Abstract CT326: Pharmacokinetic/pharmacodynamic study of sequence specificity of the PARP inhibitor, olaparib and carboplatin in recurrent women's cancers
Authors: Chiou Victoria L. , Annunziata Christina , Lipkowitz Stanley , Minasian Lori , Gordon Nicolas , Yu Minshu , Steinberg Seth , Houston Nicole , Kohn Elise , Lee Jung-min 
Published: August 2015

Abstract
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 women's 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 1&2 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&lt;0.05). Intra-pt and inter-cohort comparisons show no significant differences in DNA DSBs, PAR incorporation and frequencies of Gr3/4 AEs as a function of the order of the schedule. Gr3/4 AEs included neutropenia (22%), anemia (12%), thrombocytopenia (10%), and carboplatin hypersensitivity (3%). Responses (54pts) included 1 CR (2%, 23mo; TNBC) and 23 PR (43%, 9[5-15]mo; 20 OvCa/3 TNBC). gBRCAm+ pts had a higher response rate (RR; 1CR/19 PR) compared to BRCAwt/unknown (4 PR; 65% v. 17%, p&lt;0.001).
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 women's cancers, especially for gBRCAm+ pts. (NCT01237067)
Treatment schedule armsCycle (cyc) 1Cyc 2Cyc 3-8Cyc 9+Arm AO tablet 200mg bid d1-7⇒C AUC4 d8C AUC4 d1⇒O tablet 200mg bid d2-8O tablet 200mg bid d1-7, C AUC4 d1or2maintenance O tablet 300mg bid
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 women's 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