A phase II clinical trial called NOBROLA has evaluated the use of olaparib monotherapy in patients with advanced triple-negative breast cancer (TNBC) who have homologous recombination deficiency (HRD) but lack germline BRCA1/2 mutations. The single-arm, open-label, multicenter study was conducted across 17 sites in Spain and funded by AstraZeneca. Results were published in the journal The Breast in November 2024.
The primary purpose of the NOBROLA trial was to assess the clinical benefit rate (CBR) of olaparib in this specific patient population, which has limited treatment options and has not been well-studied in previous clinical trials. The study aimed to enroll adult patients with advanced TNBC who lacked germline BRCA1/2 mutations but had HRD as determined by either the Myriad myChoice HRD Plus CDx or FoundationOne CDx tests.
Out of 114 patients initially screened, only six met the eligibility criteria and received treatment with olaparib. This low enrollment was primarily due to the rarity of HRD in TNBC patients without germline BRCA1/2 mutations. The study was prematurely terminated because of the slow accrual rate. Eligible patients received oral olaparib at a dose of 300 mg twice daily in 28-day cycles until disease progression or other discontinuation criteria were met.
The demographic data showed that all six patients were women with a median age of 60 years (range 45-76). All had metastatic disease and had received up to three prior lines of treatment in the advanced setting. The patients had varied metastatic sites, including bone, brain, liver, lung, and lymph nodes.
Despite the small sample size, the results showed promising activity for olaparib in this patient population. The CBR at 24 weeks was 50% (95% CI, 11.8-88.2), with three patients achieving partial responses. The overall response rate (ORR) was also 50%. The median time to response was 1.9 months, and the median duration of response was 4.9 months. Progression-free survival (PFS) reached a median of 6.2 months, while overall survival (OS) was 19.4 months.
Regarding safety, treatment-emergent adverse events (TEAEs) were mostly grade 1-2, occurring in 83.3% of patients. Grade 3 TEAEs were observed in 66.6% of patients, with anemia being the most frequent (33%). No grade 4 TEAEs or treatment-related deaths were reported. The most common TEAEs of any grade were anemia (83% of patients) and fatigue (50% of patients).
The study has several notable limitations. The extremely small sample size of just six patients significantly weakens the statistical power of the results and limits their generalizability. The premature termination of the trial due to slow accrual further complicates the interpretation of the findings. Additionally, the heterogeneous definition of HRD status, arising from differences in assessment methods and the complexity of HRR pathways, adds another layer of uncertainty to the results.
Despite these limitations, the authors concluded that olaparib monotherapy showed antitumor activity in 50% of the treated patients. They suggest that these results warrant further investigation in larger trials. The researchers also highlight the challenges of conducting studies in patient populations with such low-frequency genetic profiles.
The potential clinical impact of this study, while limited by its small scale, is nonetheless intriguing. It suggests that PARP inhibitors like olaparib may have efficacy beyond just BRCA1/2-mutated cancers, potentially expanding treatment options for a subset of TNBC patients with HRD. However, the authors note that if future trials yield similar results in these rare patient populations, regulatory bodies may need to reconsider the requirements for drug approvals, potentially allowing for smaller studies rather than large phase III trials.
This study also underscores the importance of precise patient selection in targeted therapies. The difficulty in identifying eligible patients highlights the need for better and more standardized methods of detecting HRD in non-BRCA1/2 mutated tumors. It also emphasizes the ongoing challenge of developing effective treatments for the heterogeneous group of cancers classified as TNBC.
In conclusion, while the NOBROLA trial was limited by its small sample size, it provides a foundation for further research into the use of PARP inhibitors in TNBC patients with HRD who lack BRCA1/2 mutations. The results suggest potential benefit in this population, but larger studies will be needed to confirm these findings and potentially change clinical practice. The study also highlights the ongoing challenges in conducting trials for rare subsets of patients within already uncommon cancer types.
References
Cortés A, López-Miranda E, Fernández-Ortega A, et al. Olaparib monotherapy in advanced triple-negative breast cancer patients with homologous recombination deficiency and without germline mutations in BRCA1/2: The NOBROLA phase 2 study. Breast. 2024;78:103834. doi:10.1016/j.breast.2024.103834
