In a European phase III trial (SUBITO) reported in The Lancet Oncology, Seefat et al found that intensified alkylating chemotherapy with autologous stem cell rescue (IACT) provided no overall survival advantage vs standard chemotherapy followed by olaparib in patients with stage IIIA-C HER2-negative breast cancer with homologous recombination deficiency (HRD).
Study Details
In the trial, 174 patients from nine sites in the Netherlands and one in France were randomly assigned to receive IACT (n = 87) or conventional chemotherapy plus olaparib (n = 87). IACT consisted of dose-dense alkylating chemotherapy (ddAC; four cycles of doxorubicin at 60 mg/m² and cyclophosphamide at 600 mg/m² every 2 weeks, with 6 mg prophylactic pegfilgrastim subcutaneously every 2 weeks). At 2 weeks after stem cell mobilization, patients received two IACT cycles 3 weeks apart (3,000 mg/m² cyclophosphamide on day 1, 250 mg/m² thiotepa on day 2, and 400 mg/m² carboplatin on days 1 and 2), followed by autologous stem cell transplantation. Conventional chemotherapy in the olaparib group consisted of four ddAC cycles followed by four cycles of carboplatin at area under the curve = 6 every 3 weeks, and 80 mg/m² paclitaxel every week for 12 weeks followed by 1 year of oral olaparib at 300 mg twice daily. All patients proceeded to surgery and radiotherapy based on local practice.
Key Findings
With a median follow-up of 41 months (interquartile range = 27–59 months), 4-year overall survival was 77.0% (95% confidence interval [CI] = 67.7%–87.7%) in the IACT group and 76.4% (95% CI = 66.9%–87.4%) in the olaparib group. Overall, death occurred in 18 patients vs 17 patients (hazard ratio = 1.11, 95% CI = 0.57–2.17, P = .37).
The most common grade 3 or 4 adverse events were decreased platelet count (99% in the IACT group vs 19% in the olaparib group), decreased neutrophil count (95% vs 61%), and anemia (62% vs 41%). Serious adverse events occurred in 47% vs 26% of patients; febrile neutropenia was the most common serious adverse event in both groups (44% vs 12%). No treatment-related deaths were reported.
The investigators concluded: “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.”
Sabine C. Linn, MD, PhD, of Netherlands Cancer Institute, Amsterdam, is the corresponding author for The Lancet Oncology article.
DISCLOSURE: The study was funded by the Dutch Cancer Society, Dutch Ministry of Health, the Netherlands Organization for Health Research and Development, AstraZeneca, MSD, and Eurocept Pharmaceuticals. For full disclosures of the study authors, visit thelancet.com.
