Homologous Recombination Repair Deficiency in Metastatic Prostate Cancer: New Therapeutic Opportunities

Abstract

More than 20% of metastatic prostate cancer carries genomic defects involving DNA damage repair pathways, mainly in homologous recombination repair-related genes. The recent approval of olaparib has paved the way to precision medicine for the treatment of metastatic prostate cancer with PARP inhibitors in this subset of patients, especially in the case of BRCA1 or BRCA2 pathogenic/likely pathogenic variants. In face of this new therapeutic opportunity, many issues remain unsolved. This narrative review aims to describe the relationship between homologous recombination repair deficiency and prostate cancer, the techniques used to determine homologous recombination repair status in prostate cancer, the crosstalk between homologous recombination repair and the androgen receptor pathway, the current evidence on PARP inhibitors activity in metastatic prostate cancer also in homologous recombination repair-proficient tumors, as well as emerging mechanisms of resistance to PARP inhibitors. The possibility of combination therapies including a PARP inhibitor is an attractive option, and more robust data are awaited from ongoing phase II and phase III trials outlined in this manuscript.

Keywords: ATM; BRCA1; BRCA2; PARP inhibitor; androgen receptor; homologous recombination repair; metastatic prostate cancer.

Figure 1

When a DNA single-strand break (SSB) happens, poly (ADP-ribose) polymerase (PARP) guides SSB repair through NAD⁺poly(ADP-ribosyl)ation (PARylation) of histones and chromatin remodeling enzymes. PARP inhibitors (PARPis) act mainly by trapping PARP and by inhibiting PARylation. Unrepaired SSB leads to DNA double-strand break (DSB) during DNA replication. DSB is mainly resolved by homologous recombination repair (HRR) during the G2/S phase of cell cycle. During G1/G2 and in HRR deficient cells, DSB is solved by the error-prone non-homologous end-joining pathway with consequent genomic instability and cell death. HRR is activated by the recognition of DSB by the MRN complex that resects DNA ends, leading to the formation of single-strand DNA (ssDNA). ssDNA is preserved from degradation by RPA. The MRN complex activates ATM and that with RPA contributes to ATR activation. ATM and ATR phosphorylate several proteins such as CHEK1/2. ATM, ATR, and CHEK1/2 mediate cell cycle arrest. FANCD2 contributes to BRCA1 activation once monoubiquitinated by FANC and phosphorylated by ATM. BRCA1-BARD1 complex facilitates DNA end resection and interacts with the bridging protein PALB2 phosphorylated by CHEK2. PALB2 recruits BRCA2. PALB2 and BRCA2 remove RPA and facilitate the assembly of RAD51. RAD51 and RAD51 paralogs mediate strand invasion of ssDNA into the intact sister chromatid, searching a homologous template for DNA synthesis by DNA polymerase (DNA pol). DNA repair process interacts with androgen receptor (AR) pathway. CYP17A1 is a key enzyme for testosterone synthesis from cholesterol. Testosterone is metabolized to 5α-dihydrotestosterone (DHT) by 5α-reductase. DHT exerts its biological effects by binding AR in the cytoplasm. A rapid non-genomic signaling pathway contributes to cell proliferation by activation of MAPR/ERK and PI3K/AKT pathways. In addition, once it has bound the ligand, AR homodimerizes and translocates into the nucleus, where it binds to the androgen response element (ARE) located at the promoter regions of genes involved in DNA damage repair, cell proliferation and apoptosis evasion. PARP plays also a role in androgen-dependent transcription. Drugs currently used in clinical practice alone or in combination with PARPis for the treatment of prostate cancer are labelled in red. Abiraterone is a CYP17A1 inhibitor. Enzalutamide, apalutamide, and darolutamide competitively inhibit DHT binding to the AR, nuclear translocation of the AR, and DNA binding. Docetaxel and cabazitaxel inhibit AR nuclear translocation by targeting AR association with microtubules. Drugs that are currently being explored in combination with PARPis are labelled in blue.