RADIOPARP Phase I Trial Evaluating Olaparib with Radiation Therapy for Triple Negative Breast Cancer Demonstrates Acceptable Toxicity Profile with Zero Grade 3+ Adverse Events

By Neil Pfister, MD, PhD, Assistant Professor of Radiation Oncology, University of Alabama at Birmingham

Presenting author: Pierre Loap, MD, MS

Poly(ADP-ribose) polymerase (PARP) inhibitors have been shown in preclinical data to enhance the effect of radiation therapy on tumor control and are among the most promising classes of molecularly-targeted agents to be administered concurrently with radiation therapy. PARP inhibitors are also utilized as antineoplastic agents to suppress locally advanced and metastatic disease. The toxicity risks due to combining radiation therapy and PARP inhibitors are poorly understood, which may lead to unnecessary suspension of systemic therapy during radiation therapy.

The RADIOPARP phase I trial investigated the safety profile of PARP1 inhibitor Olaparib in combination with 50 Gy of ionizing radiation to the breast or chest wall. Twenty-four patients with locoregionally advanced or metastatic triple negative breast cancer were enrolled. Olaparib was orally administered at increasing dose levels (50mg, 100mg, 150mg or 200mg twice a day) and was effectively escalated to 200 mg twice a day without dose limiting toxicities. Radiation therapy consisted of 50 Gy to the breast or chest wall with or without lymph node irradiation.

At one-year follow-up, no treatment-related grade ≥3 toxicities were observed. There were three persistent grade 2 adverse events (one each of breast pain, fibrosis and deformity). No cardiac, pulmonary or digestive toxicities were identified. The authors conclude that “the one-year toxicity evaluation report of the RADIOPARP phase I trial, evaluating Olaparib associated with breast radiotherapy in triple negative breast cancer patients, demonstrated an excellent late tolerance profile of this combination with few grade 2 skin toxicity and no grade ≥3 treatment-related adverse events." It remains possible that rare, higher grade toxicities may manifest in larger patient cohorts. RADIOPARP provides important clinical data that PARP inhibitors may be continued safely during treatment with therapeutic radiation.

Lead author Pierre Loap, MD, MS, offers the following perspective: "In a metastatic context, suspension of Olaparib during irradiation by fear of adverse events might not be justified but may ultimately hamper tumoral control. Targeted treatments should not be systematically interrupted during radiotherapy."

Molecularly targeted therapies are predicted to affect tumor and normal tissue response to irradiation, however clinical data are scant. The RADIOPARP trial contributes to the body of literature supporting the safety of continuing targeted therapies during radiation therapy. Future radiation oncologist-led investigations should continue to investigate ionizing radiation and targeted molecular agents across molecularly defined tumor subtypes.

Abstract 14 - One-Year Toxicity Report of the RADIOPARP Phase I Trial Evaluating Olaparib With Radiotherapy for Triple Negative Breast Cancer was presented on October 24, 2021, during the SS 01 – Breast session, Techniques and Toxicity.

Published October 26, 2021

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