Homologous repair deficiencies and current insights in clinical evaluation of PARP inhibitors in prostate cancer

Maximilian Marhold,Thaïs Topakian

doi:10.1007/s12254-020-00599-9

Maximilian Marhold, Thaïs Topakian

Open Access

https://doi.org/10.1007/s12254-020-00599-9

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Journal: Memo	Publication Date: Apr 15, 2020
Citations: 1	License type: CC BY 4.0

Affiliation: Medical University of Vienna

Abstract

SummaryHomologous repair deficiency is a clinically relevant molecular aberration in prostate cancer. The goal of this short review is to summarize the study landscape of treatments targeting these aberrations through discussion of the most relevant clinical trials. Due to its shortness, this review does not claim to be exhaustive and a major focus is being laid on PARP inhibitors in clinical development for prostate cancer.

Highlights

Prostate cancer (PCa) is the most frequently diagnosed noncutaneous cancer in men and was ranked third regarding incidence among all cancers in the European Union in 2018 [1]
Analyzing the the Cancer Genome Atlas (TCGA) prostate cancer database, Kim et al found mutations and copy-number variations of DNA damage repair (DDR) genes in 30% of localized PCa indicating that DDR alterations might occur early during disease progression [5]
Li et al identified an androgen receptor (AR) and c-myb upregulated homologous recombination repair (HRR) gene signature that correlated with castration resistance, metastasis, relapse and reduced survival and demonstrated that targeting AR by enzalutamide led to downregulation of this specific gene set [10]. These findings suggest PARP inhibitors (PARPi) as an alternative therapeutic approach for androgen deprivation therapy (ADT) irrespective of HRR status and indicate a potential combinatory effect with antiandrogens such as apaor enzalutamide

Summary

Introduction

Prostate cancer (PCa) is the most frequently diagnosed noncutaneous cancer in men and was ranked third regarding incidence among all cancers in the European Union in 2018 [1]. Generation sequencing studies of prostate tumors revealed a high number of recurrent gene mutations interfering with homologous recombination repair (HRR). Analyzing the TCGA prostate cancer database, Kim et al found mutations and copy-number variations of DNA damage repair (DDR) genes in 30% of localized (nonmetastatic) PCa indicating that DDR alterations might occur early during disease progression [5].

Results

Conclusion