R (ANITA). Niraparib in Combination with Pembrolizumab in Patients with Triple-negative Breast SC66 Purity & Documentation Cancer or Ovarian Cancer (TOPACIO). A Study in Ovarian Cancer Patients Evaluating Rucaparib and Nivolumab as Maintenance Treatment 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 Sufferers with Recurrent or Refractory Ovarian, Fallopian Tube or Major 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 Mixture with Olaparib in Sufferers with Advanced Solid Tumors. Phase I/II Study from the Anti-Programmed Death Ligand-1 Antibody MEDI4736 in Combination with Olaparib and/or Cediranib for Sophisticated Strong Tumors and Sophisticated or Recurrent Ovarian, Triple Unfavorable Breast, Lung, Prostate and Colorectal Cancers. Phase 2 Multicohort Study to Evaluate the Safety and Efficacy of Novel Therapy Combinations in Patients with Recurrent Ovarian Cancer (OPAL): tsr42, BEVA. Open-Label Safety and Tolerability Study of INCB057643 in Subjects with Advanced Malignancies. Selumetinib and Olaparib in Strong Tumors. Trial Status Recruiting Active, not recruiting (partially pending results) Recruiting Recruiting Recruiting Recruiting Recruiting RecruitingNiraparib Rucaparib OlaparibNCT03574779 NCT02711137 NCTNot yet recruiting Active, not recruiting RecruitingInt. J. Mol. Sci. 2018, 19,12 of2.4.two. Combinations with Selective DNA Damage-Repair Inhibitors Combination of PARPi with targeted agents that negatively influence HR could overcome HR-restoration and boost PARPi efficacy in HR proficient tumors. The underlying rationale for these combinations is once again the concept 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 tactic could therefore sensitize major or Science Inhibitors targets acquired (upon restoration) HR proficient tumors to PARPi. Currently studied companions are inhibitors of HSP90 (onalespib), WEE1 (Adavosertib), ATM/ATR (AZD6738), and antiangiogenic agents (cediranib, bevacizumab) (see Table 2). The ATM-CHK2 pathway and the ATR/CHK1/WEE1 pathway have a important part in cell-cycle regulation. They are targets of cell-cycle checkpoints inhibitors, which abrogate S and G2 arrests and thus impair typical DNA-damage repair just before mitosis is completed [77]. Clinical final results from their combinations with PARPi are awaited. Hypoxia induced by antiangiogenic agents seem to downregulate BRCA1/2 and RAD51 in cancer cells [78,79]. Remarkably, cediranib (a VEGFR3 inhibitor) has already shown incredibly optimistic final results in combination with olaparib in a phase II trial with 90 individuals with recurrent platinum-sensitive HGSOC tumors, specifically in those BRCA1/2 wild-type. This mixture showed 17.7 months in PFS when compared with 9 months with olaparib alone inside the intention-to-treat population, when a post-hoc exploratory analyses showed 16.5 and five.7 months, respectively, in BRCA1/2 wild-type individuals [80]. This outcome has led to a plethora of trials assessing diverse 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 other than HR, like polymerase- (Pol) involved in microhomology-mediated finish joining (.
