A poly(ADP-ribose) polymerase (PARP) inhibitor that has shown promising anticancer activity in the presence of BRCA1 or BRCA2 gene mutations also appears to be effective in the treatment of more common, nonhereditary ovarian tumors.
Olaparib (also known as AZD2281) is an oral drug that blocks the activity of the protein poly(ADP-ribose) polymerase. Because both PARP and BRCA proteins are involved in DNA repair, inhibiting PARP in a tumor that already lacks a BRCA gene prevents cancer cells from repairing their DNA, thus enhancing the effectiveness of DNA-damaging chemotherapy. Approximately 5% to 10% of cases of breast cancer and ovarian cancer exhibit a mutation of the BRCA1 or BRCA2 gene.
Recently, a Canadian research team undertook a phase 2, multicenter, open-label, nonrandomized study to assess whether olaparib could be safely used in women with advanced triple- negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer who had not inherited the BRCA mutations. The 65 women with ovarian cancer and 26 with breast cancer received olaparib 400 mg twice per day for 4 weeks.
Of the 63 evaluable women with ovarian cancer, 11 of the 46 women (24%) without BRCA1 or BRCA2 mutations experienced a substantial reduction in tumor size, as did 7 of the 17 (41%) with mutations. None of the women with breast cancer had a confirmed objective response as per Response Evaluation Criteria in Solid Tumors (RECIST) rules (www.recist.com), which define when a person with cancer improves, or responds, as opposed to staying the same (stable) or worsening (progression).
Olaparib was generally well tolerated and most adverse effects were mild. The most common were:
- fatigue in 70% of patients with ovarian cancer and 50% of patients with breast cancer
- nausea in 66% of ovarian patients and 62% of breast patients
- vomiting in 39% of ovarian patients and 35% of breast patients
- decreased appetite in 36% of ovarian patients and 27% of breast patients.
The researchers conclude that olaparib may be a promising treatment for women with ovarian cancer, and that therapies targeting DNA repair mechanisms seem to provide new hope for the treatment of ovarian cancer (Lancet Oncol. 2011;12:852-861). ONA