Veliparib, a PARP Inhibitor, Active in Recurrent BRCA-Positive Ovarian Cancer
Tampa, FL—The poly (ADP-ribose) polymerase (PARP) inhibitor veliparib demonstrated activity in relapsed and/or refractory BRCA-mutated ovarian cancer, according to the results of a phase 2 clinical trial reported at the 2014 Society of Gynecologic Oncology meeting.
Almost 25% of 50 evaluable patients had objective responses, including 2 patients with complete responses. Approximately 50% of the patients had stable disease lasting ?16 weeks.
The median progression-free survival was 8.1 months among patients who had received as many as 3 previous systemic regimens, reported Robert L. Coleman, MD, Professor of Gynecologic Oncology and Reproductive Medicine, M.D. Anderson Cancer Center, Houston, TX.
“Veliparib demonstrated activity in both platinum-sensitive and platinum-resistant disease,” said Dr Coleman. “A criticism of PARP inhibitors is that they are not active in patients who have developed resistance to other therapies. These results indicate that veliparib has activity in some of the patients, who generally have few remaining treatment options.”
Laboratory studies suggest that targeting of the DNA-repair defect in BRCA-mutated tumors had potential as a therapeutic strategy. In contrast to some other PARP inhibitors in development, veliparib blocks both isomers of the enzyme. This small-molecule inhibitor demonstrated efficacy across several preclinical models of tumors, including ovarian cancer.
This was a nonrandomized, open-label trial involving patients with ovarian cancers harboring BRCA mutations. Patients had BRCA1/BRCA2-deficient epithelial ovarian, fallopian tube, or primary peritoneal cancers. The patients had received from 1 to 3 previous regimens and had a performance status of 0 to 2.
All patients received veliparib 400 mg twice daily, and treatment continued until disease progression, development of unacceptable toxicity, or voluntary withdrawal from the study. The prespecified response rate of ?25% was necessary for continuing the clinical investigation.
Of the 50 patients included in the safety and efficacy analysis, 8 remain in the study. More than 80% of the patients had high-grade serous tumors.
Overall, 14 patients received 1 previous regimen, 18 patients received 2 previous regimens, and 18 patients received 3. All but 4 patients had received radiotherapy, all but 3 had exposure to immunotherapy, and only 1 patient had not undergone debulking surgery.
A majority (60%) of the patients had platinum-resistant disease, defined as a platinum-free interval of <6 months. Three fourths of the patients had BRCA1-mutated tumors, and 12 had founder mutations, which were BRCA1 in 8 patients and BRCA2 in 4.
Hematologic adverse events were generally mild. The most common nonhematologic events were nausea and other gastrointestinal events.
Overall, 11 patients had partial responses and 2 had complete responses, with an overall response rate of 26%, which met the predefined criteria for continuing the clinical evaluation of veliparib. Response assessment was ongoing in 6 patients, some of whom had unconfirmed responses. A similar proportion of patients with platinum-sensitive or platinum-resistant disease derived benefit from veliparib. n