Olaparib Monotherapy in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a breast cancer subtype characterized by the absence of estrogen receptors and progesterone receptors as well as normal HER2 protein expression.¹ TNBC accounts for approximately 15% of all breast cancers, and despite strong treatment response rates, these patients have a dismal prognosis compared with those with other breast cancer subtypes. There are currently no targeted treatments that have a clear role in primary TNBC.¹ TNBC is resistant to endocrine- and molecular-targeted therapy, thus surgery and systemic chemotherapy are the only options for treatment.²

TNBC treatment is being advanced by researchers worldwide.2 More promising results in clinical studies on TNBC treatment have emerged in the past 2 to 3 years. Several promising treatments for patients with TNBC have been approved as a result of the findings, including the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib for germline BRCA mutation–associated breast cancer.²

Germline BRCA mutation–associated breast cancers represent 3% to 5% of cases.² These patients have biological characteristics that cause genomic instability and make them susceptible to DNA-damaging drugs, such as PARP inhibitors.²

The majority of the current targets are tyrosine kinases; however, DNA repair machinery could also be targeted.³ Some DNA repair abnormalities have been linked to sensitivity to platinum and PARP inhibitors such as olaparib, implying that treatment with a PARP inhibitor could exploit a synthetic lethal interaction in the presence of homologous repair pathway alteration. PARP inhibitors such as olaparib, which is known to have immunogenic effects, are susceptible to tumors with a lack of homologous repair.³

Patients with TNBC received olaparib monotherapy 300 mg twice daily for up to 10 weeks in the phase 2 PETREMAC trial, regardless of BRCA or tumor protein P53 gene (TP53) mutation status, with the goal of decreasing tumor size before chemotherapy.¹ For patients who did not show signs of tumor regression after 10 weeks, olaparib monotherapy was stopped and chemotherapy was started. Only 1 patient had grade >2 toxicity while receiving olaparib monotherapy. Olaparib monotherapy showed a 56.3% objective response rate in patients with treatment-naïve, unselected primary TNBC, and a 51.9% response rate in patients without germline BRCA1/2 or germline PALB2 mutations.¹

Patients with germline BRCA mutation–associated breast cancer are increasingly receiving PARP inhibitors, and clinical phase 3 findings show that these patients may benefit from the slowing of disease progression.² Furthermore, the outcomes are superior to chemotherapy in terms of adverse events and quality of life.² When given to treatment-naïve patients with large TNBC tumors, with germline or somatic homologous repair deficiency, olaparib monotherapy produced a high response rate.¹ Whereas the effectiveness of PARP inhibitor monotherapy in TNBC has yet to be proven, it does suggest a possible sequential method for TNBC downstaging before chemotherapy.¹

References

1. Eikesdal HP, Yndestad S, Elzawahry A, et al. Olaparib monotherapy as primary treatment in unselected triple negative breast cancer. Ann Oncol. 2021;32:240-249.
2. Shen M, Pan H, Chen Y, et al. A review of current progress in triple-negative breast cancer therapy. Open Med (Wars). 2020;15:1143-1149.
3. Fumet J-D, Limagne E, Thibaudin M, et al. Precision medicine phase II study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment. BMC Cancer. 2020;20:748.