In patients with BRCA1 or BRCA2 germline mutation–positive early breast cancer, new medicines are needed to prevent recurrence.1 Breast cancer treatment should be adjusted based on the intrinsic risk for recurrence and/or individual sensitivity to various chemotherapies, according to the precision medicine paradigm.2 This approach is supported by a recent trial with olaparib in women with a BRCA1/2 mutation, which implies that identifying genetic abnormalities at the time of diagnosis may assist a growing percentage of patients.2
Patients with HER2-negative, early breast cancer with BRCA1 or BRCA2 germline pathogenic variants and high-risk clinicopathologic factors who had received local treatment and neoadjuvant or adjuvant chemotherapy, were enrolled in a phase 3 trial. Patients were given either 1 year of oral olaparib or placebo at random (in a 1:1 ratio). Invasive disease-free survival was the primary outcome.1 The olaparib group had an invasive disease-free survival rate of 85.9% versus 77.1% in the placebo group. Olaparib was associated with fewer fatalities than the placebo group (59 and 86, respectively).1
Breast cancer susceptibility genes (BRCA1 and BRCA2) code for proteins that are required for high-fidelity DNA double-strand break repair. Deletions or mutations in these genes affect homologous recombination repair, providing considerable hazards to genomic integrity, especially in breast and ovarian cancer.3 Poly (ADP-ribose) polymerase (PARP) is a key player in DNA single-strand break repair. Olaparib, an oral PARP inhibitor, traps PARP at DNA single-strand breaks, slowing replication forks and causing irreversible DNA double-strand breaks, which have been linked to tumor-specific cell death in BRCA mutation–positive malignancies.3
Olaparib was found to be beneficial as a later-line therapy in a case study of a 63-year-old woman with a somatic BRCA2 mutation who was diagnosed with estrogen receptor–positive, progesterone receptor–positive, and HER2-negative invasive lobular carcinoma 7 years earlier. While the patient was receiving adjuvant endocrine therapy, she had a metastatic recurrence in bone 2.5 years after neoadjuvant chemotherapy. The patient was then given numerous therapy lines, with eribulin and capecitabine providing clinical improvement, followed by cutaneous and hepatic progression prior to olaparib treatment. The olaparib treatment provided a clinical response that lasted 8 months.
The US Food and Drug Administration approved olaparib for the treatment of patients with deleterious or suspected deleterious germline BRCA mutation–positive, HER2-negative metastatic breast cancer who received chemotherapy in the neoadjuvant, adjuvant, or metastatic setting in January 2018. The approval was granted based on the findings of the phase 3 OlympiAD trial, which found that olaparib monotherapy improved median progression-free survival (7.0 months) when compared with standard chemotherapy (4.2 months).3
- Tutt ANJ, Garber JE, Kaufman B, et al; for the OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384:2394-2405.
- Narod SA. Adjuvant olaparib - should all patients with breast cancer have genetic testing? Nat Rev Clin Oncol. 2021;18:607-608.
- Schwartzberg LS, Kiedrowski LA. Olaparib in hormone receptor-positive, HER2-negative metastatic breast cancer with a somatic BRCA2 mutation. Ther Adv Med Oncol. 2021;13:17588359211006962.