PARP inhibitor promising in BRCA-related cancers

An investigational new PARP inhibitor, BMN 673, is showing early responses in patients with heavily pretreated, advanced, BRCA-related cancers of the breast and ovary. These phase I clinical trial results were presented in Boston, Massachusetts, at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 19-23, 2013.

When DNA is damaged in human cells, two proteins, PARP 1 and 2, recruit proteins that can repair the damage associated with loss of BRCA proteins. Mutations in BRCA genes often result in inefficient repair of damaged DNA, which increases the risk for developing certain cancers, including cancers of the breast and ovary. Inhibiting PARP, therefore, prevents the repair of damaged DNA, leading to cell death. While some PARP inhibitors have been tested in various settings, none are approved to date.

"BMN 673 is the most potent PARP inhibitor in clinical development and has optimized pharmaceutical properties: it is well absorbed orally, has substantial single-agent antitumor activity, and has a long half-life allowing once-daily dosing," said Zev A. Wainberg, MD, assistant professor of medicine at the Jonsson Comprehensive Cancer Center of the University of California Los Angeles School of Medicine. "The clinical data to date are promising and compare favorably with results from clinical trials with other PARP inhibitors. We observed high objective and clinical benefit response rates in BRCA-related breast and ovarian cancers at low, oral, once-daily doses.

"Based on this phase I study, we feel there's a good chance that patients with BRCA-related cancers who meet the study eligibility criteria will have disease control for a meaningful period of time with relatively few side effects," stated Wainberg. He added that randomized trials are still necessary.

He and colleagues conducted a phase I trial to evaluate the safety and efficacy of BMN 673 in a two-stage dose escalation/expansion study. So far, they have recruited 39 and 41 patients to the escalation phase and expansion phase, respectively. Patients were 18 to 82 years old and had undergone one to 13 prior therapies.

Fifty participants—18 with breast cancer, 28 with ovarian cancer, three with pancreatic cancer, and one with prostate cancer—had BRCA mutations in their tumors. To date, among the patients with BRCA mutations in their tumors, 44% of those with ovarian cancer and 44% with breast cancer had an objective response. Overall, 82% of the ovarian cancer patients and 72% of the breast cancer patients had clinical benefit.

In patients being treated at the 1 mg dose recommended for future trials, 50% of the breast cancer patients with BRCA mutations had an objective response and 86% had clinical benefit. Of the three patients with pancreatic cancer, two have had stable disease.

Fewer than 20% of the patients had grade 3 adverse events including fatigue, anemia, neutropenia, and thrombocytopenia. One patient had a grade 4 toxicity.

Given the high objective and clinical benefit response rates in breast cancer patients, the investigators have recently initiated a phase 3 trial in metastatic breast cancer with BRCA mutations.

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