4 GBq every 6 weeks; 6 cycles) or an ARPI change (abiraterone/enzalutamide). ctDNA samples were obtained at baseline and on day 1 of each treatment cycle. ctDNA fraction (i.e. relative amount of ctDNA in the sample) was assessed, as well as alterations in key prostate cancer drivers.

Baseline ctDNA fraction proved to have prognostic value: Participants with a baseline ctDNA fraction >0.5% had a shorter radiographic PFS than those with a ctDNA fraction ≤0.5%, regardless of treatment received (13.6 vs 2.55 months). Early ctDNA clearance was associated with longer radiographic PFS. Lower baseline ctDNA fractions were observed in responders than in non-responders, regardless of therapy, suggesting that the ctDNA fraction also has predictive value.

In addition, genomic analysis of ctDNA showed that known prognostic genetic biomarkers, including the presence of AR amplification, chromosome 8q and MYC amplification, and TP53 deleterious alterations, have predictive value. For example, in the ¹⁷⁷Lu-PSMA arm, the median radiographic PFS was improved in participants without 8q amplification compared with participants with 8q amplification (11.0 vs 8.6 months in case of low ctDNA fraction; 9.2 vs 2.5 months in case of high ctDNA fraction). Likewise, the presence of AR amplification or TP53 deleterious alterations was associated with a poorer median radiographic PFS in the ¹⁷⁷Lu-PSMA arm.

“Baseline ctDNA in patients with taxane-naïve mCRPC has both prognostic and predictive value. Early ctDNA fraction dynamics indicate expected radiographic PFS and tumour response. In addition, the presence of specific genomic alterations in ctDNA has predictive value, ” summarised Prof. de Bono.

1. Sartor O, et al. Ann Oncol. 2023;34(suppl 2):S1324-S1325.
2. De Bono JS, et al. Baseline ctDNA analysis and associations with outcome in taxane-naïve patients with mCRPC treated with [¹⁷⁷LU]Lu-PSMA-617 versus change of ARPI in PSMAfore. Abstract 5008, ASCO Annual Meeting 2024, 31 May–4 June, Chicago, IL, USA.

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Posted on 18 July 202418 July 2024