Pazopanib Maintenance Therapy Delays Relapse of Advanced Ovarian Cancer

An oral targeted drug already approved by the US Food and Drug Administration for the treatment of kidney cancer and soft tissue sarcoma has been found to extend disease-free survival in women with advanced ovarian cancer, according to study results presented at the 2013 ASCO Annual Meeting.

The phase III, randomized, multicenter clinical trial (AGO-OVAR16) showed that pazopanib (Votrient), following initial successful chemotherapy, extended disease-free survival by an average of 5.6 months compared with a placebo in patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC).

The goal of treatment with pazopanib would be to maintain the successful but typically short-lived response experienced by these patients after initial treatment, said the study’s lead author, Andreas du Bois, MD, PhD, a professor of Gynecologic Oncology at Kliniken Essen Mitte in Essen, Germany. Since there is no test available to predict a patient’s risk for relapse, a maintenance therapy such as this one would be used for most patients in this population, experts at the ASCO meeting noted.

If approved in this setting, pazopanib would be the first maintenance therapy for the treatment of ovarian cancer in the United States, although bevacizumab (Avastin) is registered for use concurrently with chemotherapy and subsequently as maintenance therapy in Europe.

“Our findings show that we finally have a drug that can maintain control over ovarian cancer growth achieved through initial treatments,” du Bois said. “If pazopanib is approved for ovarian cancer, many patients will experience longer disease-free and chemotherapy free periods. During this time, the patient keeps control over the disease instead of the disease having control over the patient’s life.”

Pazopanib is an oral, multikinase inhibitor of VEGFR-1, -2, -3, PDGFR-a (alpha) and -ß, and c-Kit that blocks several targets involved in tumor angiogenesis, which “plays a major role” in AEOC, du Bois said. Ovarian cancer is the fifth-leading cause of cancer death among women in developed countries, and has the highest mortality risk among all gynecological tumors. At the time of diagnosis, 70% of patients already have advanced disease, which is associated with a cure rate of only 20% to 25%, according to ASCO.

While 70% to 85% of patients are free of their tumors after initial treatment with surgery and chemotherapy, three-fourths of them experience recurrences, and half of those recurrences take place within the first year, du Bois said. Such patients typically live 2 to 4 years from the time of diagnosis, and can receive up to 5 lines of treatment during the course of their disease, he said. The study was designed to evaluate the efficacy, safety, and tolerability of pazopanib maintenance therapy in patients who had not progressed after first-line platinum-taxane chemotherapy for AEOC, with a primary end point of progression-free survival (PFS). Secondary end points included overall survival, safety, and quality of life.

In the study, 940 patients, most of whom had stage III/IV AEOC (91%), were randomized 1:1 to receive either pazopanib or placebo daily for 24 months. All patients had prior surgery and 5 or more rounds of chemotherapy that prevented the disease from worsening. Patients in the pazopanib arm had a prolonged PFS vs placebo (HR = 0.766; 95% confidence interval, 0.64-0.91; P =.0021; median 17.9 vs 12.3 months, respectively). The first interim analysis for overall survival (189 patients) showed no difference between arms, but those data will not be considered mature until it includes 551 events, du Bois noted.

As compared with a placebo, pazopanib treatment was associated with a higher incidence of adverse events (AEs) and serious AEs (26% vs 11%), several of them class-specific, including elevated liver enzymes. The most common were hypertension, diarrhea, nausea, headache, fatigue, and neutropenia, du Bois said. Fatal AEs were reported in three patients on pazopanib and one patient on placebo.

An immediate goal for this research is to combine pazopanib with other targeted drugs and personalize therapy according to patient and tumor characteristics according to an ASCO press release. “Relapses remain all too common for women with advanced ovarian cancer. This large trial shows us that targeting multiple molecular cancer drivers can have a substantial impact on this cancer’s ability to grow, giving our patients significantly longer time before relapse.

This study offers a realworld example of how the precision medicine era of cancer research is paying off in areas where no alternate approved drugs exist,” said Carol Aghajanian, MD, ASCO spokesperson and gynecologic cancers expert and chief of Gynecologic Medical Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City. While bevacizumab (Avastin) is approved in Europe as a maintenance therapy for these diseases, it was studied in combination with chemotherapy, and then as a continuation therapy, which “was not a pure maintenance therapy setting. We don’t know which part of the bevacizumab trial [sparked] the efficacy,” du Bois said. “This differs from the population we have, since ours had successful primary treatment and 85% had no residual tumors.”

The study of pazopanib—along with previous unsuccessful attempts to combine it with chemotherapy in this population—suggests that the drug will be best used as maintenance therapy in this population, du Bois said. Future studies, he said, should address the optimal sequencing of pazopanib and chemotherapy.

1. du Bois A, Floquet A, Kim JW, et al. Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: results of an international Intergroup trial (AGO-OVAR16). J Clin Oncol. 2013;31(suppl; abstr LBA5503).

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