Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer

Abstract

Purpose Our preclinical studies showed that the PARP inhibitor, olaparib prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic (PK/PD) effects, safety and activity of the combination. Patients and Methods Eligible patients had metastatic or recurrent women’s cancer. Olaparib tablets were introduced (100 or 200mg bid, days 1-7) in a 3+3 dose escalation with carboplatin AUC4 or 5 q21 days, up to eight cycles, followed by olaparib 300mg bid maintenance. Patients were randomized to starting schedule: cohort A (olaparib days 1-7, carboplatin on day 8) or B (carboplatin on day 1, olaparib days 2-8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib PK, platinum-DNA adducts, comet assay and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib PK and platinum-DNA adducts. Results 77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200mg bid+carboplatin AUC4 as the MTD. Olaparib clearance was increased ~50% when carboplatin was given 24hr before olaparib. In vitro experiments demonstrated carboplatin pre-exposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum-DNA adducts were not different as a function of the order of drug administration. Responses included 2 CR and 31 PR (46%) with a higher RR in BRCA mutation carriers compared to non-mutation carriers (68% v.19%). Conclusions Tablet olaparib with carboplatin is a safe and active combination. Carboplatin pre-exposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib.

Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women’s cancers

“…Figure 1a depicts the olaparib concentration–time profiles for all patients ( n = 58), encompassing 870 sample points, as well as the near ten-fold inter-patient variability in plasma concentrations. This dataset had noncompartmental PK published along with the clinical trial efficacy and safety [26]. In that report, olaparib apparent oral systemic clearance (CL T / F ; calculated as Dose/AUC INF ) was approximately 50% faster when carboplatin was administered 24 h prior.…”

“…Briefly, eligibility criteria for inclusion on this trial consisted of having recurrent/refractory epithelial ovarian, fallopian, primary peritoneal, uterine papillary serous, malignant mixed Mullerian tumors, or any type of breast cancer (confirmed histologically or cytologically at the NCI). A full list of eligibility criteria and study design can be found in the clinical summary [26]. Patients assigned to Arm A were administered olaparib beginning on cycle 1 day 1 (C1D1) for 7 days with carboplatin treatment beginning on C1D8 of a 21-day cycle.…”

“…Several clinical trials have demonstrated that olaparib monotherapy affords a PFS benefit, especially in a germline BRCA mutated patient population, while having an overall mild adverse event (AE) profile consisting mostly of grade 1–2 nausea (∼32%), fatigue (∼30%), and vomiting (∼20%) [5–13]. Further, numerous trials have combined olaparib with various other agents, including VEGF inhibitors cediranib [14–16] and bevacizumab [17], the anthracycline doxorubicin [18], the topoisomerase inhibitor topotecan [19], paclitaxel [20], and platinum compounds cisplatin [21–23] and carboplatin [24–26]. …”

“…Recently, olaparib was studied as being administered orally in tablet formulation (BID days 1–7) before or after carboplatin in order to identify the optimal sequence for in vivo efficacy and safety [26]. Other study endpoints sought to determine the MTD, which was 200 mg BID olaparib + AUC4 carboplatin, as well as study the pharmacokinetics (PK) and pharmacodynamics (PD) of this sequenced combination.…”

Efficacy of the PARP Inhibitor Veliparib with Carboplatin or as a Single Agent in Patients with Germline BRCA1- or BRCA2-Associated Metastatic Breast Cancer: California Cancer Consortium Trial NCT01149083

“…Intriguing data from a recent study of olaparib and carboplatin indicate sequence specific effects on pharmacokinetics, suggesting that carboplatin should be administered prior to olaparib (43). The addition of veliparib to a combination of carboplatin and paclitaxel is also promising.…”