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PARP Inhibitor Veliparib Active in Recurrent BRCA-Positive Ovarian Cancer

TOP - October 2014, Vol 7, No 4 - Gynecologic Cancers
Charles Bankhead

The PARP inhibitor veliparib demonstrated activity in relapsed/refractory BRCA-mutated ovarian cancer, according to results from a phase 2 trial conducted by the Gynecologic Oncology Group.

Almost one-fourth of 50 evaluable patients had objective responses, including 2 patients with complete responses. Additionally, about half of the patients had stable disease of 16 weeks or longer.

Median progression-free survival was 8.1 months among patients who had received as many as 3 prior systemic regimens, according to Robert L. Coleman, MD, at the Society of Gynecologic Oncology annual meeting in Tampa, Florida.

“Veliparib demonstrated activity in both platinum-sensitive and platinum-­resistant disease,” said Coleman, professor of gynecologic oncology and reproductive medicine at MD Anderson Cancer Center in Houston, Texas. “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 suggested targeting of the DNA-repair defect in BRCA-mutant tumors had potential as a therapeutic strategy. In contrast to some other PARP inhibitors in development, veliparib blocks both isomers of the enzyme. The small-molecule inhibitor demonstrated efficacy across several preclinical models of tumors, including ovarian cancer.

Coleman reported data from a nonrandomized, open-label trial involving patients with germline BRCA mutations. Investigators enrolled patients who had BRCA1/2-deficient epithelial ovarian, fallopian tube, or primary peritoneal cancers. The patients had received from 1 to 3 prior regimens.

All patients received veliparib at a dose of 400 mg twice a day, and treatment continued until disease progression, development of unacceptable toxicity, or voluntary withdrawal from the study. The statistical design of the trial specified a response rate ≥25% for continuing clinical investigation.

Of the 50 patients included in the analysis of safety and efficacy, 8 remain in the study.

A majority of the patients (58%) were 40 to 59 years of age, and an additional 30% were 60 to 69 years of age. Two-thirds of the patients had performance status 0 and the rest had performance status 1. More than 80% of the patients had high-grade serous tumors.

Treatment history consisted of 1 prior regimen in 14 patients (28%), 2 in 18 patients (36%), and 3 in 18 patients (36%). 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 of the patients (30 [60%]) had platinum-resistant disease, which investigators defined as a platinum-free interval <6 months. Three-fourths of the patients had BRCA1-mutant tumors, and 12 had founder mutations, which were BRCA1 in 8 patients and BRCA2 in 4 patients.

Hematologic adverse events were generally mild, as 1 patient had grade 3 neutropenia and 1 patient had grade 4 thrombocytopenia.

The most common nonhematologic adverse events were nausea (42 of 50 patients) and other gastrointestinal adverse events (32 patients). No patient had grade 4 nonhematologic events, and grade 3 events consisted of 2 cases of nausea and 1 case related to metabolism/nutrition.

Coleman reported that 11 patients had confirmed partial responses and 2 had confirmed complete responses, resulting in an overall response rate of 26%, which met the predefined criteria for continuing 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 treatment with veliparib.




Reference
Coleman RL, Sill M, Aghajanian C, et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation—a Gynecologic Oncology Group study. Presented at: 2014 Annual Meeting of the Society of Gynecologic Oncology; March 22-25, 2014; Tampa, FL. Abstract 136.

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Last modified: September 9, 2019