R (ANITA). Niraparib in Mixture with Pembrolizumab in Sufferers with Triple-negative Breast Cancer or Ovarian Cancer (TOPACIO). A Study in Ovarian Cancer Sufferers Evaluating Rucaparib and Nivolumab as Maintenance Remedy Following Response to Front-Line Platinum-Based Chemotherapy (ATHENA). Avelumab and Talazoparib in Untreated Sophisticated Ovarian Cancer (JAVELIN OVARIAN PARP one hundred). Olaparib, Durvalumab, and Tremelimumab in Treating Individuals with DBCO-PEG4-Maleimide Epigenetics Recurrent or Refractory Ovarian, Fallopian Tube or Primary Peritoneal Cancer with BRCA1 or BRCA2 Mutation. PARP-inhibition and CTLA-4 Blockade in BRCA-deficient Ovarian Cancer. A Phase I/II Study of MEDI4736 in Combination with Olaparib in Individuals with Advanced Solid Tumors. Phase I/II Study of the Anti-Programmed Death Ligand-1 Antibody MEDI4736 in Mixture with Olaparib and/or Cediranib for Sophisticated Solid Tumors and Sophisticated or Recurrent Ovarian, Triple Adverse Breast, Lung, Prostate and Colorectal Cancers. Phase two Multicohort Study to Evaluate the Safety and Efficacy of Novel Remedy Combinations in Individuals with Recurrent Ovarian Cancer (OPAL): tsr42, BEVA. Open-Label Safety and Tolerability Study of INCB057643 in Subjects with Advanced Malignancies. Selumetinib and Olaparib in Solid Tumors. Trial Status L-Quisqualic acid Epigenetic Reader Domain Recruiting Active, not recruiting (partially pending outcomes) Recruiting Recruiting Recruiting Recruiting Recruiting RecruitingNiraparib Rucaparib OlaparibNCT03574779 NCT02711137 NCTNot however recruiting Active, not recruiting RecruitingInt. J. Mol. Sci. 2018, 19,12 of2.four.two. Combinations with Selective DNA Damage-Repair Inhibitors Combination of PARPi with targeted agents that negatively influence HR could overcome HR-restoration and improve PARPi efficacy in HR proficient tumors. The underlying rationale for these combinations is once more the notion of synthetic lethality, this time chemically induced: by concurrently blocking option DNA damage-repair pathways, cancer cells turn out to be unviable [75,76]. This method could therefore sensitize main or acquired (upon restoration) HR proficient tumors to PARPi. At present studied companions are inhibitors of HSP90 (onalespib), WEE1 (Adavosertib), ATM/ATR (AZD6738), and antiangiogenic agents (cediranib, bevacizumab) (see Table two). The ATM-CHK2 pathway as well as the ATR/CHK1/WEE1 pathway have a key role in cell-cycle regulation. They are targets of cell-cycle checkpoints inhibitors, which abrogate S and G2 arrests and therefore impair standard DNA-damage repair just before mitosis is completed [77]. Clinical benefits from their combinations with PARPi are awaited. Hypoxia induced by antiangiogenic agents appear to downregulate BRCA1/2 and RAD51 in cancer cells [78,79]. Remarkably, cediranib (a VEGFR3 inhibitor) has currently shown incredibly positive results in combination with olaparib within a phase II trial with 90 individuals with recurrent platinum-sensitive HGSOC tumors, particularly in these BRCA1/2 wild-type. This combination showed 17.7 months in PFS compared to 9 months with olaparib alone inside the intention-to-treat population, although a post-hoc exploratory analyses showed 16.5 and 5.7 months, respectively, in BRCA1/2 wild-type patients [80]. This result has led to a plethora of trials assessing different combinations of a PARPi and an antiangiogenic agent. Other potential druggable targets are RAD51 [81,82], RAD52 [83,84] and proteins involved in DNA-damage repair pathways besides HR, for example polymerase- (Pol) involved in microhomology-mediated end joining (.
