After halting development of its PARP inhibitor olaparib nearly 2 years ago, AstraZeneca is reviving the drug and launching two phase III trials based on a retrospective analysis of phase II data that showed a marked effect in ovarian cancer patients with a BRCA mutation.

AstraZeneca announced in September the launch of two phase III studies for its PARP inhibitor olaparib in patients with BRCA-mutated ovarian cancer. The initiative comes nearly 2 years after an interim analysis of a phase II trial of olaparib in a broader population of ovarian cancer patients showed no overall survival benefit, which led AstraZeneca to discontinue the drug's development in 2011.

The drug maker decided to forge ahead with phase III trials of olaparib after a retrospective analysis of the phase II data showed a marked effect in ovarian cancer patients with a BRCA mutation, says Jane Robertson, MD, executive global clinical director at AstraZeneca. “We were getting a lot of pleas from the investigators who had worked on it in the early part of the program to carry on the development,” she says.

Median progression-free survival in patients with a BRCA mutation reached 11.2 months with olaparib maintenance therapy compared with 4.3 months with placebo, according to the subgroup analysis presented at the American Society of Clinical Oncology (ASCO) 2013 Annual Meeting in June. Median overall survival for patients with a BRCA mutation was 3 months longer among those who received olaparib compared with placebo, a finding potentially confounded by 22.6% of placebo patients later receiving another PARP inhibitor.

Difficulty identifying the right dose and schedule for a new oral tablet formulation also necessitated the drug's nearly 2-year hiatus, Robertson explains. “We didn't give up on olaparib,” she says. “Now, we're confident we have the right dose and schedule, and we have a clear patient population we know benefits that we can focus our phase III studies on.”

The two phase III studies are investigating the PARP inhibitor as maintenance monotherapy. The U.S.-based SOLO 1 study will test olaparib in BRCA-mutated ovarian cancer patients who have a complete or partial response to platinum-based chemotherapy in the first-line setting. The Europe-based SOLO 2 trial will test the drug in patients who have a complete or partial response to platinum-based chemotherapy for BRCA-mutated ovarian cancer that has relapsed. Results from both studies are expected by 2016.

Susan Domchek, MD, director of the Basser Research Center at the University of Pennsylvania's Abramson Cancer Center in Philadelphia, has conducted research with olaparib in BRCA-mutation carriers with ovarian, breast, pancreatic, and prostate cancers. “The resurgence of interest in these drugs is very exciting,” she says of PARP inhibitors.

“These new studies emphasize that we must target the group of patients who are most likely to respond based on the cancer's underlying biology,” says Domchek, who presented a separate phase II olaparib study at the ASCO meeting. “For olaparib, that's BRCA1- and BRCA2-mutation carriers.”

BRCA1/2 mutations, which are present in about 15% of ovarian cancers, disable the cancer cell's ability to repair double-strand DNA breaks through homologous recombination. Treatment with olaparib blocks PARP, an enzyme involved in the repair of single-strand DNA breaks. Without these pathways it is thought that cells are unable to repair their DNA, and may die.

AstraZeneca recently launched a study in Asia to test olaparib in advanced gastric cancer. The company also plans to assess its effectiveness in BRCA-mutated breast cancer and lung cancer.

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