Evolution of Potentially Actionable Genomic Alterations in Advanced Prostate Cancer: A Real-World Analysis of Serial...

Area of Science:

• Oncology
• Genomics
• Molecular Diagnostics

Background:

• Longitudinal genomic profiling using serial circulating tumor DNA (ctDNA) testing provides a noninvasive method for monitoring clonal evolution in advanced prostate cancer.
• Real-world data on the frequency and characteristics of newly emergent, actionable genomic alterations detected via serial ctDNA testing is limited.

Purpose of the Study:

• To evaluate the frequency and nature of newly emergent and potentially actionable genomic alterations identified through serial ctDNA testing in advanced prostate cancer patients.
• To assess the clinical relevance of these alterations for on-label therapies, off-label therapies, and clinical trials.

Main Methods:

• Retrospective analysis of advanced prostate cancer patients undergoing serial Guardant360 ctDNA testing (October 2020 - March 2023).
• Identification of new genomic alterations absent in baseline tests, focusing on those with therapeutic implications.
• Analysis of tumor mutational burden (TMB) changes and treatment outcomes in a subset of patients.

Main Results:

• Among 479 patients with multiple ctDNA tests, 57.8% showed new, potentially actionable alterations.
• These alterations were relevant for on-label therapies (16.7%), off-label therapies (16.5%), and clinical trials (55.7%).
• Tumor mutational burden (TMB) increased from low to high in 11% of patients; limited treatment responses were observed with targeted therapies and immunotherapy.

Conclusions:

• Serial ctDNA testing is valuable for detecting emergent genomic alterations and capturing clonal dynamics in advanced prostate cancer.
• These findings highlight the potential of serial genomic profiling to identify actionable therapeutic targets.
• Further research is needed to establish optimal retesting frameworks and treatment decision-making strategies based on serial ctDNA results.