Veliparib Shows Responses in Ovarian Cancer

Robert Coleman, MD

Major objective responses to treatment were demonstrated in one-fourth of patients with relapsed or refractoryBRCA-mutant ovarian cancer with the investigational PARP inhibitor, veliparib, according to results from a phase II study released at the Society of Gynecologic Oncology 45th Annual Meeting on Women’s Cancer.

“This multicenter open-label, phase II clinical trial demonstrated singleagent 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.”

Responses occurred in patients with platinum-sensitive and platinumresistant disease and in cancers withBRCA1orBRCA2mutations. The 50 evaluable patients had a median progression- free survival (PFS) of 8.1 months and overall survival (OS) of 19 months.

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

PARP 1 and 2 are essential to maintenance of normal cellular DNA repair. Mutations inBRCA1or2cause dysfunctional DNA repair that leads to cancer development and progression.

Veliparib is one of several PARP inhibitors in various stages of clinical evaluation as treatment 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 hadBRCA1/2-deficient cancer, had received as many as 3 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, OS, and PFS at 6 months.

Investigators enrolled 52 patients, 2 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 8 were ≥70 years. All but 9 of the 50 evaluable patients had highgrade serous tumors.

Treatment history consisted of 1 prior chemotherapy regimen in 28% of patients (n = 14), 2 prior regimens in 36% (n = 18), and 3 prior regimens in 36% (n = 18). All but 1 patient had undergone debulking surgery.

The study population comprised 20 patients with platinum-sensitive disease (platinum-free interval &ge;6 months) and 30 with platinum-resistant disease (platinum-free interval <6 months). Additionally, 39 patients hadBRCA1mutations, and 11 hadBRCA2mutations.

Confirmed objective responses consisted of 2 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 6 patients.

Objective responses occurred in 6 patients with platinum resistance and in 7 patients whose disease remained platinum sensitive. The 13 objective responses included 10 patients withBRCA1mutations and 3 withBRCA2mutations.

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

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

Reference

1. 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&rsquo;s Cancer; March 22-25, 2014; Tampa, FL. Abstract 136.