PARP Inhibitors in Prostate Cancer—The Preclinical Rationale and Current Clinical Development

Abstract

Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. However, recent studies have proposed therapeutic potential for PARP inhibitors in tumors with a variety of vulnerabilities generating dependence on PARP beyond the synthetic lethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initially thought. Importantly, PARP-associated DNA repair pathways are also closely connected to androgen receptor (AR) signaling, which is a key regulator of tumor growth and a central therapeutic target in prostate cancer. In this review, we provide an extensive overview of published and ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss the underlying biology. Several clinical trials are currently studying PARP inhibitor mono- and combination therapies in the treatment of prostate cancer. Integration of drugs targeting DNA repair pathways in prostate cancer treatment modalities allows developing of more personalized care taking also into account the genetic makeup of individual tumors.

Keywords: DNA damage repair; PARP inhibitors; castration resistant prostate cancer; precision medicine.

Figure 1

Basic principles and components of major DNA damage response (DDR) pathways in which Poly(ADP-ribose) polymerase 1 (PARP1) has a fundamental role. PARP1 detects the DNA lesion in single strand break repair (SSBR) and in homologous recombination (HR), which is the most common form of homology directed repair [11,20]. PARP1 generally takes part in recruiting repair factors to the lesion site and later interacts with or promotes activity of enzymes during physical repair stage of DDR [12,13,14,15,26].

Figure 2

PARP inhibitors (PARPi) reduce the catalytic activity of PARPs. In addition, PARPi trap PARP at the site of DNA damage by preventing PARP from detaching from DNA. Cytotoxic PARP-DNA complexes prevent replication fork from progressing and lead to cell death unless damage is repaired [32,36].