PARP inhibitors in metastatic prostate cancer

Abstract

Poly-ADP ribose polymerase inhibitors (PARPi) are an emerging therapeutic option for the treatment of prostate cancer. Their primary mechanism of action is via induction of synthetic lethality in cells with underlying deficiencies in homologous recombination repair (HRR). In men with metastatic castrate-resistant prostate cancer (mCRPC) and select HRR pathway alterations, PARPi treatment has been shown to induce objective tumor responses as well as improve progression free and overall survival. Presently, there are two PARPi, olaparib and rucaparib, that are FDA approved in the treatment of mCRPC. Ongoing research is focused on identifying which HRR alterations are best suited to predict response to PARPi so that these therapies can be most effectively utilized in the clinic. While resistance to PARPi remains a concern, combination therapies may represent a mechanism to overcome or delay resistance.

Moving toward improved immune checkpoint immunotherapy for advanced prostate cancer

“…99,100 Olaparib, rucaparib, niraparib, and talazoparib are PARPis that have been approved for the treatment of men with mCRPC with DDR alterations. [101][102][103] These therapies have various implications for other treatments, such as DNAdamaging radiotherapy, platinum-based chemotherapies, and possibly immunotherapy. Presumably, DNA damage, which leads to genomic instability, could result in neoantigens that stimulate tumor immunogenicity.…”

“…This is because mutations in both alleles of homologous repair genes such as BRCA1 and BRCA2 lead to defects in the DNA repair process, thus the cells become more dependent on non‐homologous end joining, which requires PARP 99,100 . Olaparib, rucaparib, niraparib, and talazoparib are PARPis that have been approved for the treatment of men with mCRPC with DDR alterations 101–103 . These therapies have various implications for other treatments, such as DNA‐damaging radiotherapy, platinum‐based chemotherapies, and possibly immunotherapy.…”

Synthesis and new DNA targeting activity of 6- and 7-tert-butylfascaplysins

“…The therapeutic landscape for mCRPC is diverse and encompasses endocrine, chemotherapy, immunotherapy, and radioligand therapy 30 . Over the last years, advancements in mCRPC treatment have been marked by the approval of several strategies, including application of second generation of androgen receptor (AR) 32 signaling inhibitors and PARP inhibitors (PARPi) 33 . Thus, docetaxel represents a primary chemotherapeutic option for CRPC, whereas abiraterone and enzalutamide, as second-generation anti-androgens also referred to as new hormonal agents (NHA) are approved for both mCRPC and hormone-sensitive prostate cancer 30 .…”

“…A PARPi olaparib can be applied in mCRPC patients bearing homologous recombination-de cient tumors, e.g. with aberrant BRCA1/2 gene 33 . Despite this progress, ultimate development of secondary drug resistance following long-term application of the therapeutics makes mCRPC eventually uncurable 34 .…”

Novel frontiers in urogenital cancers: from molecular bases to preclinical models to tailor personalized treatments in ovarian and prostate cancer patients

“…Similar results have been obtained in clinical trials with rucaparib [ 87 ]. Based on these studies PARPi were approved by FDA for PC treatment in 2020 and the importance of these pathways in PC therapy response is also confirmed by the number of clinical trials already performed or currently ongoing [ 88 ]. Additionally, ongoing trials focusing on components like the ATR-CHK1-WEE1 axis suggest potential novel therapeutic options, as single agents or combinations, for PC.…”