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2025 CRIS Cancer Foundation – PCF Young Investigator Award

Mechanisms of Resistance to PARP Inhibitor in Metastatic Resistant-Castration Prostate Cancer: Triton3 Cohort

Alice Bernard-Tessier, MD   
Gustave Roussy         

Mentors: Himisha Beltran, Karim Fizazi, Yohann Loriot

Description:

  • Metastatic castration-resistant prostate cancer (mCRPC) with BRCA1/2 and ATM gene alterations represents a subset of patients who may benefit from treatment with PARP inhibitors such as olaparib and rucaparib. However, the mechanisms driving treatment resistance remain incompletely characterized. Elucidating these resistance mechanisms is critical for optimizing the efficacy of PARP inhibitors and developing strategies to overcome therapeutic resistance in mCRPC.
  • Dr. Alice Bernard-Tessier’s project will determine the prevalence and dynamics of mutations that restore the BRCA1/2 gene in BRCA1/2-mutated (BRCA+) mCRPC patients treated with PARP inhibitors and their prognostic implications. Furthermore, she will investigate genomic and molecular mechanisms beyond BRCA1/2 gene restoration that contribute to PARP inhibitor resistance.  
  • This study will leverage longitudinal plasma samples from the phase 3 TRITON3 clinical trial, which tested rucaparib in patients with mCRPC. Circulating tumor DNA present in plasma samples will be genomically sequenced to evaluate mutations in 55 genes involved in PARP inhibitor sensitivity and resistance and known prostate cancer drivers.
  • If successful, this study will provide the most extensive and comprehensive genomic landscape of BRCA+ mCRPC treated with PARP inhibitors to date, elucidate resistance mechanisms, and may uncover novel therapeutic targets. 

What this means to patients: PARP inhibitors are a type of precision medicine approved for mCRPC with alterations in certain genes, the most common of which are in BRCA1/2; unfortunately, treatment resistance is common. Dr. Bernard-Tessier’s project will integrate genomic, molecular, and clinical data to identify mechanisms of resistance to PARP inhibitors. These findings will inform the development of innovative treatment strategies, including combination approaches to ultimately improve outcomes for patients with BRCA-mutated mCRPC.