BRCA1/2-mutated early triple-negative breast cancer (TNBC)

Neoadjuvant olaparib (Lynparza) in combination with carboplatin displayed promising efficacy in patients with BRCA1/2-mutated early triple-negative breast cancer (TNBC) with homologous recombination deficiency (HRD), according to findings from the phase 2 ABCSG 45 (EUCT 2024-512821-10-00) presented during the 2025 ASCO Annual Meeting.¹

Findings from ABCSG 45 revealed that patients with disease harboring BRCA1/2 mutations who received the combination (n = 22) achieved a residual cancer burden (RCB) 0/1 rate of 77.3% (95% CI, 56.6%-89.9%); notably, all patients achieved RCB 0 status. Comparatively, patients with disease harboring BRCA1/2 who received docetaxel plus epirubicin and cyclophosphamide (TAC; n = 20) experienced a RCB 0/1 rate of 65.0% (95% CI, 43.3%-81.9%), with an RCB 1 rate of 5.0%.

“In patients with [TNBC] with BRCA1/2 pathogenic variants, 6 cycles of neoadjuvant carboplatin plus olaparib were well tolerated and resulted in [RCB 0/1] rates of more than 77%,” Christian F. Singer, MD, MPH, said during the presentation.

Singer is an oncologist in the Department of Obstetrics and Gynecology and Center for Breast Health at the Comprehensive Cancer Center of the Medical University of Vienna in Austria.

Unpacking the Study Design and Baseline Characteristics

ABCSG 45 was a prospective trial that enrolled Austrian patients with early invasive, HRD-positive TNBC.² Key inclusion criteria included the presence of BRCA1/2 pathogenic variants or a Genomic Instability Score of at least 42 and a T-stage of at least T1c.¹ Patients with locally advanced or inoperable disease were excluded.

After undergoing a core biopsy, patients were randomly assigned 1:1 to receive olaparib via step-up dosing at 100 mg, then 200 mg, and 300 mg twice daily on days 4 to 19 of each cycle, then at 100 mg twice daily on days 4 to 19 of each cycle, in combination with carboplatin at an area under the concentration curve of 5 every 3 weeks, both for 6 cycles, or TAC.¹ Patients in the TAC arm received 6 cycles of docetaxel at 75 mg every 3 weeks, epirubicin at 50 mg/m² every 3 weeks, and cyclophosphamide at 500 mg/m² every 3 weeks. After the completion of 6 cycles of neoadjuvant therapy, all patients proceeded to surgery.

The primary end point was RCB 0/1 rate. Secondary end points included pathologic complete response rate, quality of life, and safety and tolerability.

At baseline, the mean age in the overall population (n = 90) was 50.9 years (SD, 12.5). Most patients were positive for genomic instability (92.2%), had T-stage T2 disease (55.6%), and N-stage N0 disease (60.0%). The mean Ki-67 score was 72.1 (SD, 17.6).

Further Efficacy Data and Safety Results

Additional findings from the study demonstrated that the RCB 0/1 rate in the overall population of the investigational arm (n = 46) was 52.2% (95% CI, 38.1%-65.9%). Patients in the TAC arm (n = 44) achieved an RCB 0/1 rate of 70.5% (95% CI, 55.8%-81.8%).

Patients with BRCA1/2–wild-type disease (n = 24) who received olaparib and carboplatin experienced an RCB 0/1 rate of 29.2% (95% CI, 14.9%-49.2%). Patients in the TAC arm (n = 24) experienced an RCB 0/1 rate of 75.0% (95% CI, 55.1%-88.0%).

In terms of safety, common any-grade adverse effects (AEs) in the investigational arm included thrombocytopenia (91%), anemia (80%), neutropenia (74%), and leukopenia (63%). Common grade 3 or higher AEs consisted of neutropenia (43%), thrombocytopenia (30%), leukopenia (9%), anemia (7%), and fatigue (2%).

Common any-grade AEs in the TAC arm included nausea (73%), fatigue (65%), and constipation (48%). Grade 3 or higher AEs were comprised of leukopenia (25%), neutropenia (18%), anemia (8%), diarrhea (3%), alopecia (3%), fatigue (3%), and thrombocytopenia (3%).

“[Our findings show that] HRD and tumoral BRCA1/2 status may help to personalize treatment decisions in [patients with] early TNBC,” Singer concluded in the presentation.

Disclosures: Singer received honoraria from AstraZeneca/MedImmune, Daiichi Sankyo, and Novartis. He holds consulting or advisory roles with AstraZeneca/MedImmune, Daiichi-Sanyko, Gilead Sciences, Novartis, and Sanofi/Aventis. He is on the speakers’ bureau for AstraZeneca/MedImmune and Novartis. He has received research funding from Amgen, Amgen, AstraZeneca/MedImmune, Myriad Genetics, Novartis, Roche, and Sanofi. He has received travel accommodations and expenses from Daiichi-Sankyo, Gilead Sciences, Novartis, and Roche.

References

1. Singer CF, Hlauschek D, Egle D, et al. Prospective randomized phase II trial to assess the efficacy and safety of neo-adjuvant olaparib/carboplatin (OC) in comparison to docetaxel/epirubicin/cyclophosphamide (TAC) in patients with early triple-negative breast cancer (TNBC) with homologous recombination deficiency (HRD): primary results from the ABCSG 45 trial. J Clin Oncol. 2025;43(suppl 16):510. doi:10.1200/JCO.2025.43.16_suppl.510
2. A clinical trial that examines whether the treatment with the medication olaparib in combination with the chemotherapy carboplatin is more effective than treatment with a standard chemotherapy (anthracycline/taxane-based) against a specific type of breast cancer (triple-negative) with a biologic characteristic (homologous recombination deficiency). EUclinicaltrials.eu. Updated January 15, 2025. Accessed August 14, 2025. https://euclinicaltrials.eu/ctis-public/view/2024-512821-10-00