Circulating tumour DNA fraction as a predictor of treatment efficacy in a randomized phase 2 trial of [¹⁷⁷Lu]Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel (TheraP ANZUP 1603).

5055 Background: The TheraP trial showed that for patients with PSMA-positive, non-FDG-discordant mCRPC progressing after docetaxel, LuPSMA significantly improved biochemical and objective response rates, progression-free survival (PFS), and quality of life compared to cabazitaxel. While subsequent studies nominated high PSMA SUVmean to inform patient prioritization for LuPSMA, limited genomic data exists to guide optimal selection of these two life-prolonging therapies. We present an exploratory analysis of ctDNA fraction (ctDNA%) in baseline samples from the TheraP trial. Methods: We analyzed 180 baseline blood samples from participants who received ≥1 cycle of protocol-assigned treatment. Plasma cell-free DNA and matched white blood cell DNA underwent targeted sequencing to estimate ctDNA%. Prespecified ctDNA% categories (<2%, 2-30%, and >30%) were associated with previously validated imaging thresholds (PSMA SUVmean ≥10 and FDG metabolic tumor volume [MTV] ≥200mL), rate of PSA reduction ≥50% (PSA50-RR), and PFS, using chi-square test, logistic regression and Cox regression, respectively. Results: ctDNA% was evaluable in 178 (99%) participants, with ctDNA ≥2% in 85%. Median ctDNA% was 28% in ctDNA≥2% samples, and balanced across treatment arms. The odds of a PSA50 response to LuPSMA vs cabazitaxel were significantly higher for men with ctDNA <2% (OR infinite, p=0.0067; PSA50-RR 100% vs 58%), with no difference at ctDNA >30% (OR 1.1, p=1.0; PSA50-RR 46% vs 44%). Higher ctDNA% was associated with shorter PFS in LuPSMA- but not cabazitaxel-treated patients (LuPSMA: HR 5.0, p<0.001 for ctDNA <2% vs >30%; cabazitaxel: HR 1.4, p=0.35 for ctDNA <2% vs >30%; interaction p=0.035). The predictive potential of ctDNA% was additive to PSMA SUVmean in LuPSMA-treated patients. Higher ctDNA% categories were enriched for patients with high FDG MTV and low PSMA SUVmean disease (Table). Conclusions: ctDNA% is a candidate predictive and prognostic biomarker for differential response to LuPSMA versus taxane chemotherapy in patients with molecular imaging-selected mCRPC progressing after docetaxel. Clinical trial information: NCT03392428 . [Table: see text]