Concurrent Olaparib and Radiotherapy in Patients With Triple-Negative Breast Cancer: The Phase 1 Olaparib and Radiation Therapy for Triple-Negative Breast Cancer Trial

Abstract

Importance: Triple-negative breast cancer (TNBC) cells are sensitive to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining PARP inhibitors with radiotherapy in patients with TNBC would enhance the biological effectiveness of the irradiation and improve locoregional control is unclear.

Objective: To assess the safety and tolerability of PARP inhibition with olaparib used concurrently with radiotherapy in patients with TNBC with residual disease after neoadjuvant chemotherapy.

Design, setting, and participants: This phase 1 prospective dose-escalation trial (Olaparib and Radiation Therapy for TNBC [RadioPARP] trial) using a time-to-event continual reassessment method was performed from September 2017 to November 2019, with follow-up until November 2021. Participants had an incomplete pathologic response after neoadjuvant chemotherapy or unresectable TNBC despite previous neoadjuvant chemotherapy, an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, and adequate organ functions.

Interventions: Olaparib was administered orally in the form of tablets and given at increasing doses (50 mg, 100 mg, 150 mg, or 200 mg twice daily). Olaparib therapy was started 1 week before radiotherapy and was continued concomitantly with radiotherapy. After breast-conserving surgery, a total dose of 50.4 Gy was delivered to the whole breast, with a 63-Gy simultaneously integrated boost to the tumor bed for patients younger than 60 years. After radical mastectomy or for unresectable tumors despite neoadjuvant chemotherapy, a total dose of 50.0 Gy was delivered to the chest wall (after mastectomy) or to the whole breast (for unresectable tumors). Regional lymph node stations could be treated with a total dose of 50.0 Gy to 50.4 Gy in cases of node-positive disease.

Main outcomes and measures: Main outcomes were the safety and tolerability of PARP inhibition with radiotherapy for early-stage, high-risk TNBC. Secondary outcomes included overall survival (OS) and event-free survival (EFS).

Results: Among the 24 patients included in the trial (100% female; median age, 46 years [range, 25-74 years]), no dose-limiting toxic effects were observed, and olaparib was escalated to 200 mg twice daily without reaching the maximum tolerated dose. No late treatment-related grade 3 or greater toxic effect was observed, and the maximum observed treatment-related toxic effects at the 2-year follow-up were grade 2 breast pain, fibrosis, and deformity in 1 patient (4.2%). Three-year OS and EFS were 83% (95% CI, 70%-100%) and 65% (95% CI, 48%-88%), respectively. Homologous recombination status was not associated with OS or EFS.

Conclusions and relevance: The findings of this phase 1 dose-escalation trial suggest that PARP inhibition with olaparib concurrently with radiotherapy for early-stage, high-risk TNBC is well tolerated and should continue to be evaluated in further clinical trials.

Trial registration: ClinicalTrials.gov Identifier: NCT03109080.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Loirat reported receiving an honorarium and travel support from Pfizer and AstraZeneca outside the submitted work. Dr Berger reported receiving grants from AstraZeneca during the conduct of the study. Dr Rodrigues reported receiving personal fees from AstraZeneca, MSD, and GSK outside the submitted work. Dr Pierga reported receiving personal fees from AstraZeneca during the conduct of the study. Dr Vincent-Salomon reported receiving grants from IBEX Technologies and AstraZeneca and receiving personal fees from Roche outside the submitted work. Dr Mosseri reported receiving grants from AstraZeneca during the conduct of the study. Dr Diallo reported receiving grants from AstraZeneca during the conduct of the study. Dr Stern reported having a patent with royalties paid regarding the signature of homologous recombination deficiency licensed to Myriad Genetics. Dr Fourquet reported receiving grants from AstraZeneca during the conduct of the study. No other disclosures were reported.

Figures

Figure.. Event-Free Survival and Overall Survival Among the 24 Patients Included in the Trial

Event-free survival was defined from the time of enrollment to local or metastatic relapse or death from any cause. Overall survival was defined from the time of enrollment to death from any cause.