Main Session
Sep 29
SS 27 - Breast Cancer 2: Multimodal Strategies in Breast Cancer: Biology, Systemic Therapy, and Psychosocial Insights

262 - Safety and Potential Radiosensitizing Effect of Olaparib in Combination with Breast Radiotherapy for TNBC Patients with Residual Disease: Long-Term Results from a Phase I Trial

05:30pm - 05:40pm PT
Room 156/158

Presenter(s)

Pierre Loap, MD - Institut Curie, Paris, Ile de France

P. Loap1, D. Loirat2, M. H. Stern2, J. Y. Pierga3, K. I. Cao2, A. Vincent-Salomon4, F. Berger5, A. Fourquet2, and Y. M. Kirova2; 1Department of Radiation Oncology-Institut Curie, Paris, France, 2Institut Curie, Paris, France, 3Institut Curie, Department of Medical Oncology, PARIS, France, 4Institut Curie, Department of Pathology, Paris, France, 5Institut Curie, Paris-St Cloud, France, Paris, France

Purpose/Objective(s):

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/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:

With a median follow-up of 59 months (range: 3–77), three patients experienced locoregional recurrences—all of whom were HRP—while six patients developed distant metastases, and five patients died. At five years, locoregional recurrence-free survival (LRRFS) was 83.9% (95% CI: 68.7%–100%), metastasis-free survival (MFS) was 69.8% (95% CI: 52.2%–93.3%), and overall survival (OS) was 73.5% (95% CI: 55.9%–96.7%). HRD status emerged as the only variable significantly associated with LRRFS. None of the 13 HRD patients experienced locoregional recurrence, compared to 3 of the 8 HRP patients (p=0.024). Five-year LRRFS was 100% in HRD patients and 60.0% (95% CI: 33.1%–100%) in HRP patients.

At 3 years, 16 patients were evaluable. Maximum toxicities included grade 2 fibrosis in two patients, one of whom also developed grade 2 telangiectasias. At 4 years, 13 patients were evaluable, and the maximal toxicity profile remained unchanged. At 5 years, 12 patients were evaluable; grade 2 fibrosis was reported in one patient, while grade 2 telangiectasias were noted in two patients. No grade =3 late toxicities were observed. Furthermore, no patients developed pulmonary or cardiac toxicities.

Conclusion:

This phase I 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.