Safety and Potential Radiosensitizing Effect of Olaparib in Combination With Breast Radiation Therapy for Patients With Triple-Negative Breast Cancer With Residual Disease: Long-Term Results From the RADIOPARP Phase 1 Trial

Pierre Loap; Delphine Loirat; Marc-Henri Stern; Jean-Yves Pierga; Kim Cao; Anne Vincent-Salomon; Frederique Berger; Alain Fourquet; Youlia Kirova

doi:10.1016/j.ijrobp.2025.05.013

Safety and Potential Radiosensitizing Effect of Olaparib in Combination With Breast Radiation Therapy for Patients With Triple-Negative Breast Cancer With Residual Disease: Long-Term Results From the RADIOPARP Phase 1 Trial

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

Authors

Pierre Loap¹, Delphine Loirat², Marc-Henri Stern³, Jean-Yves Pierga², Kim Cao⁴, Anne Vincent-Salomon⁵, Frederique Berger⁶, Alain Fourquet⁴, Youlia Kirova⁴

Affiliations

¹ Department of Radiation Oncology, Institut Curie, Paris, France. Electronic address: pierre.loap@gmail.com.
² Department of Medical Oncology, Institut Curie, Paris, France.
³ Department of Genetics, Institut Curie, Paris, France.
⁴ Department of Radiation Oncology, Institut Curie, Paris, France.
⁵ Department of Anatomopathology, Institut Curie, Paris, France.
⁶ Department of Biostatistics, Institut Curie, Paris, France.

PMID: 40393566
DOI: 10.1016/j.ijrobp.2025.05.013

Abstract

Purpose: Patients with triple-negative breast cancer (TNBC) 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 1 trial (RADIOPARP) evaluated the long-term safety and potential radiosensitizing effects of olaparib combined with breast radiation therapy in patients with TNBC.

Methods and materials: This dose-escalation trial enrolled 24 nonmetastatic patients with TNBC 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 twice daily) for 7 days before normofractionated radiation therapy (50-50.4 Gy in 25-28 fractions). HRD status was determined using genomic analyses. Safety was assessed through dose-limiting toxicities and long-term adverse events, whereas secondary endpoints included locoregional recurrence-free survival, metastasis-free survival, and overall survival.

Results: The median follow-up was 59 months. No grade ≥ 3 toxicities were reported, and grade 2 toxicities (fibrosis and telangiectasias) were rare. Among patients with HRD (n = 13), no locoregional recurrences were observed, whereas 3 of 8 patients with homologous recombination-proficient experienced recurrences (P = .024). Five-year locoregional recurrence-free survival was 100% for patients with HRD and 60.0% for patients with homologous recombination-proficient. Metastasis-free survival was 69.8%, and overall survival was 73.5%, with no significant differences by HRD status.

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