PARP Inhibitor Meets Goals in Phase II Ovarian Cancer Trial

Robert Coleman, MD

One-quarter of patients with relapsed or refractory BRCA-mutant ovarian cancer attained major objective responses to treatment with the investigational PARP inhibitor veliparib, results of a phase II study showed.

Responses occurred in patients with platinum-sensitive and platinum-resistant disease and in cancers with BRCA1 or BRCA2 mutations. The 50 evaluable patients had a median progression-free survival (PFS) of 8.1 months and overall survival of 19 months, according to a report at the Society of Gynecologic Oncology 45th Annual Meeting on Women’s Cancer in Tampa, Florida.

“This multicenter, open-label, phase II clinical trial demonstrated single-agent efficacy and acceptable toxicity among women with recurrent BRCA-positive ovarian, fallopian tube, and primary peritoneal cancer,” said Robert L. Coleman, MD, professor of Gynecologic Oncology at The University of Texas MD Anderson Cancer Center in Houston. “The study met its prespecified level of clinical activity to warrant further investigation.”

“We observed objective response in both platinum-sensitive and -resistant cohorts, and secondary endpoints of PFS, overall survival, and event-free survival at 6 months appear to be favorable,” he added.

PARP, including PARP 1 and 2, is essential to maintenance of normal cellular DNA repair. Mutations in BRCA1 or 2 cause dysfunctional DNA repair that leads to cancer development and progression.

Veliparib is one of several PARP inhibitors in various stages of clinical evaluation as treatments for ovarian and other types of cancer. Veliparib inhibits both PARP isomers.

Coleman reported findings from a Gynecologic Oncology Group phase II trial involving patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Eligible patients had BRCA1/2-deficient cancer, had received as many as three prior regimens, and were performance status 0 to 2.

All patients received veliparib monotherapy at a dosage of 400 mg twice daily, which could be reduced in stages to 200 mg twice daily to manage toxicity. Treatment continued until disease progression, development of unacceptable toxicity, or withdrawal from the study. The primary endpoint was response rate (RECIST criteria) and tolerability. Secondary endpoints consisted of PFS, overall survival, and PFS at 6 months.

An objective response rate ≥25% defined the agent as “interesting” and warranting further clinical investigation.

Investigators enrolled 52 patients, two of whom were excluded for clerical error and insufficient pathologic data. Most of the patients were aged 40 to 49 years (n = 15, 30%), 50 to 59 years (n = 14, 28%), or 60 to 69 years (n = 15, 30%). Two patients were younger than 40 years and eight were ≥70 years. All but nine of the 50 evaluable patients had high-grade serous tumors.

Treatment history consisted of one prior chemotherapy regimen in 28% of patients (n = 14), two prior regimens in 36% (n = 18), and three prior regimens in 36% (n = 18). All but one patient had undergone debulking surgery.

The study population comprised 20 patients with platinum-sensitive disease (platinum-free interval ≥6 months) and 30 with platinum-resistant disease (platinum- free interval <6 months). Additionally, 39 patients had BRCA1 mutations and 11 had BRCA2 mutations.

Confirmed objective responses consisted of two complete and 11 partial responses, resulting in an overall response rate of 26%. Coleman said 24 patients had stable disease for at least 16 weeks (including some patients with unconfirmed responses), and investigators were awaiting response data for six patients.

Objective responses occurred in six patients with platinum resistance and seven whose disease remained platinum sensitive. The 13 objective responses included 10 patients with BRCA1 mutations and three with BRCA2 mutations.

The study population had a 6-month event-free survival of 60%.

Hematologic toxicity was mostly grade 1/2 and consisted of neutropenia in 20 patients, thrombocytopenia in 10, and anemia in 24. Nonhematologic adverse events also were primarily grade 1/2 and included nausea in 42 patients, “other gastrointestinal” in 32, metabolic in 23, neurologic in 22, and psychiatric in 15.

Coleman said the results provided support for phase III clinical investigation of veliparib in advanced ovarian cancer.

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: SGO 45th Annual Meeting on Women’s Cancer; March 22-25, 2014; Tampa, FL. Abstract 136.