A phase 2 trial (TBCRC-056) presented at the 2024 San Antonio Breast Cancer Symposium reveals that neoadjuvant treatment with niraparib (Zejula) and dostarlimab-gxly (Jemperli) shows promising activity in patients with germline BRCA-mutated, estrogen receptor-positive (ER+), and HER2-negative breast cancer. The study, led by Erica L. Mayer, MD, MPH, from Dana-Farber Cancer Institute, suggests a potential non-chemotherapeutic approach for this patient population.
The trial's arm C evaluated 18 patients with ER+/HER2-negative breast cancer treated with niraparib (200 mg orally daily) plus dostarlimab (500 mg intravenously every 3 weeks) for 18 weeks. Patients had stage I to III disease with tumors 1 cm or larger and germline BRCA1/2 or PALB2 mutations. The primary objective was to assess the pathological complete response (pCR) rate and changes in stromal tumor-infiltrating lymphocytes (sTILs).
Efficacy Outcomes
The pathological complete response (pCR) rate was 16.7% (90% CI, 4.7%-37.7%). The residual cancer burden (RCB)-0/I rate, indicative of minimal residual disease, was 44.4%. Further breakdown showed RCB-I at 27.8%, RCB-II at 22.2%, and RCB-III also at 22.2%. Patients requiring additional neoadjuvant therapy had an 11.1% response rate.
Biomarker Analysis
Analysis of paired basal-like (BL) and C2 sTILs in 12 patients showed an 11.9% increase in sTILs after 3 weeks of therapy (P = .09), with mean sTILs increasing from 11.9% to 23.8%. Notably, higher baseline sTILs correlated with pCR (P = .04) and a continuous overall response of 1.10 (90% CI, 1.01-1.20). Similarly, higher baseline sTILs were associated with RCB0-I response (P = .09) and continuous OR of 1.08 (90% CI, 1.00-1.17).
Safety Profile
The most common grade 3 treatment-related adverse effects included rash (27.8%), elevated alanine transaminase (16.7%), and nausea (5.6%). All 18 patients completed therapy and underwent surgery.
Expert Commentary
Dr. Mayer emphasized the significance of these findings, stating, "Given the activity of preoperative PD-1 inhibition for ER-positive breast cancer, additional evaluation of targeted non-chemotherapy approaches is of great interest in this patient population." She also noted that increased baseline sTILs were associated with pathologic response at surgery.
Context and Future Directions
While previous data suggested limited benefit from combining anti-PD-L1 therapy with PARP inhibitors in BRCA-mutated breast cancer, this study suggests potential in less immunosuppressed early-stage settings. Dr. Mayer concluded, "Additional exploration of the immunosuppressive components of the tumor microenvironment may help fully realize the impact of combining immunologic approaches with PARP inhibition."
