Although the association between VEGF and ovarian cancer has been known for quite some time, researchers are still struggling to use drugs that inhibit VEGF and angiogenesis in patients with the disease.
Jason A. Konner, MD
Although the association between VEGF and ovarian cancer has been known for quite some time, researchers are still struggling to use drugs that inhibit VEGF and angiogenesis in patients with the disease. Bevacizumab appeared promising in clinical trials but has yet to receive FDA approval for treating ovarian cancer, so other agents are being looked at as promising novel therapies. At the 2012 Chemotherapy Foundation Symposium, Jason A. Konner, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City, reviewed some of the promising newer agents that may provide a benefit for this difficult-to-treat group of patients.
PARP plays an important role in the repair of single-strand DNA breaks. Single-strand breaks can become double-strand breaks that are, in turn, repaired by a complex that contains BRCA1 and BRCA2, two genes that have deleterious mutations associated with ovarian cancer. Researchers have theorized that inhibiting the PARP enzyme should selectively kill cells with those genetic abnormalities, so PARP inhibitors are being explored as a treatment option for ovarian cancer.
One investigational PARP inhibitor, veliparib, is being assessed in a number of clinical trials. In the Gynecologic Oncology Group (GOG) 9923 phase I study, carboplatin and paclitaxel chemotherapy were given in combination with bevacizumab along with escalating doses of veliparib. Additional trials are currently recruiting patients to assess the efficacy of veliparib in combination with other agents such as topotecan.
“The problem with veliparib is we still don’t know its single-agent efficacy,” Konner said. “A recent single-agent phase II study was completed by GOG. It accrued very quickly, and we’re waiting for efficacy data on that.”
Other agents have also shown promising data. Cabozantinib, an oral tyrosine kinase inhibitor (TKI) that recently became FDA-approved to treat medullary thyroid cancer, is being investigated in a number of additional tumor types, including ovarian cancer. “That’s probably the most promising oral TKI for ovarian cancer, having shown the most pronounced response rates in early trials,” Konner said.
The results of a phase II randomized discontinuation trial examining cabozantinib in advanced ovarian cancer were presented at the 2011 ASCO Annual Meeting. The study was halted because a high rate of clinical activity was observed. The overall response rate among patients with progressive measurable disease at 12 weeks was 24%, and clinical activity was observed regardless of whether patients had previously been treated with platinum-based therapy (J Clin Oncol. 2011;29[suppl; abstr 5008]). A randomized phase II trial has been designed to compare cabozantinib with paclitaxel in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cavity cancer.
Another agent under investigation for the treatment of ovarian cancer is aflibercept. Aflibercept is a dual inhibitor of VEGF-A and placental growth factor (PlGF), proteins that promote angiogenesis. The drug was recently approved for the treatment of metastatic colorectal cancer, and studies have shown that it might also benefit patients with ovarian cancer.
Results of a phase II multi-institutional study combining aflibercept with docetaxel in patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer found that the combination of agents was generally effective (J Clin Oncol. 2011;29[suppl; abstr 5017]). Objective response rate was confirmed in 25 of 46 patients (54%), with 11 patients achieving a complete response and 4 patients whose disease did not recur for a median of 18.4 months once off treatment. The median progression-free survival was 6.43 months, and the median overall survival was 26.6 months.
Konner said that aflibercept mimics bevacizumab in several ways, and that the outlook for aflibercept may be similar to bevacizumab, in that it may struggle to find FDA approval for ovarian cancer.
“It’s unclear what role, if any, aflibercept will have in the future, since it’s not clear that there are any advantages over bevacizumab,” Konner said.