ESTRO 2020 Abstract Book

S241 ESTRO 2020

Results Median follow up was 51 months for 1318 pats (98 pts excluded: incorrect selection, no data, no follow up). FIGO 2009 stage distribution was IB 241 (18%) (IB2 118), IIA 67 (5%), IIB 683 (52%), IIIA 13 (1%), IIIB 183 (14%), IVA 34 (3%), IVB 97 (7%). 686 (52%) were node-positive (N+). 1080 (82%) had squamous Ca, 188 (14%) adeno, 49 (4%) adenosquamous. Mean EBRT dose was 46±2Gy. 95% received cisplatin. IGABT technique was intracavitary (IC) in 57% and IC/interstitial (IS) in 43%. Mean CTV HR volume was 33±19 cm 3 . Mean CTV HR D 90% was 89±9Gy 10 , for stage IIIB 87±8 Gy 10 , IVA 83±10Gy 10 . Mean D 2cm³ for bladder was 76±10Gy 3 , rectum 63±7Gy 3 , sigmoid 64±7Gy 3 , bowel 63±10Gy 3, rectovaginal point 66±9Gy 3 . Overall 331 pts had recurrence (multiple events possible) - local 98, pelvic lymph nodes 89 (overall pelvis 164), PAN 106. 184 pts had recurrence beyond PAN. At the time of analysis, 363 pts had died, 281 from disease progression. At 5 years, LC was 92%, PC 87%, DC 74%, OS 74%, DFS 68% (table 1a, figure 1). For IIIB disease, 5-year LC was 91%, PC 85%, OS 64%, for IVA LC was 91%, PC 81%, OS 52%. 3/5-year OS was 87/81% for N- pts and 76/67% for N+ pts. Crude G3-5 morbidity at 5 years was genito-urinary 6.5% (n=81), gastro-intestinal 7.6% (n=95), vagina 6.1% (n=76). Conclusion MRI-based IGABT in combination with chemo-RT results in excellent and stable long-term local, pelvic, disease control and survival across all stages with limited serious morbidity. These results compare overall favourably with RetroEMBRACE, especially for advanced disease (compare table 1a and 1b) and should be used as the benchmark for routine clinical practice as well as for design of future clinical trials. The results will also provide the frame for further EMBRACE related analyses.

OC-0438 Clinical pharmacodynamics support biological effectivity of low dose olaparib as radiosensitizer R. De Haan 1 , D. Pluim 2 , M. Verwijs 1 , G. Sonke 3 , M. Van den Heuvel 4 , B. Van Triest 1 , C. Vens 5 , M. Verheij 1 1 Netherlands Cancer Institute, Radiotherapy, Amsterdam, The Netherlands ; 2 Netherlands Cancer Institute, Pharmacology, Amsterdam, The Netherlands ; 3 Netherlands Cancer Institute, Medical Oncology, Amsterdam, The Netherlands ; 4 Netherlands Cancer Institute, Thoracic Oncology, Amsterdam, The Netherlands ; 5 Netherlands Cancer Institute, Cell Biology, Amsterdam, The Netherlands Purpose or Objective Poly ADP-ribose polymerase (PARP) inhibitors are promising radiosensitizers. Currently identified recommended phase II PARP inhibitor doses in combination with radiotherapy are 10-fold lower than the EMA/FDA approved dose as single agent. The purpose of this study is to investigate the biologically effective dose range of olaparib for its use as radiosensitizer by assessing pharmacokinetics (PK) and pharmacodynamics (PD). We therefore assessed the inhibition of pre-treatment poly ADP ribose (PAR) levels and the prevention of radiation induced PARylation. 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.