Poly(ADP-Ribose) Polymerase Inhibitors in Prostate Cancer: Molecular Mechanisms, and Preclinical and Clinical Data
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Poly(ADP‑Ribose) Polymerase Inhibitors in Prostate Cancer: Molecular Mechanisms, and Preclinical and Clinical Data Dawid Sigorski1,2 · Ewa Iżycka‑Świeszewska3 · Lubomir Bodnar1,2
© The Author(s) 2020
Abstract Genomic instability is one of the hallmarks of cancer. The incidence of genetic alterations in homologous recombination repair genes increases during cancer progression, and 20% of prostate cancers (PCas) have defects in DNA repair genes. Several somatic and germline gene alterations drive prostate cancer tumorigenesis, and the most important of these are BRCA2, BRCA1, ATM and CHEK2. There is a group of BRCAness tumours that share phenotypic and genotypic properties with classical BRCA-mutated tumours. Poly(ADP-ribose) polymerase inhibitors (PARPis) show synthetic lethality in cancer cells with impaired homologous recombination genes, and patients with these alterations are candidates for PARPi therapy. Androgen deprivation therapy is the mainstay of PCa therapy. PARPis decrease androgen signalling by interaction with molecular mechanisms of the androgen nuclear complex. The PROFOUND phase III trial, comparing olaparib with enzalutamide/abiraterone therapy, revealed increased radiological progression-free survival (rPFS) and overall survival (OS) among patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA1, BRCA2 or ATM mutations. The clinical efficacy of PARPis has been confirmed in ovarian, breast, pancreatic and recently also in a subset of PCa. There is growing evidence that molecular tumour boards are the future of the oncological therapeutic approach in prostate cancer. In this review, we summarise the data concerning the molecular mechanisms and preclinical and clinical data of PARPis in PCa.
Key Points Molecular tumour profiling is a new approach for personalised targeted therapy in cancer patients. PARP inhibitors are a new promising class of drugs that show clinical efficacy in genomically defined, heavily pre-treated prostate cancer patients. Olaparib and rucaparib were recently approved by the US Food and Drug Administration (FDA) for prostate cancer.
* Dawid Sigorski [email protected] 1
Department of Oncology, Collegium Medicum, University of Warmia and Mazury, Al. Wojska Polskiego 37, 10‑228 Olsztyn, Poland
2
Clinical Department of Oncology and Immuno‑Oncology, Warmian-Masurian Cancer Center of The Ministry of The Interior and Administration’s Hospital, Olsztyn, Poland
3
Department of Pathology and Neuropathology, Medical University of Gdańsk, Gdańsk, Poland
Many clinical trials are ongoing to determine the efficacy of PARP inhibitors in different prostate cancer stages, different prostate cancer hormonal statuses, and in various drug combinations. The major challenges remain the proper indication of genomic alterations with regard to the effectiveness of the treatment.
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1 Introduction Several germline and somatic genetic alterations are associated with prostate cancer (PCa) initiation, promotion and progr
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