Although olaparib has demonstrated substantial clinical benefits as maintenance therapy in BRCA mutation-carrying women with newly diagnosed advanced ovarian cancer, its effectiveness in patients without BRCA mutations remains poorly investigated. This study aims to provide the first evidence on the efficacy of mono-olaparib maintenance therapy in such context. Using real-world data from 11 high-volume tertiary care centers in China, a retrospective cohort study was conducted to assess the efficacy and safety of olaparib as first-line maintenance therapy in patients with BRCA wild-type ovarian cancer. The primary objective was 1-year progression-free survival rate. Safety was also evaluated. Fifty patients with a median age of 54 years were included, and all of them tested negative for BRCA mutations but positive for homologous recombination deficiency (HRD). The 1-year PFS rate was 75.2% (95% CI, 63.4 to 89.2), and the median PFS was 21.0 months (95% CI, 13.8 to 28.2). All the patients received olaparib at a starting dose of 300 mg twice daily, and none experienced serious adverse events (AEs). Eight (16%) patients had dose adjustment, but none discontinued olaparib treatment due to AEs. We provide the first evidence that mono-olaparib could be a safe and effective maintenance treatment option for patients newly diagnosed with HRD-positive/BRCA wild-type ovarian cancer.
Humans ; Female ; Phthalazines/adverse effects* ; Piperazines/administration & dosage* ; Middle Aged ; Ovarian Neoplasms/genetics* ; Retrospective Studies ; Adult ; Aged ; Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage* ; China ; Maintenance Chemotherapy ; BRCA2 Protein/genetics* ; Antineoplastic Agents/adverse effects* ; Progression-Free Survival ; BRCA1 Protein/genetics*

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors and histone deacetylase (HDAC) inhibitors have recently emerged as promising anticancer drugs. The aim of this study was to investigate the effect of combination treatment with the PARP inhibitor PJ34 and HDAC inhibitor SAHA on the proliferation of liver cancer cells. Cell proliferation and apoptosis were assessed in three human liver cancer cell lines (HepG2, Hep3B and HCC-LM3) treated with PJ34 (8 μmol/L) and SAHA (1 μmol/L), alone or combined, by Cell Counting Kit-8 assay and flow cytometry, respectively. The nude mice bearing subcutaneous HepG2 tumors were administered different groups of drugs (10 mg/kg PJ34, 25 mg/kg SAHA, 10 mg/kg PJ34+25 mg/kg SAHA), and the inhibition rates of tumor growth were compared between groups. The results showed that combined use of PJ34 and SAHA could synergistically inhibit the proliferation of liver cancer cell lines HepG2, Hep3B and HCC-LM3. The apoptosis rate of HepG2 cells treated with PJ34+SAHA was significantly higher than that of HepG2 cells treated with PJ34 or SAHA alone (P<0.05). In vivo, the tumor inhibition rates were 53.5%, 61.4% and 82.6% in PJ34, SAHA and PJ34+SAHA groups, respectively. The combined use of PJ34 and SAHA could significantly inhibit the xenograft tumor growth when compared with use of PJ34 or SAHA alone (P<0.05). It was led to conclude that PJ34 and SAHA can synergistically suppress the proliferation of liver cancer cells.
Animals ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drug Synergism ; Hep G2 Cells ; Histone Deacetylase Inhibitors ; administration & dosage ; pharmacology ; Humans ; Hydroxamic Acids ; administration & dosage ; pharmacology ; Liver Neoplasms ; drug therapy ; Mice ; Phenanthrenes ; administration & dosage ; pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors ; administration & dosage ; pharmacology ; Xenograft Model Antitumor Assays

PARP is an important protein in DNA repair pathways especially the base excision repair (BER). BER is involved in DNA repair of single strand breaks (SSBs). If BER is impaired, inhibiting poly(ADP-ribose) polymerase (PARP), SSBs accumulate and become double stand breaks (DSBs). The cells with increasing number of DSBs become more dependent on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining. Patients with defective HR, like BRCA-deficient cell lines, are even more susceptible to impairment of the BER pathway. Inhibitors of PARP preferentially kill cancer cells in BRCA-mutation cancer cell lines over normal cells. Also, PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs. These two principles have been tested clinically. Over the last few years, excitement over this class of agents has escalated due to reported activity as single agent in BRCA1- or BRCA2-associated ovarian or breast cancers, and in combination with chemotherapy in triple negative breast cancer. This review covers the current results of clinical trials testing those two principles. It also evaluates future directions for the field of PARP inhibitor development.
Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Benzamides ; administration & dosage ; Benzimidazoles ; administration & dosage ; Breast Neoplasms ; drug therapy ; enzymology ; genetics ; DNA Breaks, Double-Stranded ; DNA Breaks, Single-Stranded ; DNA End-Joining Repair ; DNA Repair ; Enzyme Inhibitors ; therapeutic use ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Homologous Recombination ; Humans ; Mutation ; Ovarian Neoplasms ; drug therapy ; enzymology ; genetics ; Phthalazines ; administration & dosage ; Piperazines ; administration & dosage ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases ; metabolism