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NIH Study: Drug Combination May Be Effective for Recurrent Ovarian Cancer

Early data support treatment with olaparib and cediranib

Significant improvement with the use of combination drug therapy for recurrent ovarian cancer has been reported at the 50th annual meeting of the American Society of Clinical Oncology, held May 30–June 3 in Chicago.

This is the first ovarian cancer study to use a combination of drugs that could be taken orally. The drugs were tested in a phase I combination study followed by a randomized phase II trial sponsored by the National Cancer Institute, part of the National Institutes of Health.

The new phase II study compared combination therapy with olaparib (which blocks DNA repair) and cediranib (an angiogenesis inhibitor) with olaparib alone. The results showed a near doubling of progression-free survival (PFS) for the combination therapy compared with use of the single drug alone.

More than 22,000 cases of ovarian cancer are diagnosed annually in the U.S. Most of these cancers (75%) are classified as the high-grade serous type. Women with these cancers have more-advanced disease at diagnosis, and their tumors are more aggressive. Treatment is divided into two categories based on the patients’ prior responses to chemotherapy regimens that included platinum:

  • Platinum-Sensitive: These patients are most likely to benefit from poly ADP-ribose polymerase (PARP) inhibition. PARP inhibitors, such as olaparib, are targeted drugs that block an enzyme involved in many functions in the cell, including the repair of DNA damage.
  • Platinum-Resistant: These patients experienced disease recurrence within 6 months of completion of conventional chemotherapy (using cisplatin or carboplatin). They are generally less responsive to subsequent treatments and have not well to PARP inhibitors. They are currently treated with non-platinum chemotherapy single agents, with or without the addition of the blood vessel inhibitor bevacizumab.

The anti-angiogenic agent cediranib (which inhibits the vascular endothelial growth factor receptor [VEGFR]) and olaparib, a PARP inhibitor, are both clinically active in recurrent ovarian cancer as individual treatments. Preclinical laboratory studies suggested that these agents add to and enhance the activity of each other, and an early phase I trial showed that the combination of cediranib and olaparib was well tolerated with minimal side effects.

For these reasons, 90 patients were randomly assigned to one of two study arms for the phase II clinical trial. The first group received capsules of olaparib (400 mg twice daily), and the second group received a combination of olaparib (200 mg in capsule form twice daily) and cediranib (300 mg by tablets once daily). The study arms were stratified by BRCA gene mutation status and by the receipt of prior anti-angiogenic therapy. The BRCA gene is one of the most commonly mutated genes in breast cancer.

Patients with a median age of 58 years were enrolled from October 2011 to June 2013. As of March 2014, median PFS was 9.2 months for olaparib and 17.7 months for the combination therapy. This difference was statistically significant. The overall rate of toxicity was higher for patients receiving the combination therapy. Fatigue, diarrhea, and hypertension were the most common adverse effects, all of which were manageable.

Based on these results, two phase III trials are being planned for the olaparib/cediranib combo in patients with platinum-sensitive and platinum-resistant ovarian cancer.

Source: NIH; June 2, 2014.

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