JCO precision oncology · 2026
Plasma-Derived Genomic Instability Status and Rucaparib Outcomes in Metastatic Castration-Resistant Prostate Cancer: TRITON2.
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Abida Wassim, Bryce Alan H, Chowdhury Simon, Patnaik Akash, Overstreet Brooke, Margolis Matthew, Safabakhsh Pegah, Fizazi Karim
Аннотация
PURPOSE: BRCA1/2 mutation testing identifies patients with metastatic castration-resistant prostate cancer (mCRPC) eligible for poly(ADP-ribose) polymerase inhibitors; however, clinical outcomes remain heterogeneous within these genotypes. We evaluated whether plasma-derived genomic instability status (GIS) was associated with outcomes beyond BRCA1/2 and PALB2 mutation status in the phase II TRITON2 study.
METHODS: This retrospective biomarker analysis included TRITON2 patients with available baseline plasma profiled using Guardant360 Liquid. GIS is a probabilistic measure of homologous recombination deficiency (HRD) inferred from genome-wide copy number variants and somatic mutational signatures. Analyses were restricted to patients with baseline tumor fraction (TF) ≥ 25%. Radiographic progression-free survival (rPFS) was analyzed using Kaplan-Meier methods and Cox models adjusted for age and baseline TF. Secondary end points included objective response rate (ORR), serum prostate-specific antigen (PSA50) declines, and overall survival (OS).
RESULTS: Among 104 patients with TF ≥ 25%, 43 (41%) had GIS detected. Compared with GIS detected, absence of GIS was associated with shorter rPFS (hazard ratio [HR], 2.81 [95% CI, 1.61 to 4.93]; P <.001). Joint stratification demonstrated patients with both GIS detected and BRCA/PALB2 mutation experienced the longest rPFS, whereas absence of GIS was associated with shorter rPFS regardless of BRCA/PALB2 mutation status. In BRCA2-mutated patients, rPFS trended being longer in those with GIS detected (compared with those without GIS detected; HR, 2.02 [95% CI, 0.95 to 4.29]; P = .069), with numerically higher ORR (25.7% v 14.3%) and PSA50 response rate (65.7% v 42.9%). No statistically significant differences in OS were observed.
CONCLUSION: Plasma-derived GIS was associated with improved rPFS and higher response rates in rucaparib-treated patients and further stratified outcomes within mutation-defined populations. These findings support genomic instability assessment as a complementary biomarker to mutation testing and warrant prospective validation.
METHODS: This retrospective biomarker analysis included TRITON2 patients with available baseline plasma profiled using Guardant360 Liquid. GIS is a probabilistic measure of homologous recombination deficiency (HRD) inferred from genome-wide copy number variants and somatic mutational signatures. Analyses were restricted to patients with baseline tumor fraction (TF) ≥ 25%. Radiographic progression-free survival (rPFS) was analyzed using Kaplan-Meier methods and Cox models adjusted for age and baseline TF. Secondary end points included objective response rate (ORR), serum prostate-specific antigen (PSA50) declines, and overall survival (OS).
RESULTS: Among 104 patients with TF ≥ 25%, 43 (41%) had GIS detected. Compared with GIS detected, absence of GIS was associated with shorter rPFS (hazard ratio [HR], 2.81 [95% CI, 1.61 to 4.93]; P <.001). Joint stratification demonstrated patients with both GIS detected and BRCA/PALB2 mutation experienced the longest rPFS, whereas absence of GIS was associated with shorter rPFS regardless of BRCA/PALB2 mutation status. In BRCA2-mutated patients, rPFS trended being longer in those with GIS detected (compared with those without GIS detected; HR, 2.02 [95% CI, 0.95 to 4.29]; P = .069), with numerically higher ORR (25.7% v 14.3%) and PSA50 response rate (65.7% v 42.9%). No statistically significant differences in OS were observed.
CONCLUSION: Plasma-derived GIS was associated with improved rPFS and higher response rates in rucaparib-treated patients and further stratified outcomes within mutation-defined populations. These findings support genomic instability assessment as a complementary biomarker to mutation testing and warrant prospective validation.