What is the role of poly (ADP-ribose) polymerase (PARP) inhibitors in the treatment of metastatic breast cancer?

Updated: Dec 27, 2019
  • Author: Pavani Chalasani, MD, MPH; Chief Editor: John V Kiluk, MD, FACS  more...
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Answer

Olaparib inhibits poly (ADP-ribose) polymerase (PARP) enzymes. In January 2018, the FDA expanded approval of olaparib to include treatment of BRCA-mutated, HER2-negative metastatic breast cancer in patients who have been previously treated with chemotherapy. Olaparib (which had previously been approved for treatment of BRCA-mutated ovarian cancer) is the first PARP inhibitor approved to treat breast cancer, and the first drug of any kind approved to treat certain patients with BRCA-mutated metastatic breast cancer. [161]

Approval was based on the OlympiAD clinical trial, which was the first phase III trial to demonstrate that PARP inhibitors are superior to chemotherapy for this class of patients. In this trial, patients with a germline BRCA mutation and HER2-negative metastatic breast cancer were assigned to receive either olaparib 300 mg PO BID (n=205) or standard therapy (n=92). Standard therapy was a choice of single-agent chemotherapy, which consisted of 21-day cycles of capecitabine (2500 mg/m2 PO on days 1-14), vinorelbine (30 mg/m2 IV on days 1 and 8), or eribulin (1.4 mg/m2 IV on days 1 and 8). Median progression-free survival (PFS) was significantly longer in those who received olaparib compared with standard therapy (7.0 months vs 4.2 months; hazard ratio, 0.58; P = 0.0009). [162]

The objective response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group. Overall survival and median time to death did not differ significantly between the 2 treatment arms after a median follow-up of 14 months (45.9% vs 47.4%; 19.3 months vs 19.6 months). [162]

In October 2018, talazoparib, another PARP inhibitor, was approved for patients with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. Approval was based on the phase III EMBRACA trial (n=431), which talazoparib reduced the risk of disease progression or death by 46% compared with chemotherapy in patients with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer. Patients were randomized in a 2:1 ratio to receive talazoparib or physician’s choice of chemotherapy (PCT), which included eribulin, gemcitabine, vinorelbine, and/or capecitabine.  [163]

The ORR was 62.6% in the talazoparib group and 27.2% in the PCT group (p < 0.001). Clinical benefit rate at 24 weeks was 68.6% in the talazoparib group and 36.1% in the PCT group. OS data are not yet mature; however, an interim OS analysis found a positive trend favoring talazoparib. The median OS was 22.3 months with the PARP inhibitor compared with 19.5 months with chemotherapy. [163]


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