The evaluation of noncytotoxic agents for the treatment of epithelial ovarian cancer has produced encouraging findings in recent months. This has led to the approval of new agents with novel mechanisms of action and continuing studies into many more potential therapies.
These are welcome developments for the treatment of patients with this malignancy. This includes approximately 22,000 women who are diagnosed annually with ovarian cancer in the United States alone.1
Although epithelial ovarian cancer is a highly chemoresponsive tumor initially, the development of resistance is a common event. In fact, the majority of women with stage III-IV ovarian cancer, the most common stage at presentation, will relapse and eventually succumb to their disease.
This review will focus on recent clinically relevant findings of noncytotoxic agents for the treatment of ovarian cancer, including an expanded indication for bevacizumab (Avastin) and a new drug approval for olaparib (Lynparza).
The Cytotoxic Therapy Landscape
The initial management of ovarian cancer typically includes a staging and debulking surgical intervention and a platinum plus taxane–based chemotherapy regimen. At the completion of this therapy, most patients will have no evidence of disease. However, up to 75% of women with advanced disease will relapse at a median time of approximately 10 months.2
After recurrence, the duration of the platinum- free interval remains as the most important prognostic factor.3,4
Patients who relapse within 6 months of completing a platinum- based regimen are classified as platinum resistant, while those who relapse more than 6 months after treatment are classified as platinum sensitive.
Standard cytotoxic treatment for the latter group of patients includes a platinum-based regimen most frequently combined with paclitaxel,5
pegylated liposomal doxorubicin,6
or gemcitabine. 7
However, the duration of response to each subsequent platinum-based regimen tends to become progressively shorter and eventually patients become platinum resistant.
Many cytotoxic agents have been evaluated in phase II clinical trials in the platinum-resistant setting. Response rates are typically 20% or lower and durations of response are short. Docetaxel,8
pegylated liposomal doxorubicin,10
are probably the most active and best-studied agents.
Only a few of these agents have been evaluated in phase III randomized trials.15-20
It can be concluded from these studies that topotecan, paclitaxel, weekly paclitaxel, pegylated liposomal doxorubicin, and gemcitabine have comparable activity.
Many other agents were studied before the use of modern chemotherapy regimens and, therefore, their true activity in today’s environment is unknown.21
Recently, etirinotecan pegol, an investigational topoisomerase I inhibitor, was reported to have encouraging activity in patients with heavily pretreated chemotherapy-resistant ovarian cancer.22
However, no further studies have been reported.
Several investigational cytotoxic agents were reported to have encouraging activity in phase II trials. However, phase III trials failed to demonstrate superiority over conventional agents.23-27
Indeed, no cytotoxic chemotherapy agent has been approved for the treatment of recurrent ovarian cancer since 2006.
Nearly 20 years ago, it was reported that VEGF was overexpressed in human ovarian tumors and that it conferred a poor prognosis.28, 29
Similarly, it was observed that VEGF was directly associated with the development of ascites and carcinomatosis in animal models and that antibodies against VEGF inhibited tumor growth and ascites formation.30,31
These and other findings prompted researchers to evaluate the potential role of angiogenesis inhibitors in clinical trials in ovarian cancer.
Bevacizumab is, by far, the most extensively studied agent in ovarian cancer. Single-arm phase II studies have demonstrated significant activity of bevacizumab as a single agent32,33
or in combination with low-dose metronomic chemotherapy.34