ESTRO 2020 Abstract book

S260 ESTRO 2020

Material and Methods We included PK/PD samples of all NSCLC and breast cancer patients treated at olaparib doses up to 50mg bi-daily (BID) in two phase 1 trials combining radical radiotherapy with olaparib. Plasma samples were collected for PK, peripheral blood mononuclear cells (PBMCs) for PD (pre-treatment, +3/12/24hrs after olaparib intake). Breast cancer tumor biopsies were taken pre-treatment and during olaparib treatment (+3hrs after intake) before radiotherapy. Olaparib concentrations were determined by HPLC-MS/MS. PAR levels were determined by commercially available ELISA, following the NCI protocol and REP assay (de Haan et al, 2017) that includes ex vivo irradiation of intact cells to activate PARylation by PARP. PAR level inhibition was based on REP assay values. Results PK/PD data from blood samples were available from 28 NSCLC patients and 7 breast cancer patients (17 treated at olaparib 25mg once daily (QD), 14 at 25mg BID and 4 at 50mg BID). Repeat biopsies were available from six out of seven breast cancer patients. Plasma olaparib concentrations increased with olaparib dose and showed an expected wide intra-patient variation. Tumor olaparib concentration varied (178-1441ng/g) with a median tumor to plasma ratio of 0.47. PD analyses demonstrate a significant reduction in PAR levels in PBMCs during olaparib treatment (>95% at +3hrs after olaparib intake for all dose levels, >90% at +12hrs in the 25mg BID dose level and 66-99% at +24hrs in the 25mg QD dose level; all p<0.0001). In pre-treatment samples, ex vivo radiation induced PAR levels by 66-fold (range 23- 174). This radiation induced PARylation was abolished during olaparib treatment. Compared to corresponding pre-treatment PBMC samples, PAR levels in pre-treatment tumor biopsy samples were higher in all but one patient (median 7-fold, range 0.6-60), and ex vivo radiation induced PARylation was lower (only 1.5-fold). Also, in tumors, olaparib abolished radiation induced PARylation. PAR levels were reduced by 89% (range 83-99.7%, Olaparib doses as low as 25mg once and twice daily inhibit PARP activation by irradiation and reduce PAR levels >95% in PBMCs and >83% in tumors, thereby showing biological effectivity. The tumor olaparib concentrations determined in this study were all within a range that has been shown to radiosensitize in preclinical models. Together this supports further development of PARP inhibitors as radiosensitizer at low doses. OC-0439 Quantifying the benefit of online adaptive radiotherapy for rectal cancer compared to plan selection R. De Jong 1 , J. Visser 1 , K. Crama 1 , N. Van Wieringen 1 , J. Wiersma 1 , D. Geijsen 1 , A. Bel 1 1 Amsterdam UMC, Radiation Oncology, Amsterdam, The Netherlands Purpose or Objective To assess the added value of online adaptive radiotherapy (online ART) for rectal cancer, by comparing online ART to a clinically implemented plan selection strategy (PS) and quantifying the benefit in terms of target coverage and dose to the organs at risk (OAR). p<0.0001). Conclusion

Material and Methods For this study Conebeam CT (CBCT) scans of the first 20 consecutive patients treated with PS between May and September 2016 were included. New dual arc VMAT plans were generated using auto planning (Plan Explorer, Raystation) for both the online ART and the PS strategy. - For the PTV of the PS strategy the ventral margins were variable for the CTV of the upper part of the mesorectum, the remaining CTV had fixed population based margins. - The PTV margin for online ART was a 3mm expansion of the entire CTV in all directions. For each fraction bowel bag, bladder and mesorectum were delineated on the daily CBCT. The dose distribution planned was used to calculate daily DVHs for both PS and online ART (Figure 1). We calculated coverage as the percentage of the prescribed dose received by 99% of the CTV volume (D99%). We calculated the volume of normal tissue irradiated with 95% of the prescribed dose per fraction by calculating the difference of the volume receiving 95% of the prescribed dose minus the volume of the CTV and the volume of different DVH parameters on the OARs per fraction (V15Gy, V30Gy, V40Gy, V45Gy, V95% and Dmean).