Sequence-specific pharmacokinetic and pharmacodynamic phase I/Ib study of olaparib tablets and carboplatin in women's cancer

 

at·ten·u·at·ed

əˈtenyəˌwādəd/ adjective adjective: attenuated

1. unnaturally thin.

   "she was a drooping, attenuated figure"

   • weakened in force or effect.

     "Roman influence became attenuated"

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abstract:
Sequence-specific pharmacokinetic and pharmacodynamic phase I/Ib study of olaparib tablets and carboplatin in women's cancer | Clinical Cancer Research

Purpose: Our preclinical studies showed the PARP inhibitor, olaparib prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic/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, days1-7) in a 3+3 dose escalation with carboplatin AUC4 or 5 q21 days, up to eight cycles, followed by olaparib maintenance. Patients were randomized to starting schedule: cohort A (olaparib days1-7, carboplatin on day8) or B (carboplatin on day1, olaparib days2-8) 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 statistically 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.