Targeting homologous recombination deficiency with intensified chemotherapy versus standard chemotherapy followed by olaparib in stage III breast cancer (SUBITO): an open-label, randomised, controlled, phase 3 trial.

Abstract / Summary

Patients with stage III, human epidermal-growth-factor-receptor 2 (HER2; also known as ERBB2)-negative breast cancer with homologous recombination deficiency (HRD) had a 4-year overall survival of 35% after anthracycline-based chemotherapy versus 78% after intensified alkylating chemotherapy with autologous stem cell rescue (IACT) in a post-hoc analysis of an earlier randomised controlled trial. In this study, we aimed to prospectively assess 4-year overall survival with IACT and establish whether this approach remains superior to a contemporary HRD-targeting regimen in patients with HER2-negative breast cancer with HRD. This open-label, randomised, controlled, phase 3 trial included patients from eight hospitals and one cancer centre in the Netherlands and one cancer centre in France. Newly diagnosed patients aged between 18-66 years with stage IIIA-C, HER2-negative, HRD breast cancer without distant metastases who had a pathogenic germline BRCA1/2 mutation or evidence of a HRD tumour on testing were randomly assigned (1:1) to receive IACT or conventional chemotherapy using interactive response technology. IACT comprised dose-dense alkylating chemotherapy (ddAC; four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 weeks intravenously), supported by 6 mg prophylactic pegfilgrastim subcutaneously every 2 weeks. 2 weeks after stem cell mobilisation, patients received two IACT cycles 3 weeks apart (3000 mg/m2 cyclophosphamide on day 1, 250 mg/m2 thiotepa on day 2, and 400 mg/m2 carboplatin intravenously on days 1 and 2), followed by autologous stem cell transplantation. Conventional chemotherapy comprised four ddAC cycles, followed by four cycles of intravenous carboplatin area under the curve 6 every 3 weeks, and 80 mg/m2 paclitaxel every week for 12 weeks (carboplatin-paclitaxel intravenously), followed by 1 year of oral olaparib (300 mg twice daily). All patients proceeded to surgery and radiotherapy according to local practice. Stratification factors were treatment centre, age, stage, and oestrogen receptor status. The primary endpoint was overall survival in the intention-to-treat population (all randomly allocated patients). The trial was registered at ClinicalTrials.gov, NCT02810743, and is ongoing, but is closed for inclusion. From Jan 25, 2017, through to Oct 5, 2023, 356 patients were screened for eligibility, and 174 patients were randomly assigned to receive IACT (n=87) or olaparib (n=87). All patients were female, and median age was 42 years (IQR 37-50). We did not ask explicit informed consent for collecting data on ethnicity of patients, because we focused on a very rare patient subgroup and therefore used pragmatic eligibility criteria following standard General Data Protection Regulation. 28 (32%) in the IACT group and 22 (25%) patients in the olaparib group had germline BRCA1/2 mutations. With a median follow-up of 41 months (IQR 27-59), the 4-year overall survival was 77·0% (95% CI 67·7-87·7 in the IACT group and 76·4% (66·9-87·4) in the olaparib group (hazard ratio for death 1·11 [95% CI 0·57-2·17]; p=0·37).The most common grade 3-4 adverse events were platelet count decreased (80 [99%] in the IACT group vs 18 [19%] in the olaparib group), neutrophil count decreased (77 [95%] in the IACT group vs 56 [61%] in the olaparib group), and anaemia (50 [62%] in the IACT group vs 37 [41%] in the olaparib group). Treatment-emergent serious adverse events occurred in 38 (47%) of 81 patients in the IACT group versus 24 (26%) of 91 patients in the olaparib group. Febrile neutropenia was the most common serious adverse event in both groups (36 [44%] in the IACT group; 11 [12%] in the olaparib group). No treatment-related deaths were reported. These data demonstrate that targeting HRD yields promising outcomes in stage III, HER2-negative, HRD breast cancer and that intensified chemotherapy with autologous stem cell rescue does not provide any advantage over state-of-the-art chemotherapy plus olaparib. Dutch Cancer Society, the Dutch Ministry of Health, the Netherlands Organization for Health Research and Development, A Sister's Hope, [Z]aan de Wandel, AstraZeneca, MSD, and Eurocept Pharmaceuticals.

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