Radioparp: A phase I of olaparib with radiation therapy (RT) in patients with inflammatory, locoregionally advanced or metastatic triple-negative breast cancer (TNBC) or patient with operated TNBC with residual disease—Preliminary results.

Abstract

571 Background: Preclinical studies have shown that cell lines and murine models of TNBC phenotype are more sensitive to PARP1 inhibitors. This evidence provides strong rationale for developing a new therapeutic approach to TNBC based on targeting the DNA-repair defects via PARP inhibition. Methods: The purpose of this study was to report the Maximal Tolerated Dose (MTD) of Olaparib (O) administered concurrently with locoregional RT and evaluate the Dose-Limiting Toxicity (DLT). Results: Twenty-four pts with performance status 0-1 were enrolled between 09/2017 and 11/2019. Of them, 21 underwent adjuvant RT-O because poor response to NAC, and 3 received preoperative RT+O because of progression after NAC. The patients’ profile is given in table. All patients received full course RT-O, as following: 4 pts at dose 50mg bid; 8 at 100x2; 7 at 150x2, and 5 at 200x2. No DLT was observed. Two pts (8.7%) experienced acute grade 3 dermatitis no grade 4 toxicities related to the RT were observed. The O-related toxicity was acceptable with mostly grade 1-2 symptoms. The only grade 3-4 hematological toxicity was lymphopenia in 11 cases. Conclusions: Dose of O was escalated to the target dose of 200 mgx2, without DLT. Further follow up is needed to evaluate the late toxicities. Clinical trial information: NCT03109080 . [Table: see text]

Emerging Therapeutic Drugs in Metastatic Triple-Negative Breast Cancer

“…51 The RadioPARP study (NCT03109080) is evaluating the combination of olaparib plus radiation therapy in TNBC. 52…”

In vitro radiosensitization of breast cancer with hypoxia‐activated prodrugs

“…46 Furthermore, regions of hypoxia and necrosis are higher in ER negative tumours, which is associated with local recurrence, radiotherapy resistance and higher rates of metastasis observed in this phenotype. 47,48 In the current study, the radiosen- 49 The increased cytotoxicity in TNBC cell lines may be because of shared characteristics with BRCA-1 deficient tumours, commonly known as sporadic BRCAness. 50 TNBCs may be susceptible to DNA repair inhibitors because these tumours have lower expression of BRCA-1/2 or of genes involved in DNA repair pathways.…”

“… 47 , 48 In the current study, the radiosensitivity obtained with KP167 in the triple negative MDAMB‐231 (SER 0.01 2.53), MDAMB‐468 (SER 0.01 2.28) and MDAMB‐436 (SER 0.01 4.55) spheroids were greater than that obtained with well‐established radiosensitisers such as KU‐55933 (SER 0.01 1.82‐MDAMB‐231, 1.68‐MDAMB‐468, 3.42‐MDAMB‐436) and Olaparib with SER 0.01 of (1.62‐MDAMB‐231, 1.68‐MDAMB‐468, 2.35‐MDAMB‐436), with the latter trialled as a radiosensitiser in the RadioParp trial (NCT03109080). 49 The increased cytotoxicity in TNBC cell lines may be because of shared characteristics with BRCA‐1 deficient tumours, commonly known as sporadic BRCAness. 50 TNBCs may be susceptible to DNA repair inhibitors because these tumours have lower expression of BRCA‐1/2 or of genes involved in DNA repair pathways.…”

“…Furthermore, regions of hypoxia and necrosis are higher in ER negative tumours, which is associated with local recurrence, radiotherapy resistance and higher rates of metastasis observed in this phenotype 47,48 . In the current study, the radiosensitivity obtained with KP167 in the triple negative MDAMB‐231 (SER 0.01 2.53), MDAMB‐468 (SER 0.01 2.28) and MDAMB‐436 (SER 0.01 4.55) spheroids were greater than that obtained with well‐established radiosensitisers such as KU‐55933 (SER 0.01 1.82‐MDAMB‐231, 1.68‐MDAMB‐468, 3.42‐MDAMB‐436) and Olaparib with SER 0.01 of (1.62‐MDAMB‐231, 1.68‐MDAMB‐468, 2.35‐MDAMB‐436), with the latter trialled as a radiosensitiser in the RadioParp trial (NCT03109080) 49 . The increased cytotoxicity in TNBC cell lines may be because of shared characteristics with BRCA‐1 deficient tumours, commonly known as sporadic BRCAness 50 .…”