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Talazoparib Monotherapy in Metastatic Castration-resistant Prostate Cancer with DNA Damage Response

Karim Fizazi1, Johann S de Bono2, A Douglas Laird3

  • 1Centre Oscar Lambret, Institut Gustave Roussy, University of Paris-Saclay, Lille, France.

European Urology Oncology
|October 31, 2025
PubMed
Abstract

Insights

High genomic loss of heterozygosity (gLOH) status in metastatic castration-resistant prostate cancer (mCRPC) patients correlated with better responses to talazoparib monotherapy. This finding highlights gLOH as a potential predictive biomarker for PARP inhibitor treatment in mCRPC.

Area of Science:

  • Oncology
  • Genetics
  • Genomic Medicine

Background:

  • The efficacy of poly(ADP-ribose) polymerase inhibitor (PARPi) monotherapy in metastatic castration-resistant prostate cancer (mCRPC) is linked to DNA damage response-homologous recombination repair (DDR-HRR) alterations.
  • The influence of genomic features beyond DDR-HRR alterations on PARPi outcomes is not well understood.

Purpose of the Study:

  • To investigate the impact of genomic alterations, including non-DDR-HRR genes and genomic loss of heterozygosity (gLOH), on treatment outcomes in mCRPC patients receiving talazoparib.
  • To explore associations between antitumor activity and gene alteration origin, non-DDR-HRR gene status, tumor mutational burden, and gLOH.

Main Methods:

  • Analysis of tumor and saliva alteration data from the TALAPRO-1 trial, which evaluated talazoparib monotherapy in heavily pretreated mCRPC patients with DDR-HRR alterations.
  • Somatic-germline zygosity prediction was used to assess genomic alterations.
  • Objective response rates (ORRs) and overall survival (OS) were calculated and compared based on various genomic features, including gLOH status.

Main Results:

  • Objective response rates (ORRs) were similar for patients with or without TP53 or PTEN alterations.
  • Tumors with ATM alterations showed a higher ORR when PTEN alterations were also present (p=0.044).
  • Patients with high gLOH status demonstrated significantly higher ORRs (53.3% vs 12.0%, p=0.0017) and longer median OS (23.7 vs 18.7 months) compared to those with low gLOH status.

Conclusions:

  • High gLOH status is associated with enhanced antitumor activity and improved responses to talazoparib monotherapy in patients with mCRPC.
  • Genomic loss of heterozygosity may serve as a predictive biomarker for PARPi treatment efficacy in this patient population.
  • Further research is needed due to the retrospective nature and small subgroup sizes of the analyses.
Keywords:
Genomic loss of heterozygosityHomologous recombination repairMetastatic castration-resistant prostate cancerTalazoparibTumor mutational burden

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