What was the need?
Triple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by a lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). TNBC has a poor prognosis, with higher rates of recurrence and significantly lower overall survival compared to other breast cancer subtypes [1,2].
In recent years, strides have been made towards more tailored approaches for TNBC treatment due, in part, to the improved classification of some variants and efforts to establish a molecular classification of TNBC. Because of the biological diversity that exists within TNBC, the identification of specific populations of patients based on the expression of markers could help in the development of targeted therapies.
One of the best-known defects in DNA repair in TNBC is due to mutations in BRCA1 or BRCA2 genes and is associated with germline inheritance. In these mutations, the deficit places increased dependence on the base-excision repair, and subsequently the function of poly(ADP-ribose) polymerase (PARP) [3,4]. As such, novel targeted therapies have focused on compounds capable of inhibiting the PARP enzyme (known as PARP inhibitors).
Interestingly, some tumors without germline BRCA mutations share similar clinicopathological and molecular characteristics with those having the mutations. Therefore, the concept of “BRCAness” was introduced to describe some sporadic tumors that share clinical and biological features with those harboring germline BRCA1/2 mutations, even though there is no BRCA1/2 mutation present. BRCAness can be acquired either by genetic inactivation of the BRCA or by homologous recombination deficiency (HRD) genes, which are involved in DNA repair [5,6].
Due to the similarities between these subtypes, it is thought that strategies like PARP inhibition which work for BRCA mutations may also be effective in patients with BRCAness.
What is the NOBROLA study testing?
The NOBROLA study aimed to assess the efficacy of olaparib (a PARP inhibitor) as a single agent for patients with advanced TNBC that have HRD and no germline BRCA mutations. Olaparib is currently approved to treat HER2-negative advanced breast cancer for patients with germline BRCA mutations [7].
What is the design of the NOBROLA?
NOBROLA is a phase IIA open-label, two-stage, single-arm clinical trial, that enrolled patients with advanced TNBC that had a BRCAness tumor, had 3 or less previous lines of treatment for advanced breast cancer, and prior taxane exposure. Patients were enrolled into one of two cohorts according to their HRD score. Cohort A included patients with an HRD score ≥ 42 and Cohort B included patients with an HRD score ≥ 33 and < 42.
The primary objective of the study is to assess the efficacy, in terms of clinical benefit rate. The study is also evaluating the overall response rate, time to response, duration of response, progression-free survival, overall survival, and safety.
Contact us to learn more about this trial.
References:
[1] Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat 2009;115:423–8.
[2] Mandapati A, Lukong KE. Triple negative breast cancer: approved treatment options and their mechanisms of action. J Clin Oncol 2022.
[3] Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21.
[4] Bai P. Biology of poly(ADP-Ribose) polymerases: the factotums of cell maintenance. Mol Cell. 2015;58:947–58.
[5] Turner N , Tutt A , Ashworth A . Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer 2004;4:814–9.
[6] McCabe et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res (2006) 66 (16): 8109–8115.
[7] Robson et al. Olaparib for metastatic breast cancer in patients with germline BRCA mutation. N Engl J Med 2017; 377:523-533.
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