Pharmacokinetic/Pharmacodynamic Study Of Sequence Specificity Of The Parp Inhibitor, Olaparib And Carboplatin In Recurrent Women'S Cancers

Background: Olaparib/carboplatin are active in gBRCA1/2m+ or BRCA-like breast and ovarian cancer (Br/OvCa). Our in vitro data suggest that pretreatment with olaparib before carboplatin attenuates C-induced DNA double stranded breaks (DSBs) and cytotoxicity. We hypothesize olaparib/carboplatin sequence may affect DNA DSBs and toxicity in pts. Methods: Eligible pts had recurrent women9s cancers, normal end-organ function, and evaluable disease. Pts were randomized to arm A or B for intra-pt and inter-cohort analysis of PK/PD endpoints. 21 pts were required per arm for 80% power to determine one SD difference between arms. PBMCs were collected prior to and 24hrs after olaparib or carboplatin on cyc 1u00262 for comet DNA damage assay and PAR incorporation ELISA. Toxicity was evaluated q3 wks, and response q2 cyc by RECISTv1.1. Results: 59 women (age 59 [25-74]; 47 OvCa (26 gBRCAm+)/10 triple negative BrCa [TNBC; 4 gBRCAm+]/1 uterine carcinosarcoma/1 endometrial Ca) were treated. All had prior therapy (median 5[2-14]). Intra-pt comparisons of PD endpoints indicated olaparib/carboplatin yields greater DNA DSBs than olaparib or carboplatin alone (median fold change compared to baseline; 1.21+/- 0.30 SD v. 1.13 or 0.97 [arm A], 1.33 +/- 0.67 SD v. 1.02 or 1.04 [arm B], both p Conclusions: Combination O/C induced greater DNA damage than single agents, consistent with the higher than expected RR. However, the O/C sequence did not impact DNA damage, PAR incorporation or toxicity. Olaparib tablets 200mg bid x 7d with carboplatin AUC 4 q 21d is active and tolerable in recurrent women9s cancers, especially for gBRCAm+ pts. (NCT01237067) Citation Format: Victoria L. Chiou, Christina Annunziata, Stanley Lipkowitz, Lori Minasian, Nicolas Gordon, Minshu Yu, Seth Steinberg, Nicole Houston, Elise Kohn, Jung-min Lee. Pharmacokinetic/pharmacodynamic study of sequence specificity of the PARP inhibitor, olaparib and carboplatin in recurrent women9s cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT326. doi:10.1158/1538-7445.AM2015-CT326