The Role of PARP Inhibitors in Metastatic Breast Cancer

Two PARP inhibitors, olaparib (Lynparza) and talazoparib (Talzenna), have been approved for the treatment of triple-negative metastatic breast cancer. PARP inhibitors have also been approved for the treatment of metastatic breast cancer in germline BRCA mutation (gBRCAm) carriers, giving patients another promising therapeutic option.

PARP inhibitors are a type of targeted therapy used in the treatment of metastatic breast cancer by blocking the activity of an enzyme, called poly (ADP-ribose) polymerase (PARP), which is involved in DNA repair. Inhibiting PARP can cause cancer cells to die. In addition, PARP inhibitors are being studied as a potential treatment option for patients with BRCA-like tumors.

PARP inhibitors are effective against tumors with mutations in DNA repair genes, most notably in patients with germline BRCA1/2 mutations. The mechanism of action of PARP inhibitors in metastatic breast cancer with germline BRCA1/2 mutation is based on the concept of synthetic lethality, which the tumor cells are more sensitive to. PARP inhibitors block the activity of PARP, an enzyme involved in DNA repair, leading to the accumulation of DNA damage in cancer cells. In normal cells, this damage can be repaired through the BRCA pathway. However, in BRCA1/2 deficient tumor cells, the BRCA pathway is already compromised, and the accumulation of DNA damage caused by PARP inhibition leads to cell death.

TBCRA-048 Study on Olaparib
The TBCRC-048 study was a phase II trial that evaluated the efficacy of olaparib in patients with metastatic breast cancer (MBC) and mutations in homologous recombination-related genes other than BRCA1/2. The study included patients with germline or somatic mutations in PALB2, ATM, CHEK2, RAD51D, and other HR-related genes. The study found that PARP inhibition with olaparib was an effective treatment for patients with MBC and germline PALB2 or somatic BRCA1/2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARP inhibitors beyond germline BRCA1/2 mutation carriers. The study also emphasized the value of molecular characterization for treatment decisions in MBC.

In addition, the TBCRC-048 study found that olaparib had a manageable safety profile, with the most common adverse events being anemia, fatigue, and nausea. It was also found that patients with hormone receptor-positive breast cancer had a lower response rate to olaparib compared to patients with triple-negative breast cancer.

Overall, the TBCRC-048 study demonstrated the efficacy of olaparib in patients with MBC and mutations in homologous recombination-related genes other than BRCA1/2, expanding the population of patients with breast cancer who may benefit from PARP inhibitors.

EMBRACA Trial on Talazoparib
The EMBRACA trial was a phase III clinical trial that evaluated the efficacy and safety of talazoparib in patients with advanced breast cancer and a germline BRCA mutation. The trial was an open-label, randomized, international study that compared the efficacy and safety of talazoparib with a protocol-specific physician's choice of chemotherapy. The trial enrolled patients with HER2-negative locally advanced or metastatic breast cancer and a germline BRCA1/2 mutation. The primary endpoint of the trial was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), objective response rate (ORR), and safety.

The EMBRACA trial found that talazoparib significantly prolonged PFS compared to chemotherapy, with a median PFS of 8.6 months in the talazoparib group and 5.6 months in the chemotherapy group. The trial also found that talazoparib had a higher ORR compared to chemotherapy, with an ORR of 62.6 percent in the talazoparib group and 27.2 percent in the chemotherapy group. However, the trial did not find a significant improvement in overall survival (OS) with talazoparib compared to chemotherapy.

EMBRACA also evaluated the safety and tolerability of talazoparib and found that the most common adverse events associated with talazoparib were anemia, fatigue, and nausea, as well as a manageable safety profile.

REFERENCES

1. TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. Pub Med website.https://pubmed.ncbi.nlm.nih.gov/33119476/. Accessed September 15, 2023.
2. TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. Journal of Clinical Oncology website.https://ascopubs.org/doi/full/10.1200/JCO.20.02151. Accessed September 15, 2023.
3. PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond. National Library of Medicine website. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454726/. Accessed September 15, 2023.
4. What is the Potential Role of PARP Inhibitors for Metastatic Breast Cancer With a Germline PALB2 Pathogenic Variant? ASCO Daily News website. https://dailynews.ascopubs.org/do/potential-role-parp-inhibitors-metastatic-breast-cancer-germline-palb2-pathogenic. Accessed September 15, 2023.
5. Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation. Journal of Clinical Oncology website. https://ascopubs.org/doi/10.1200/jco.2014.56.2728. Accessed September 15, 2023.