Olaparib Monotherapy in Germline BRCA Mutation–Positive, HER2-Negative Metastatic Breast Cancer in the Real-World Setting

Patients with germline BRCA mutation–positive, HER2-negative, advanced or metastatic breast cancer may benefit from poly (ADP-ribose) polymerase (PARP) inhibitors as a targeted treatment.¹ BRCA1 and BRCA2 loss-of-function mutations are found in at least 5% of patients with unscreened breast cancer.² In the randomized phase 3 OlympiAD study, olaparib monotherapy significantly improved progression-free survival (PFS) in patients with germline BRCA mutation–positive, HER2-negative metastatic breast cancer compared with a chemotherapy treatment of the physician’s choice.¹

PARP inhibitors are drugs that disrupt PARP enzyme activity and PARylation processes, preventing DNA repair.³ Competition with nicotinamide adenine dinucleotide for interaction with the PARP catalytic domain is required for their mechanism of action.³ In 2005, 2 research groups independently discovered that PARP inhibition causes synthetic lethality in mutated BRCA1 or BRCA2 tumors, highlighting the strong relationship between BRCA and PARP inhibitors.³

Following the OlympiAD research, olaparib was approved for patients with HER2-negative metastatic breast cancer who had previously received chemotherapy.³ The phase 3 trial included 302 patients with malignancies that had genetic BRCA mutations but no HER2 overexpression, regardless of hormone receptor status (ie, estrogen receptor or progesterone receptor).³

Randomized clinical trials conducted in well-controlled environments provide solid evidence of treatment efficacy and safety.¹ Their findings, however, may have limited application in clinical practice. Clinical efficacy data collected in real-world situations can help fill in the gaps in the evidence and improve knowledge of therapy benefits and drawbacks. The LUCY trial, a phase 3b study, looked at the clinical effectiveness of olaparib monotherapy in patients with BRCA mutation–positive, HER2-negative metastatic breast cancer in a setting that was meant to mimic real-world clinical practice. The results of this study showed that olaparib is efficacious in patients with germline BRCA mutation–positive, HER2-negative metastatic breast cancer. Overall, olaparib was well-tolerated, indicating that it could be a clinically useful and targeted therapeutic option for these patients with a high unmet need. Olaparib’s clinical efficacy was in line with previous findings from the phase 3 OlympiAD trial. The median PFS of the LUCY study (8.1 months) was similar to that of the olaparib arm in the OlympiAD trial at data cutoff, which was encouraging (7.0 months).¹

The PARP inhibitors olaparib and talazoparib have been approved as monotherapies for deleterious and suspected deleterious germline BRCA mutation–positive, HER2-negative metastatic breast cancer.² Olaparib is approved for metastatic breast cancer in the United States and locally advanced or metastatic breast cancer in Europe. Talazoparib is approved in the United States and Europe for locally advanced or metastatic breast cancer.²

PARP inhibitors 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.² 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 may 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/metastatic stage.²

References

1. Gelmon KA, Fasching PA, Couch FJ, et al; for the Collaborating Investigators. Clinical effectiveness of olaparib monotherapy in germline BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: phase IIIb LUCY interim analysis. Eur J Cancer. 2021;152:68-77.
2. Cortesi L, Rugo HS, Jackisch C. An overview of PARP inhibitors for the treatment of breast cancer. Target Oncol. 2021;16:255-282.
3. Faraoni I, Graziani G. Role of BRCA mutations in cancer treatment of poly(ADP-ribose) polymerase (PARP) inhibitors. Cancers (Basel). 2018;10:487.