Loap P, Loirat D, Stern MH, Pierga JY, Cao K, -Salomon AV, Berger F, Fourquet A, Kirova Y.

Int J Radiat Oncol Biol Phys. 2025 May 18:S0360-3016(25)00481-X. doi: 10.1016/j.ijrobp.2025.05.013.

Introduction

Triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant therapy face a high risk of locoregional recurrence, particularly when homologous recombination deficiency (HRD) is present. HRD tumors, characterized by impaired double-strand break repair, are theoretically sensitive to PARP inhibitors through synthetic lethality. This phase I trial evaluated the long-term safety and potential radiosensitizing effects of Olaparib combined with breast radiotherapy in TNBC patients.

Materials and Methods

This dose-escalation trial enrolled 24 non-metastatic TNBC patients treated between 2015 and 2019. Patients had either residual disease after neoadjuvant therapy (n=21, adjuvant setting) or unresectable tumors (n=3, preoperative setting). Olaparib was administered at escalating doses (50–200 mg BID) for seven days before normofractionated radiotherapy (50–50.4 Gy in 25–28 fractions). HRD status was determined using genomic analyses. Safety was assessed through dose-limiting toxicities (DLTs) and long-term adverse events, while secondary endpoints included locoregional recurrence-free survival (LRRFS), metastasis-free survival (MFS), and overall survival (OS).

Results

Median follow-up was 59 months. No grade ≥3 toxicities were reported, and grade 2 toxicities (fibrosis and telangiectasias) were rare. Among HRD patients (n=13), no locoregional recurrences were observed, while three of eight homologous recombination proficient (HRP) patients experienced recurrences (p=0.024). Five-year LRRFS was 100% for HRD patients and 60.0% for HRP patients. MFS was 69.8%, and OS was 73.5%, with no significant differences by HRD status.

Conclusion

The trial demonstrates the long-term safety of combining Olaparib with radiotherapy and suggests its potential to enhance locoregional control in HRD tumors. Further studies are warranted to confirm these findings and refine treatment strategies for high-risk TNBC patients.