PracticeUpdate Oncology May 2019

CONFERENCE COVERAGE 28

Olaparib and Neratinib Prove Synergistic inModels of HER2-Positive Ovarian Cancer, and PARP Inhibitors May Be Used Repeatedly T he combination of olaparib and neratinib has been found to be synergistic in HER2-positive, BRCA wildtype ovarian cancer cell lines and xenografts, Overall, 21 patientswere identified. As initial PARP inhibitor therapy, 12 patients (57.1%) received veliparib; 6 patients (28.6%), olaparib; and 3 patients (14.3%), rucaparib.

the outcome of flow cytometry-based assays shows. Alessandro D. Santin, MD, of the Yale University School of Medicine in New Haven, Connecticut, and col- leagues set out to evaluate the efficacy of olaparib + neratinib in HER2-positive, BRCA wildtype ovarian cancer cell lines and xenografts. They performed the cell viability experiments of olap- arib, neratinib, and the combination in four primary BRCA1/2 -proficient ovarian cancer models that over- express HER2. The efficacy of single-agent olaparib, neratinib, and the combination was evaluated in HER2-positive ovarian cancer xenograft models. In vitro, olaparib and neratinib as single agents were both effective in suppressing primary ovarian tumor cell line growth. Neratinib, however, exhibited more prominent tumor suppression activity than olaparib in HER2-positive ovarian cancer models. Importantly, the drug combination demonstrated syn- ergy in all four primary ovarian cancer models tested and was superior to single-agent olaparib or neratinib in vivo and in vitro. Accordingly, mice treated with the combination of olap- arib and neratinib experienced a significantly longer overall survival than control mice (P = .0005), mice treated with olaparib (P = .0005), and mice treated with neratinib (P = .0013). Reverse transcriptase polymerase chain reaction and immunoblotting of ovarian cancer cells treated with neratinib showed decreased BRCA1/2 and increased poly ADP-ribose polymerase inhibitor (PARP) activity. Studies in breast cancer models have shown that high HER2 expression resulted in sensitization of breast cancer to PARP inhibitors regardless of BRCA status. Dr. Santin concluded that the study demonstrated syn- ergy of olaparib and neratinib in HER2-positive ovarian cancer models. The combination may represent a novel therapeutic option for chemotherapy-resistant patients with ovarian cancer with HER2-positive, homologous, recombination-proficient tumors. In another study of PARP inhibition, Kathleen G. Essel, MD, of the University of Oklahoma Health Sciences Center in Oklahoma City, and colleagues sought to describe the treatment experience of patients with prior exposure to a PARP inhibitor who are receiving a PARP inhibitor as part of treatment for recurrent epi- thelial ovarian cancer. They conducted a multi-institutional, retrospective review of patients with epithelial ovarian cancer who received at least two lines of therapy containing a PARP inhibitor.

Initial PARP inhibition resulted in 10 complete responses, three partial responses, four cases of sta- ble disease, and two of progressive disease. The initial PARP inhibitor was used as maintenance in 2 patients. The initial PARP inhibitor was discontinued due to: • The planned number of cycles was reached (n=10) • Progression (n=7) • Toxicity (n=2) • Adverse effects of other chemotherapy (n=1) • Patient choice (n=1) As the second PARP inhibitor, 9 patients (42.9%) received niraparib; 6 patients (28.6%), olaparib; and 6 patients (28.6%), rucaparib. The second cycle of PARP inhibition resulted in three partial responses, 13 cases of stable disease, and 2 progressive disease. The second PARP inhibitor was used as maintenance in 3 patients. Notably, the 3 patients who experienced a partial response to the second PARP inhibitor harbored a BRCA mutation. All patients who experienced a partial response with a second PARP inhibitor had experienced a complete response to the first PARP inhibitor. The second PARP inhibitor was discontinued due to: • Progression (n=12) • Toxicity (n=6) • Financial reasons (n=1) • Provider choice (n=1) Overall, 1 patient remains on therapy with the second PARP inhibitor. A total of 1 patient (5.0%) experienced grade 3/4 anemia; 5 patients (25.0%), grade 3/4 thrombocytopenia; and 1 patient (5.0%), grade 3/4 neutropenia. In this small cohort of patients, overall response to initial PARP inhibition did not predict overall response to the second PARP inhibitor. Toxicity after in the initial PARP inhibitor was not sig- nificantly associated with toxicity following the second PARP inhibitor. Dr. Essel concluded that a second PARP inhibitor demon- strated activity in patients with recurrent epithelial ovarian cancer but only in thosewith excellent responses to PARP inhibition and who had a BRCA mutation. Prior PARP inhibition did not predict response or tox- icity to the second PARP inhibitor. Now that three PARP inhibitors have been approved for different indications, repeat use of PARP inhibition may become more common. More data are needed regard- ing the efficacy and safety of this approach. www.practiceupdate.com/c/81364

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