A Summary of PARP Inhibitors for the Treatment of Breast Cancer

Breast cancer is the world’s second most prevalent cancer and the most common malignancy in women, with 2.09 million new cases reported in 2018 (accounting for 12% of all cancers).¹ Despite improvements in survival rates, breast cancer remains the fourth most common cause of cancer death in women, with 627,000 deaths in 2018.¹

BRCA1 and BRCA2 loss-of-function mutations are found in ≥5% of unscreened patients with breast cancer. These breast cancer susceptibility genes code for DNA homologous recombination repair proteins. Oral poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of breast cancer, such as olaparib and talazoparib have been approved as monotherapies for deleterious or suspected deleterious germline BRCA mutation–positive, HER2-negative breast cancer. Olaparib is approved for the treatment of patients with metastatic breast cancer in the United States and locally advanced or metastatic breast cancer in Europe. In the United States and Europe, talazoparib is approved for the treatment of patients with locally advanced or metastatic breast cancer. Olaparib and talazoparib monotherapies showed significant progression-free survival improvements in phase 3 trials when compared with chemotherapy.¹

In a phase 3 trial, veliparib (ABT-888) combined with platinum-based chemotherapy showed promise for locally advanced or metastatic breast cancer. Variances in efficacy and safety among PARP inhibitors (olaparib, talazoparib, veliparib, niraparib, rucaparib) could be attributed to differences in PARP trapping on DNA potency and cytotoxic specificity. PARP medications are being studied in early breast cancer, in novel combinations, and in patients with somatic BRCA mutations and other homologous recombination repair gene alterations who do not have inherited BRCA mutations.¹

PARP inhibitors in combination with immune checkpoint inhibitors are now being studied in phase 2/3 trials for the treatment of patients with triple-negative breast cancer. To identify individuals who potentially benefit from PARP inhibitor therapy, further testing for BRCA and other mutations as well as genetic counseling is needed. PARP inhibitors have the potential to improve breast cancer treatment beyond the locally advanced and metastatic stage.¹

For patients with locally progressed or metastatic BRCA mutation–positive, HER2-negative breast cancer, PARP inhibitor treatments are a welcome addition to the therapy arsenal. PARP inhibitors have already shown anticancer effects in patients with advanced breast cancer with germline BRCA1/2 mutation as a single drug. Olaparib and talazoparib dramatically increased response rate, progression-free survival, and quality of life when compared with nonplatinum chemotherapy at the physician’s discretion.²

Patients and healthcare professionals need clear instructions on testing for BRCA mutations because this additional option provides focused therapy for patients with BRCA mutation–positive disease. PARP inhibitors’ oral formulation, together with their superior safety profiles compared with chemotherapy, have the potential to improve patient experience and adherence. As our understanding of the disease improves, we may be able to begin using PARP inhibitors in patients with early-stage breast cancer and in combination with other treatments.¹

Going forward, PARP inhibitors should be part of any treatment plan for patients with BRCA1/2 mutation who become diagnosed with breast cancer. In addition, their use will most certainly expand beyond the metastatic scenario to include adjuvant and neoadjuvant conditions. PARP inhibitors outperformed chemotherapy in the OlympiAD and EMBRACA trials in terms of survival and quality of life.³

References

1. Cortesi L, Rugo HS, Jackisch C. An overview of PARP inhibitors for the treatment of breast cancer. Target Oncol. 2021;16:255-282.
2. Gonçalves A, Bertucci A, Bertucci F. PARP inhibitors in the treatment of early breast cancer: the step beyond? Cancers (Basel). 2020;12:1378.
3. Palleschi M, Tedaldi G, Sirico M, et al. Moving beyond PARP inhibition: current state and future perspectives in breast cancer. Int J Mol Sci. 2021;22:7884.