PARP inhibitors extend survival in ovarian cancer, especially for women with a BRCA mutation
Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-2505.
Ovarian cancer is the deadliest malignancy affecting women in the United States. While patients are likely to respond to their initial chemotherapy and surgery, there is a significant risk for cancer recurrence, from which the high mortality rates arise.
Maintenance therapy has considerable potential for preventing recurrences. Based on the results of a large Gynecologic Oncology Group study,11 in 2017 the US Food and Drug Administration (FDA) approved bevacizumab for use in combination with and following standard carboplatin and paclitaxel chemotherapy for women with advanced ovarian cancer. In the trial, maintenance therapy with 10 months of bevacizumab improved progression-free survival by 4 months; however, it did not improve overall survival, and adverse events included bowel perforations and hypertension.11 Alternative targets for maintenance therapy to prevent or minimize the risk of recurrence in women with ovarian cancer have been actively investigated.
PARP inhibitors work by damaging cancer cell DNA
PARP is a key enzyme that repairs DNA damage within cells. Drugs that inhibit PARP trap this enzyme at the site of single-strand breaks, disrupting single-strand repair and inducing double-strand breaks. Since the homologous recombination pathway used to repair double-strand DNA breaks does not function in BRCA-mutated tissues, PARP inhibitors ultimately induce targeted DNA damage and apoptosis in both germline and somatic BRCA mutation carriers.12
In the United States, 3 PARP inhibitors (olaparib, niraparib, and rucaparib) are FDA approved as maintenance therapy for use in women with recurrent ovarian cancer that had responded completely or partially to platinum-based chemotherapy, regardless of BRCA status. PARP inhibitors also have been approved for treatment of advanced ovarian cancer in BRCA mutation carriers who have received 3 or more lines of platinum-based chemotherapy. Because of their efficacy in the treatment of recurrent ovarian cancer, there is great interest in using PARP inhibitors earlier in the disease course.
Olaparib is effective in women with BRCA mutations
In an international, randomized, double-blind, phase 3 trial, Moore and colleagues sought to determine the efficacy of the PARP inhibitor olaparib administered as maintenance therapy in women with germline or somatic BRCA mutations.13 Women were eligible if they had BRCA1 or BRCA2 mutations with newly diagnosed advanced (stage III or IV) ovarian, fallopian tube, or peritoneal cancer and a complete or partial response to platinum-based chemotherapy after cytoreduction.
Women were randomly assigned in a 2:1 ratio, with 260 participants receiving twice daily olaparib and 131 receiving placebo.
Results. After 41 months of follow-up, the disease-free survival rate was 60% in the olaparib group, compared with 27% in the placebo arm. Progression-free survival was 36 months longer in the olaparib maintenance group than in the placebo group.
Adverse events. While 21% of women treated with olaparib experienced serious adverse events (compared with 12% in the placebo group), most were related to anemia. Acute myeloid leukemia occurred in 3 (1%) of the 260 patients receiving olaparib.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
For women with deleterious BRCA1 and/or BRCA2 mutations, administering PARP inhibitors as a maintenance therapy following primary treatment with the standard platinum-based chemotherapy improves progression-free survival by at least 3 years.
For women with deleterious BRCA1 and/or BRCA2 mutations, administering PARP inhibitors as a maintenance therapy following primary treatment with the standard platinum-based chemotherapy improves progression-free survival by at least 3 years.
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