Targeted Drug Combo Improves Outcomes in Ovarian Cancer

CHICAGO — A small phase 2 study has raised the possibility of treating ovarian cancer with targeted agents and no chemotherapy.

The combination of 2 investigation therapies, olaparib and cediranib (both under development by AstraZeneca), was significantly more active in recurrent platinum-sensitive ovarian cancer than olaparib alone (median progression-free survival, 17.7 vs 9.0 months).

"This is the first study to explore the use of a PARP inhibitor and an antiangiogenic drug in ovarian cancer," said lead study author Joyce Liu, MD, MPH, an instructor in medical oncology at the Dana-Farber Cancer Institute in Boston.

She presented the findings here at the 2014 Annual Meeting of the American Society of Clinical Oncology®.

"The observed activity compares favorably to standard chemotherapy, and the toxicity profile was acceptable," she reported. "The most common side effects were hypertension, diarrhea, and fatigue, and they were manageable with dose reductions."

The rates of tumor shrinkage were markedly higher in the combination group than in the olaparib group (80 vs 48%).

However, Dr. Liu cautioned that this strategy is not yet ready for clinical practice; both drugs are investigational and have not received regulatory approval for any indication. The drugs have shown activity when used alone in the treatment of ovarian cancer, and the olaparib data have been submitted for approval. The cediranib data are being evaluated with a view to filing for approval.

"The study is interesting, but it is too early to have any clinical application," agreed Don Dizon, MD, director of the Gillette Center for Gynecologic Oncology at the Massachusetts General Hospital in Boston. Aside from the drugs being investigational, the study itself has a number of limitations. "It's too small, there are no overall survival data, and we need a trial that compares these therapies with the standard of care," he explained.

However, Dr. Dizon noted that the study suggests the possibility of other treatment options and that women can be spared the adverse effects of chemotherapy. "That said, the study also shows that targeted therapies are not always less toxic," he said. "They also have side effects, but they are different from those seen with chemotherapy."

Higher Response Rates

The study involved 90 patients with recurrent platinum-sensitive high-grade serous or BRCA-related ovarian cancer at 9 centers who received olaparib 400 mg twice daily. Half the cohort was then randomized to receive cediranib 30 mg daily.

Patients were stratified by BRCA status; there were 48 known BRCA mutation carriers. Patients who had not received previous antiangiogenic therapy in the recurrent setting and patients who had previously received a PARP inhibitor were included in the analysis.

As of January, there were 2 complete responses and 21 partial responses in the olaparib group (objective response rate [ORR], 56%), and 3 complete responses and 33 partial responses in the combination group (ORR, 84%; P = .008).

"The 8.7-month increase in progression-free survival was highly statistically significant," said Dr. Liu, "with a P value of .5 and a hazard ratio of 0.42."

Marked Difference in Non-BRCA Patients

Because previous trials have suggested that women with BRCA mutations have increased sensitivity to PARP inhibitors, the researchers looked at the activity of the combination in women with and without BRCA mutations.

"In women with a BRCA mutation, there was a trend of increased activity in favor of the olaparib and cediranib combination, with median progression-free survival going from 16.5 months in the single-agent arm to 19.4 months in the combination arm," Dr. Liu reported.

However, in patients without the mutation or with unknown mutation status, the difference in progression-free survival was much more marked in the olaparib group than in the combination group (5.7 vs 16.5 months; P = .008).

Overall, grade 3/4 toxicity was higher with the combination than with olaparib alone (70% vs 7%), as was fatigue (27% vs 7%), diarrhea (23% vs 0%), and hypertension (39% vs 0%).

"If we put this together with other studies of platinum-sensitive patients, the progression-free survival matches up very well with what we have seen with chemotherapy," said study discussant Jonathan Ledermann, MD, from the University College London Cancer Institute in United Kingdom.

Both of the drugs were active in the group without known BRCA mutations, and most of the adverse effects appear to be driven by cediranib, he pointed out. It will be important to know what dose to use going forward, he said.

Another question that remains is whether this combination can replace standard chemotherapy, but that will require further study, Dr. Ledermann explained.

AstraZeneca notes that the National Cancer Institute is planning to conduct 2 phase 3 trials to investigate the combination of olaparib plus cediranib in ovarian cancer, and the 2 drugs are also being investigated individually in clinical trials in ovarian cancer.

Olaparib has already shown efficacy as a monotherapy in ovarian cancer, and was recently granted Priority Review designation by the US Food and Drug Administration (FDA) for the treatment of platinum-sensitive relapsed ovarian cancer in patients who have a BRCA mutation. This indication will be discussed at an FDA Oncologic Advisory Committee meeting on June 25. Olaparib is also under regulatory review in Europe.

Cediranib has also shown some efficacy in ovarian cancer. In the phase 3 ICON 6 trial of platinum-sensitive relapsed ovarian cancer, progression-free and overall survival were significantly better when cediranib was given during and after chemotherapy than when chemotherapy was used alone.

According to AstraZeneca, the company has consulted with regulatory agencies in the United States and the European Union to understand how these results can best support a potential regulatory submission for approval of cediranib in ovarian cancer, and is now working on new analyses of the cediranib data with a view to regulatory submissions later this year.

This study was supported by the National Cancer Institute, National Institutes of Health. The authors have disclosed no relevant financial relationships.

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract  LBA5500. Presented May 31, 2014.

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Cite this: Targeted Drug Combo Improves Outcomes in Ovarian Cancer - Medscape - Jun 01, 2014.