In a French phase I trial reported in JAMA Oncology, Loap et al found that concurrent olaparib and radiotherapy was well tolerated in patients with triple-negative breast cancer who had incomplete pathologic response or unresectable disease after neoadjuvant chemotherapy. Survival outcomes with the approach were also described.
As stated by the investigators, “Triple-negative breast cancer cells are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining PARP inhibitors with radiotherapy in patients with triple-negative breast cancer would enhance the biological effectiveness of the irradiation and improve locoregional control is unclear.”
Study Details
In the multicenter study, 24 patients enrolled between September 2017 and November 2019 received increasing doses of olaparib at 50 mg, 100 mg, 150 mg, or 200 mg twice daily starting 1 week prior to and continued concurrently with radiotherapy. Radiotherapy after breast-conserving surgery consisted of a total dose of 50.4 Gy to the whole breast, with a 63-Gy simultaneously integrated boost to the tumor bed in patients aged < 60 years.
A total dose of 50.0 Gy was delivered to the chest wall after radical mastectomy or to the whole breast for unresectable tumors despite neoadjuvant chemotherapy. In node-positive disease, regional lymph node stations could be treated with a total dose of 50.0 to 50.4 Gy.
The main outcome measure was safety/tolerability. Event-free survival and overall survival were secondary outcome measures.
Key Findings
Median follow-up was 34 months. No dose-limiting toxicities of olaparib were observed, with dose escalation to 200 mg twice daily occurring without reaching the maximum tolerated dose. Acute non–dose limiting grade 3 or 4 adverse events consisted of grade 3 lymphocele in one patient (4.2%), grade 3 breast pain in one (4.2%), grade 3 radiodermatitis in two (8.3%), grade 3 lymphopenia in eight (33.3%), and grade 4 lymphopenia in three (12.5%).
No late treatment-related grade ≥ 3 toxicity was observed. The maximum grade treatment-related toxicities observed at 2-year follow-up were grade 2 breast pain, fibrosis, and deformity in one patient (4.2%) who had received olaparib at the dose of 100 mg twice daily.
A total of eight patients (33.3%) had disease control failure (at 2, 8, 11, 12, 14, 16, 23, and 28 months, respectively); the first site of disease progression was locoregional in two patients and distant in six. Event-free survival rates at 1, 2, and 3 years were 88%, 71%, and 65%. Overall survival rates at 1, 2, and 3 years were 96%, 83%, and 83%. On univariate analysis, positive nodal status was associated with significantly poorer event-free survival (hazard ratio = 11.4, P = .02). Homologous recombination status was not significantly associated with either event-free or overall survival.
The investigators concluded, “The findings of this phase I dose-escalation trial suggest that PARP inhibition with olaparib concurrently with radiotherapy for early-stage, high-risk triple-negative breast cancer is well tolerated and should continue to be evaluated in further clinical trials.”
Pierre Loap, MD, of the Department of Radiation Oncology, Institut Curie, Paris, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by a grant from AstraZeneca. For full disclosures of the study authors, visit jamanetwork.com.
