SUBITO Trial Compares Intensified Chemotherapy With Olaparib

Key Takeaways

• Overall survival findings were closely aligned between groups, with a reported hazard ratio for death of 1.11.
• Grade 3-4 cytopenias were common, serious adverse events occurred more often with intensified chemotherapy, and no treatment-related deaths were reported.
• The authors concluded that intensified chemotherapy with autologous stem cell rescue did not provide an advantage over chemotherapy plus olaparib.

In the SUBITO phase 3 trial, 4-year overall survival was 77.0% with intensified alkylating chemotherapy plus stem cell rescue and 76.4% with conventional chemotherapy followed by 1 year of olaparib. Those closely matched topline results came from a head-to-head comparison in newly diagnosed stage IIIA-C, HER2-negative breast cancer with homologous recombination deficiency and no distant metastases. The trial focused on this biomarker-selected, locally advanced population to compare an intensified alkylating strategy with chemotherapy plus olaparib.

This open-label, randomized, controlled, phase 3 trial enrolled patients aged 18-66 years with stage IIIA-C, HER2-negative breast cancer with homologous recombination deficiency and no distant metastases. Eligibility required either a pathogenic germline BRCA1/2 mutation or HRD-positive tumor testing, and investigators screened 356 patients before randomizing 174 in a 1:1 ratio. Eighty-seven patients entered each group, and all participants were female with a median age of 42 years at enrollment. The intensified arm used four dose-dense doxorubicin and cyclophosphamide cycles, then cyclophosphamide, thiotepa, and carboplatin with autologous stem cell transplantation. The comparison arm received four dose-dense doxorubicin and cyclophosphamide cycles, then carboplatin-paclitaxel and oral olaparib 300 mg twice daily for 1 year, with surgery and radiotherapy according to local practice.

At a median follow-up of 41 months (IQR 27-59), the primary endpoint was overall survival in the intention-to-treat population. This analysis included all randomly assigned patients rather than a reduced treatment subset. Four-year overall survival remained closely aligned between the intensified chemotherapy and olaparib groups during the reported follow-up period. The hazard ratio for death was 1.11, with a 95% CI of 0.57 to 2.17. The reported p value was 0.37.

The most common grade 3-4 adverse events across both groups were platelet count decreased, neutrophil count decreased, and anaemia. Rates were 80/81 versus 18/91 for platelet count decreased, 77/81 versus 56/91 for neutrophil count decreased, and 50/81 versus 37/91 for anaemia. Treatment-emergent serious adverse events were more frequent with intensified chemotherapy, occurring in 38/81 versus 24/91. Febrile neutropenia was the most common serious adverse event, reported in 36/81 and 11/91, respectively, and no treatment-related deaths were reported. The authors said targeting HRD was associated with promising outcomes in this population, but intensified chemotherapy with autologous stem cell rescue did not provide an advantage over chemotherapy plus olaparib.