September 17, 2024
By Catlin Nalley
Findings from the SUBITO trial, which explored intensified alkylating chemotherapy with autologous stem cell rescue (IACT) or conventional chemotherapy followed by olaparib (CCT-O) among Stage III, HER2-negative, homologous recombination-deficient breast cancer patients, were recently presented during ESMO 2024 in Barcelona (Abstract LBA14). The researchers found that both DNA double-strand break-inducing regimens showed encouraging 4-year overall survival rates in this patient population, particularly when achieving a pathologic complete response.
“Stage III, HER2-negative breast cancer has a dismal prognosis,” noted study author Sabine Linn, MD, Professor of Translational Oncology focusing on breast cancer at Utrecht University, The Netherlands. “We also know that homologous recombination deficient (HRD) breast cancer is particularly sensitive to DNA double-strand break-inducing agents, such as alkylating agents, platinum compounds, or PARP inhibitors.”
In a previous posthoc analysis, Linn and colleagues “identified patients with Stage III breast cancer who derived substantial benefit from IACT when compared to second generation chemotherapy (4-year overall survival (OS) 78% vs. 35%).”
However, prospective confirmation was required and, furthermore, the researchers posed the question: “Could similar OS be achieved with third-generation, platinum-containing chemotherapy with 1 year of olaparib?”
In this multicenter, open-label, Phase III trial patients with Stage III, HER2-negative, BRCA1-like or germline BRCA1/2 mutated (gBRCAm) breast cancer were randomized 1:1 to “IACT [4x dose-dense doxorubicin-cyclophosphamide (ddAC), followed by 2 cycles of carboplatin 800 mg/m2, thiotepa 250 mg/m2, and cyclophosphamide 3,000 mg/m2 with autologous stem cell rescue], or CCT-O (4xddAC-4x carboplatin-paclitaxel and 1 year of olaparib).”
The primary endpoint was overall survival. Secondary endpoints included the following: safety and quality of life, and OS in patients with BRCA1-like breast cancer without gBRCAm. The analysis registered 356 patients and 70 percent had an HRD tumor, according to Linn. Of these patients, 174 were randomized to IACT (n=87) or CCT-O (n=87) and all patients underwent surgery.
“The 4-year overall survival rate was 77 percent for patients who had received intensified alkylating chemotherapy and confirmed the earlier results,” noted Linn during her presentation at ESMO. “The 4-year overall survival of the optimized conventional arm was virtually identical (76.4%) and demonstrated that similar results can be obtained with a third-generation, carboplatin-containing regimen followed by 1 year of olaparib.”
Linn and colleagues observed no significant heterogeneity among subgroups. “The BRCA wild-type group had a 4-year OS slightly above 70 percent while 40 percent of patients who had achieved pathologic complete response had a very impressive 4-year overall survival of around 97 percent in both arms,” she explained.
While toxicity was worse in the intensified alkylating chemotherapy arm, quality of life was similar between the two arms up to 3 years after surgery, according to Linn. No treatment-related deaths occurred.
Concluding her discussion, Linn noted, “We prospectively validated a 4-year overall survival outcome of 77 percent with intensified alkylating chemotherapy in Stage III, homologous recombination-deficient breast cancer. Adding 1 year of adjuvant olaparib to third-generation chemotherapy leads to similar overall survival. Stage III patients with a pathologic complete response at surgery had an excellent survival with both HRD-targeting treatment regimens.
“It appears feasible to accomplish an academic, biomarker-driven RCT in a niche population,” she concluded. “The future direction, according to the study, team, should focus on how to make intensified alkylating chemotherapy or adjuvant PARP inhibition available for Stage III, BRCA wild-type patients with homologous recombination deficient breast cancer.”
Catlin Nalley is a contributing writer