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Abstract

Metastatic castration-resistant prostate cancer (mCRPC) represents one of the most intractable challenges in contemporary clinical oncology. In this context, prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (TRNT) with [177Lu]Lu-PSMA-617 has emerged as a transformative therapeutic approach, offering new hope for patients with otherwise limited treatment options. Despite its promise, resistance to [177Lu]Lu-PSMA ligands is observed in approximately 30% of patients, underscoring the urgent need for improved strategies to overcome primary treatment failure. In response to these limitations, the field has shifted toward innovative radiotherapeutic combinations. Among them, tandem therapy—uniting the potent alpha-emitting [225Ac]Ac-PSMA-617 with the clinically approved [177Lu]Lu-PSMA-617—has demonstrated remarkable potential to enhance antitumor efficacy while minimizing dose-limiting toxicities. The aim of this work is to deliver a comprehensive evaluation of clinical real-world data from patients with mCRPC treated with [225Ac]Ac-/[177Lu]Lu-PSMA-617 under compassionate care regulations. This thesis explores the use of tumor fraction (TFx) estimation, derived via the ichorCNA algorithm from ultra-low-pass whole genome sequencing (ULP-WGS) of circulating free DNA (cfDNA), as a biomarker to monitor treatment response and resistance in mCRPC patients receiving tandem actinium-lutetium therapy. Serial cfDNA samples from 78 mCRPC patients revealed that TFx strongly correlated with PSA levels and offered superior sensitivity in capturing metastatic burden. High pre-treatment TFx was linked to a markedly increased risk of relapse, while genomic profiling uncovered two distinct subgroups—one with low TFx and minimal copy number variations (CNVs), and another with elevated TFx and high genomic instability. Strikingly, patients with lower CNV burden experienced longer survival, underscoring its potential as a powerful prognostic biomarker. Pre-treatment status emerged as a critical determinant of survival, offering key insights into the role of prior exposure to TRNT and chemotherapy in influencing long-term outcomes. Gene signature linked to high CNV burden was identified, highlighting key chromosomes and relapse-associated genes as potential drivers of poor prognosis and therapeutic targets.