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Peer-reviewedCC BY-NC-NDJCO precision oncology

Plasma-Derived Genomic Instability Status and Rucaparib Outcomes in Metastatic Castration-Resistant Prostate Cancer: TRITON2.

  • Wassim Abida1
  • Alan H Bryce2
  • Simon Chowdhury3
  • Akash Patnaik4
  • Brooke Overstreet5
  • Matthew Margolis5
  • Pegah Safabakhsh5
  • Karim Fizazi6
6 affiliations
  1. 1Memorial Sloan Kettering Cancer Center, New York, NY.
  2. 2City of Hope, Goodyear, AZ.
  3. 3Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
  4. 4University of Chicago, Chicago, IL.
  5. 5Guardant Health, Redwood City, CA.
  6. 6Oscar Lambret Centre, Lille, France.
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{abida2026plasmaderived,
  title = {{Plasma-Derived Genomic Instability Status and Rucaparib Outcomes in Metastatic Castration-Resistant Prostate Cancer: TRITON2.}},
  author = {Wassim Abida and Alan H Bryce and Simon Chowdhury and Akash Patnaik and Brooke Overstreet and Matthew Margolis and Pegah Safabakhsh and Karim Fizazi},
  journal = {JCO precision oncology},
  year = {2026},
  month = oct,
  doi = {10.1200/po-26-00390},
  url = {https://europepmc.org/article/MED/42886888},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Plasma-Derived Genomic Instability Status and Rucaparib Outcomes in Metastatic Castration-Resistant Prostate Cancer: TRITON2.
AU  - Wassim Abida
AU  - Alan H Bryce
AU  - Simon Chowdhury
AU  - Akash Patnaik
AU  - Brooke Overstreet
AU  - Matthew Margolis
AU  - Pegah Safabakhsh
AU  - Karim Fizazi
PY  - 2026
DA  - 2026/10/16
JO  - JCO precision oncology
DO  - 10.1200/po-26-00390
UR  - https://europepmc.org/article/MED/42886888
AB  - 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.
SN  - 2473-4284
ER  -