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 ofprostate cancer and castration resistance. Prostate cancer with DNA repair defects may bevulnerable to therapeutic targeting by Poly(ADP‐ribose) polymerase (PARP) inhibitors. PARPenzymes modify target proteins with ADP‐ribose in a process called PARylation and are inparticular involved in single strand break repair. The rationale behind the clinical trials that led tothe current use of PARP inhibitors to treat cancer was to target the dependence of BRCA‐mutantcancer cells on the PARP‐associated repair pathway due to deficiency in homologousrecombination. However, recent studies have proposed therapeutic potential for PARP inhibitorsin tumors with a variety of vulnerabilities generating dependence on PARP beyond the syntheticlethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initiallythought. Importantly, PARP‐associated DNA repair pathways are also closely connected toandrogen receptor (AR) signaling, which is a key regulator of tumor growth and a centraltherapeutic target in prostate cancer. In this review, we provide an extensive overview of publishedand ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss theunderlying biology. Several clinical trials are currently studying PARP inhibitor mono‐andcombination therapies in the treatment of prostate cancer. Integration of drugs targeting DNArepair pathways in prostate cancer treatment modalities allows developing of more personalizedcare taking also into account the genetic makeup of individual tumors.

Sarcopenia in aging, obesity, and cancer

“…As noted above, under Cell Biology, PARP inhibitors can improve mitochondrial function and may preserve muscle mass ( 34 – 40 ). Thus, PARP inhibitors need to be further evaluated for impact on sarcopenia, especially in malignancies where they are already part of the therapeutic armamentarium such as breast, ovarian, pancreas, and some cases of prostate cancer ( 128 – 131 ). Interestingly, dietary supplementation of NAD+ and/or its precursors is currently undergoing extensive investigation to promote healthy aging ( 132 , 133 ), although specific information on sarcopenia is not available.…”

Precision Medicine, Artificial Intelligence, and Genomic Markers in Urology. Do we need to Tailor our Clinical Practice?

“…2,4,17,[34][35][36] The potency of trapping PARP enzymes differ significantly between inhibitors, with a trapping efficiency following a downstream fashion: talazoparib, niraparib, olaparib, rucaparib, and veliparib. 37 (►Figs. 2 and 3) The last study published was the PROfound phase 3 openlabel trial, which evaluated PARPi (olaparib) in men with mCRPC who had progressed receiving an androgen-signaling-targeted inhibitor (enzalutamide or abiraterone).…”

“…36,39 Thus, these findings encouraged the FDA to grant priority review of these two drugs. 36,37,39 The recently published TOPARP-B phase 2 trial (2019) aimed to evaluate the association between DDR gene alterations in mCRPC and response to olaparib 300 mg or 400 mg. Results showed that olaparib has antitumor activity against mCRPC with DDR alterations; the composite response was 54.3% in the 400 mg arm versus 39.1% in the 300 mg arm, suggesting that the ideal dose should be 400 mg, twice a day (at a expense of higher toxicity).…”

“…34 There is a rationale that PARPi in combination with androgen-signaling-targeted inhibitor could improve PSA or radiologic response rate vs androgen-signaling-targeted inhibitor alone based on the premise that the androgen receptor (AR) pathways drive progression to mCRPC, which is due mainly to adaptive mechanisms that enable persistent AR signaling. 37 Data shows that AR regulates transcription of several sets of MMR genes, PARP-1 can act as an AR co-factor and are upregulated in exposure to androgen deprivation therapy (ADT). 1,17,37 Stratification and molecular subtype identification in UC have gained popularity in recent years.…”

“…37 Data shows that AR regulates transcription of several sets of MMR genes, PARP-1 can act as an AR co-factor and are upregulated in exposure to androgen deprivation therapy (ADT). 1,17,37 Stratification and molecular subtype identification in UC have gained popularity in recent years. The TCGA and several studies have shown that gene-expression datasets of UC suggest it could be classified in 6 molecular subtypes: NEURAL, LUMINAL, papillary-like (PAP), HER2L, mesenchymal-like (MES), squamous-cell carcinoma (SCC) and bladder carcinoma subtype of large meta-cohort databases (BOLD).…”