Rates of radiotherapy-associated adverse events were considerably higher with the concurrent addition of low doses of the PARP inhibitor olaparib compared with radiotherapy alone in patients with inflammatory breast cancer in the adjuvant setting, according to the results of a toxicity analysis from the SWOG 1706 trial prior to maturing efficacy findings.1
“This study suggests a clinically relevant increase in toxicity with the concurrent administration of breast and nodal radiotherapy, even with low-dose olaparib,” said Reshma Jagsi, MD, DPhil, FASCO, FASTRO, Lawrence W. Davis Professor and Chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, during her presentation of the findings at the 2025 American Society for Radiation Oncology (ASTRO) Annual Meeting.
Dr. Jagsi provided a comprehensive review of how these data compare with safety findings from other early-phase studies of radiotherapy with PARP inhibition for patients with breast cancer.
Background
As novel systemic therapies have improved options and outcomes for patients with breast cancer, particularly in the adjuvant setting, their integration has raised questions about the optimal timing of adjuvant radiotherapy with these agents. This question is especially important regarding agents that may have a radiosensitizing effect on tumor cells and tissue, such as PARP inhibitors, according to Dr. Jagsi during her presentation.
This study suggests a clinically relevant increase in toxicity with the concurrent administration of breast and nodal radiotherapy [with PARP inhibition], even with low-dose olaparib.— RESHMA JAGSI, MD, DPhil, FASCO, FASTRO
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After addressing this question by reviewing available studies and data, the European Society for Radiotherapy and Oncology (ESTRO)-endorsed consensus recommendations on the use of systemic therapies with radiotherapy for patients with cancer suggested that PARP inhibitors should not yet be used with radiotherapy outside of clinical trials, as more comprehensive efficacy and safety data are needed for these combinations.2
Recent early-phase trials have shown conflicting tolerability data for PARP inhibitors given in combination with radiotherapy for patients with breast cancer. In the phase I RADIOPARP trial, olaparib administered at 200 mg twice daily in combination with radiotherapy was found to be tolerable in patients with triple-negative breast cancer, with no late treatment-related grade 3 or higher adverse events reported.3 Yet in the phase I TBCRC 024 study of veliparib administered concurrently with chest wall and nodal radiotherapy in patients with inflammatory or locoregionally recurrent breast cancer, substantial late, severe toxicity was observed.4
Study Methods
The SWOG 1706 trial was first initiated to address unsatisfactory control of inflammatory breast cancer even after patients receive neoadjuvant chemotherapy, mastectomy, and comprehensive locoregional postmastectomy radiotherapy.
The study is a randomized phase II trial of chest wall and regional node radiotherapy administered with or without olaparib in patients with inflammatory breast cancer. Patients were to be followed for 8 years.
Patients with inflammatory (T4d) nonmetastatic breast cancer were enrolled in the study and underwent standard neoadjuvant systemic therapy and modified radical mastectomy, at which point they were randomly assigned to receive radiotherapy with olaparib or radiotherapy alone. For the study, a low dose of 25 mg twice daily was selected for olaparib. Radiation consisted of 50 Gy of chest wall and nodal radiotherapy, including bolus, plus 10 Gy boost.
The adverse event–focused analysis explored the distribution of radiation dermatitis, acute toxicities in the chest wall, and other adverse events observed during radiotherapy that were considered possibly, probably, or definitely related to treatment. Chest wall–related adverse events included skin and subcutaneous tissue events, folliculitis, skin infection, injury/poisoning, wound complications, and breast or chest wall pain.
Safety Findings
A total of 146 patients were evaluable for this safety analysis, with a median age of 54.1 years. Grade 3 or higher radiation dermatitis was reported in 24.7% of patients in the olaparib arm and 5.5% of those in the radiotherapy-alone arm (P = .003).
Grade 3 or higher acute chest wall adverse events were observed in 24.7% of patients in the olaparib and radiotherapy arm vs 6.8% of the radiotherapy-alone arm (P = .006).
“So, all those other events were [experienced] in those same patients who were having radiation dermatitis,” Dr. Jagsi noted during her presentation.
Most radiation dermatitis and acute chest wall toxicities were grade 2 in each arm.
“We need to be mindful of introducing new techniques and try to identify which patients might be at higher risk [for experiencing acute toxicity],” Dr. Jagsi said when presenting an image of a patient on the trial who developed radiation-induced lichenoid dermatitis.
Additionally, patients in the olaparib and radiotherapy arm were found to be more likely to experience any-grade gastrointestinal toxicity (45.2%) than those in the radiotherapy-alone arm (26.0%; P = .025), as well as laboratory investigation abnormalities (19.2% vs 0%; P < .001).
Cross-Trial Comparisons
During her presentation, Dr. Jagsi put these results into the context of other similar studies, explaining that the results of SWOG 1706 are consistent with that of the U.S.-based trials of veliparib and rucaparib with radiotherapy.4 However, the findings contrasted with the results of the small, French RADIOPARP trial, which she said used much higher doses of olaparib (200 mg twice daily) and different radiotherapy techniques.3 Updated findings from the RADIOPARP study, also presented at the ASTRO Annual Meeting, showed that no grade 3 or higher toxicities were observed through 5 years.5 At 5 years, grade 2 skin toxicities were reported in 25% of patients.
“Differences in these findings likely reflect differences in radiation dose targets and techniques across these studies,” Dr. Jagsi suggested during her presentation, stressing that SWOG 1706 included a very high–risk patient population, necessitating the bolus radiation.
She also pointed to the OlympiA trial of adjuvant olaparib in patients with high-risk early-stage breast cancer with germline pathogenic BRCA variants, in which grade 3 or higher adverse events were rare.6 However, in this study, olaparib was administered after the patients completed local therapy, which included radiotherapy.
“What this study suggests is that as PARP inhibitors become more commonly used, there should be continued caution, particularly for considering concurrent administration during radiotherapy outside of the investigational context,” Dr. Jagsi concluded during her presentation.
DISCLOSURE: Dr. Jagsi has received research and grant compensation from the National Institutes of Health, Doris Duke Charitable Foundation, Komen Foundation, and the American Cancer Society. She also reported stock options from Equity and a leadership role with JAMA Oncology.
REFERENCES
1. Jagsi R, Meisner A, Chalasani P, et al: Acute toxicity in SWOG 1706, a randomized trial comparing radiotherapy for inflammatory breast cancer with or without concurrent olaparib. ASTRO Annual Meeting 2025. Abstract 258. Presented September 29, 2025.
2. Meattini I, Becherini C, Caini S, et al: International multidisciplinary consensus on the integration of radiotherapy with new systemic treatments for breast cancer: European Society for Radiotherapy and Oncology (ESTRO)-endorsed recommendations. Lancet Oncol 25:E73-E83, 2024.
3. Loap P, Loirat D, Berger F, et al: Concurrent olaparib and radiotherapy in patients with triple-negative breast cancer: The phase 1 olaparib and radiation therapy for triple-negative breast cancer trial. JAMA Oncol 8:1802-1808, 2022.
4. Jagsi R, Griffith KA, Bellon JR, et al: Concurrent veliparib with chest wall and nodal radiotherapy in patients with inflammatory or locoregionally recurrent breast cancer: The TBCRC 024 phase I multicenter study. J Clin Oncol 36:1317-1322, 2018.
5. Loap P, Loirat D, Stern MH, et al: 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. ASTRO Annual Meeting 2025. Abstract 262. Presented September 29, 2025.
6. Tutt ANJ, Garber JE, Kaufman B, et al: Adjvuant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 384:2394-2405, 2021.
