Poly (ADP-ribose) polymerase (PARP) inhibitors have antitumor activity in advanced prostate cancer associated with loss of homologous recombination repair (HRR) function. About 20% of all patients with advanced prostate cancer present germline or tumor mutations in HRR-related genes, the most common being BRCA2, mutated in approximately 10% of all advanced prostate cancers. Challenges related to sample availability, tumor heterogeneity and access to NGS technology need to be addressed for a successful implementation of genomic stratification in routine clinical practice. The recent regulatory approvals of PARP inhibitors olaparib and rucaparib represent the first molecular biomarker-guided drugs for men with prostate cancer. While these findings represent a significant advance in the field of precision medicine and prostate cancer, there are still many unsolved questions on the optimal use of PARP inhibitors in this disease. Several clinical trials have shown that different mutations in various genes are associated with distinct magnitudes of sensitivity to PARP inhibitors, with BRCA2 mutations associating with more frequent and durable responses, questioning the benefit for subset of patients with mutations in other HRR-associated genes. In this review, we scrutinize the clinical development of different PARP inhibitors for the treatment of advanced prostate cancer, and we discuss how the study of additional biomarkers and the design of rational drug combinations can maximize patient benefit from this drug class.
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http://dx.doi.org/10.1530/ERC-21-0133 | DOI Listing |
Future Oncol
December 2024
Department of Medical Oncology, BC Cancer Agency, Vancouver, Canada.
Metastatic prostate cancer remains incurable. Though significant progress has been made in the field, the search for agents that improve outcomes for patients is ongoing. Several clinical trials have explored the benefit of combining PARP inhibitors (PARPi) with androgen receptor pathway inhibitors (ARPIs) for metastatic castrate resistant prostate cancer (mCRPC), especially those cancers with alterations in homologous recombination repair (HRR) genes.
View Article and Find Full Text PDFBiomol Ther (Seoul)
December 2024
Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Gangneung 25457, Republic of Korea.
In cancer cells, survival genes contribute to uncontrolled growth and the survival of malignant cells, leading to tumor progression. Neurons are post-mitotic cells, fully differentiated and non-dividing after neurogenesis and survival genes are essential for cellular longevity and proper functioning of the nervous system. This review explores recent research findings regarding the role of survival genes, particularly DX2, in degenerative neuronal tissue cells and cancer cells.
View Article and Find Full Text PDFCancer Treat Rev
December 2024
Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. Electronic address:
BMC Cancer
December 2024
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Background: There is increasing interest in enhancing the response of the PARP inhibitor olaparib, which is currently approved for pancreatic ductal adenocarcinoma (PDAC) patients with defects in DNA damage repair associated with germline BRCA1/2 mutations. Moreover, agents that can mimic these defects in the absence of germline BRCA1/2 mutations are an area of active research in hopes of increasing the number of patients eligible for treatment with PARP inhibitors. The extent to which regorafenib, an FDA-approved tyrosine kinase inhibitor, can be used to enhance the efficacy of PARP inhibitors in PDAC cells without known BRCA1/2 mutations remains to be investigated.
View Article and Find Full Text PDFNPJ Precis Oncol
December 2024
Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
Understanding the genomic landscape of breast cancer brain metastases (BCBMs) is key to developing targeted treatments. In this study, targetable genomic profiling was performed on 822 BCBMs, 11,988 local breast cancer (BC) biopsies and 15,516 non-central nervous system (N-CNS) metastases (all unpaired samples) collected during the course of routine clinical care by Foundation Medicine Inc (Boston, MA). Clinically relevant genomic alterations were significantly enriched in BCBMs compared to local BCs and N-CNS metastases.
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