Real-World Outcomes of DNA Damage Repair Altered Metastatic Castration-Resistant Prostate Cancer: Insights from...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• DNA Damage Repair (DDR) gene variants are present in about 25% of metastatic prostate cancer (PC) patients.
• The prognostic and predictive roles of these DDR variants in PC remain unclear.

Purpose of the Study:

• To investigate the prevalence of DDR aberrations in metastatic prostate cancer (mPC).
• To evaluate the prognostic and predictive impact of DDR variants on chemotherapy (taxanes) and next-generation hormonal therapies (NHT).

Main Methods:

• Retrospective analysis of 287 mPC patients treated between 2017-2022.
• Comparison of clinical outcomes (PFS, OS) between DDR-mutated (DDRmut) and wild-type (DDRwt) cohorts.
• Evaluation of formalin-fixed paraffin-embedded (FFPE) tissue for DDR analysis.

Main Results:

• 21.9% of patients had DDR mutations, most commonly BRCA2, ATM, and BRCA1.
• Family history of related cancers predicted DDRmut status (47.0% vs. 14.0%).
• DDRmut patients showed a trend towards shorter progression-free survival (PFS) with first-line NHT (12 vs. 18 months; p=0.04), but not with taxanes or third-line Cabazitaxel.

Conclusions:

• FFPE prostate tissue is reliable for DDR variant evaluation.
• BRCA1/2 and ATM variants define a molecular subgroup in mPC.
• This subgroup may benefit from first-line taxanes over standard hormonal therapy intensification.