Characterizing Longitudinal Molecular Changes in ctDNA in Patients with Metastatic Castration-Resistant Prostate Cancer.

Circulating tumor DNA (ctDNA) next-generation sequencing complements tissue-based testing and offers insights into prognosis, treatment selection, and tumor evolution. Despite advances in metastatic castration-resistant prostate cancer (mCRPC) therapies, resistance remains a challenge. This real-world study evaluates longitudinal ctDNA changes following systemic treatments. We analyzed data from Guardant INFORM, a clinical genomic database linking ctDNA profiles with claims data. Patients with prostate cancer who received androgen receptor (AR) pathway inhibitors (ARPi), poly (ADP-ribose) polymerase inhibitors (PARPi), or taxanes and had ctDNA testing within 3 months before and after treatment discontinuation were included. We evaluated pre- and posttreatment mutational differences and survival outcomes (overall survival, time to treatment discontinuation, and time to next treatment), stratifying by treatment type and AR alterations. From 36,774 patients with prostate cancer, we identified 678 with paired pre-/post-ARPi, 188 with paired pre-/post-PARPi, and 844 with paired pre-/post-taxane ctDNA samples. After ARPi, the most frequent AR alterations included AR amplification (pre%/post%; 10.8%/25.6%), AR L702H (1.3%/7.9%), and AR T878A (2.9%/7.1%). Following PARPi, the most common homologous recombination repair gene alterations were ATM (25%/23.4%), BRCA2 (22.9%/17%), BRCA1 (4%/2.1%), and CDK12 (5.9%/5.9%). After taxane, frequent alterations included TP53 (47.2%→54%), AR (33.2%/49.9%), PIK3CA (9.4%/15.9%), and EGFR (9.6%/14.6%). All treatment cohorts showed a significant increase in mutation burden after therapy (mean increase 2.0-4.2 alterations; P < 0.001). Across all three treatment groups, the presence of AR alterations was consistently associated with inferior clinical outcomes. Our study revealed dynamic shifts in genetic mutations in patients with mCRPC following ARPi, PARPi, and taxanes. Furthermore, our findings highlight associations between AR alterations and clinical outcomes, emphasizing the potential for personalized treatment strategies.