Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer

Abstract

Purpose Veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase 1 trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase 2 trial to determine the response rate of veliparib in combination with cyclophosphamide compared to cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC). Methods Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression. Results Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit. Conclusion This is the first trial that evaluated single agent, low dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression free survival.

A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

“…Several PARP inhibitors are currently in development for the treatment of patients with tumors harboring HRD, including those with a BRCA1/2 mutation (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Single-agent olaparib is approved in the United States for the treatment of patients with advanced germline BRCA1/2-mutated ovarian cancer who have received three or more lines of chemotherapy (27,28).…”

Metronomic cyclophosphamide‑induced long‑term remission after recurrent high‑grade serous ovarian cancer: A case study

“…Moreover, Kummar et al demonstrated in a small randomized trial of oral cyclophosphamide with or without velaparib (a PARP inhibitor) that low-dose cyclophosphamide is associated with responses and prolonged disease stabilization in pre-treated HGSOCs (11). There was a 19,4% (7/36 patients) overall response in the cyclophosphamide-only arm.…”

“…Nevertheless, PARP inhibitors have three main disadvantages. Firstly, recent studies demonstrated that HGSOCs become resistant to PARP inhibitors (11). Secondly, PARP inhibitors as well as bevacizumab combined with chemotherapy may cause significant side effects (15,16,19).…”

Epithelial Ovarian Cancers: On-Target is Better than Near-Target

“…Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit. It was well tolerated and clinical activity was observed; the addition of Veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival [87].…”