New Agents Offer Hope in Ovarian Cancer, But Challenges Remain

May 5, 2015
Laura Martin

The treatment of patients with ovarian cancer has evolved from an approach focused on chemotherapy and surgery to one involving targeted therapies and monoclonal antibodies.

Robert C. Bast, Jr, MD

The treatment of patients with ovarian cancer has evolved from an approach focused on chemotherapy and surgery to one involving targeted therapies and monoclonal antibodies. Chief among the recent approvals in ovarian cancer were the VEGF inhibitor bevacizumab (Avastin) and the PARP inhibitor olaparib (Lynparza).

Bevacizumab gained approval in November 2014 in combination with chemotherapy for patients with platinum-resistant recurrent ovarian cancer. This decision was based on a 62% improvement in progression-free survival experienced by patients treated with bevacizumab compared with chemotherapy in the phase III AURELIA trial.

Shortly following this decision, in December 2014, the FDA approved olaparib along with a companion diagnostic to detectBRCAmutations for the treatment of women with BRCA-positive advanced ovarian cancer following treatment with three or more prior lines of chemotherapy. This accelerated approval was based on a 34% objective response rate seen in patients with BRCA-positive ovarian cancer in a single-arm phase II study.

TargetedOnc:Can you highlight some of the changes seen in the treatment of ovarian cancer in recent years?

To gain insight into the evolving field and remaining challenges,TargetedOncinterviewed Robert C. Bast, Jr, MD, vice president of Translational Research at the University of Texas MD Anderson Cancer Center. Bast highlighted the approval of bevacizumab as a major advance for patients with ovarian cancer; however, he added that early detection remained a significant challenge to improving outcomes.Bast: Care of patients with ovarian cancer really has evolved. For the last 15 years, a combination of carboplatin and paclitaxel after cytoreductive surgery has been the standard of care. We have tried to periodically add other conventional drugs and it has not improved outcomes. At the present time, bevacizumab has improved progression-free survival, but has only improved overall survival in a subset of patients. Bevacizumab is probably the major advance in community care after carboplatin and paclitaxel.

One of the most exciting things in the last few years has been the focus on better surgery. We have known for a while that taking out as much of the tumor as possible improves outcomes for patients, probably by influencing the effect of the chemotherapy. As we look retrospectively at different studies, we have found that if the disease can be completely resected, the results will be better. This is the case for any solid tumor. Our usual resection rate is about 30%, and we can identify a subset of patients with a 90% resection rate.

Where do you see treatment going in the future?

For the individuals who are not resected upfront, three cycles of chemotherapy reduce the disease enough that, post-operation, an 80% complete resection rate can be achieved. In other studies, upfront complete resection is correlated dramatically with improved outcomes. We don’t know if three cycles of chemotherapy followed by resection will have results as good as upfront resection; however, with this strategy, the tumor can be completely removed for 80% of an individual. That is very promising.About half of high-grade serous ovarian cancers have theBRCAmutation. Only about 20% have germline or somatic mutations ofBRCA1orBRCA2. There are problems with homologous repair in about 30%. Tests are being done to identify those individuals. Olaparib [which is approved for advanced ovarian cancer] and other PARP inhibitors, in combination with other targeted therapies, are currently being evaluated at different centers including MD Anderson.

With the new agents recently approved, what is the biggest challenge in the treatment of ovarian cancer?

The other possibility is PI3 kinase activation. About half of high-grade serous ovarian cancers have abnormalities in activation of PI3 kinase. There are combinations of PI3 kinase pathway inhibitors that are being investigated. There are severe toxicities from those combinations at this point, so we are going to have to determine how we can improve the therapy index going forward.Over the last two decades, the 5-year survival rate for patients with ovarian cancer has improved significantly. However, we currently are curing no more than 30% of long-term ovarian cancers. That is related both to the persistence of drug-resistant cancer cells, but also to late diagnosis. If you can detect ovarian cancer in stage I or II, when it is still limited to the ovaries or the pelvis, you can cure 70% to 90% of patients with available surgery and chemotherapy. When the disease has spread to the rest of adnominal cavity or farther, as is the case in stage III or IV, the cure rate slips to less than 20%.

At present time, we are only detecting one-fourth of patients with stage I or II disease. One of the goals over the last 20 years has been to develop better early detection. There is currently a trial at MD Anderson where we are detecting stage I or II disease through CA-125 testing each year, which measures the amount of cancer antigen in the blood. When that goes up, we do an ultrasound or another imaging test and if that appears abnormal, then we do surgery.

How far are we from applying these findings to oncology practice?

There is a larger trial, the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), in which 200,000 women are being studied. Of that 200,000, 50,000 are getting CA-125 testing each year and an ultrasound if their levels go up. That trial will turn out later this year and we are very much excited to find out if that test improves survival by improving early detection. At present time, only about 80% of ovarian cancers express CA-125, so we know we will miss 20% with this test.At present time there is not a screening test that is approved for ovarian cancer for women at conventional risk for the disease. If the UKCTOCS trial is strongly positive, a community oncologist may consider using a rising CA-125 to trigger an ultrasound and detect early cancer. However, we need to first find out how that trial is going to turn out. Even if that trial is positive, we can do better. Using autoantibodies may improve the screening with CA-125 even further.