Efficacy and Safety Exposure‐Response Analyses of Olaparib Capsule and Tablet Formulations in Oncology Patients

Abstract

Olaparib is a poly ADP-ribose polymerase inhibitor that induces synthetic lethality in tumors with deficient homologous recombination repair. Population exposure-response analyses were performed to evaluate the efficacy and safety of olaparib exposure in patients with cancer. Data from multiple phase I/II/III clinical studies from both capsule and tablet formulations were combined for efficacy (N = 410) and safety (N = 757) analyses. Exposureprogression-free survival (Cox proportional hazards model indicated that a 300 mg b.i.d. tablet was statistically superior to the 200 mg b.i.d. tablet dose (hazard ratio of 0.96), although the difference was small. Exposure-safety logistic regression models and hemoglobin models predicted similar probability of safety events or hemoglobin decrease with largely overlapping 95% confidence intervals at 300 mg b.i.d. tablet, 200 mg b.i.d. tablet, and 400 mg b.i.d. capsule. The analyses provided key assessments to support the approval of olaparib 300 mg tablet therapeutic dose in patients with ovarian and breast cancer, regardless of their breast cancer (BRCA) mutation status.Poly (ADP-ribose) polymerases (PARPs) are a family of related enzymes that play an important role in various cellular processes. 1 In tumor cells that lack functional components of homologous recombination repair (such as mutations in breast cancer (BRCA1 and BRCA2), DNA double-strand breaks cannot be repaired accurately or effectively and will result in tumor cell death. 2 Olaparib (Lynparza, AstraZeneca, Cambridge, UK) is a first-inclass oral PARP inhibitor. 2 The olaparib capsule formulation was first marketed in 2014 and has received marketing approval for the treatment of patients with BRCA mutated ovarian cancer in more than 50 countries, including those in the European Union, the United States, Switzerland, Australia, and Canada. The recommended capsule dose is 400 mg b.i.d. The olaparib tablet formulation 3 has subsequently received marketing approval for the treatment of patients with relapsed ovarian cancer in the European Union,

Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment

“…In this study, we found a 13% increase and 13% decrease in olaparib C max and a 15% and 8% increase in olaparib AUC seen in patients with mild or moderate hepatic impairment, respectively, vs those with normal hepatic function; these variations in olaparib exposure were not considered clinically relevant 19,20 . Variation in olaparib exposure was notable in the moderate hepatic impairment group; however, this was largely because of 1 patient who had increased exposure to olaparib (indicated by AUC 0–t and C max values; see the Supplementary Materials for further information on this patient).…”

Pharmacokinetics and Safety of Olaparib in Patients with Advanced Solid Tumours and Renal Impairment

“…Population pharmacokinetic-pharmacodynamic simulations have suggested that for patients with an AUC > 100 µg h/mL, a clinically significant decrease in haemoglobin may occur, particularly in patients with low baseline haemoglobin. This study has demonstrated that some patients with moderate renal impairment had very high exposure to olaparib (five patients had an AUC > 100 μg h/mL) compared with the mean exposure to olaparib for patients with normal renal function (43.7 μg h/mL) [12]. Patients with very high exposure to olaparib may experience reduced haemoglobin levels and therefore a risk of developing anaemia.…”

“…Population pharmacokinetic-pharmacodynamic analyses of 410 patients with ovarian cancer with normal renal function or mild renal impairment evaluated the efficacy (progression-free survival) of olaparib tablets at 300 mg bid and 200 mg bid. The exposure-progression-free survival, Cox proportional hazards model indicated that the 300-mg bid tablet dose was statistically superior to the 200-mg bid tablet dose, although the difference was numerically small [12].…”

“…Overall, the analyses performed according to the new criteria did not impact on the dosing recommendations derived from the original analysis. Based on the potential for increased exposure (AUC) in patients with moderate renal impairment, these patients should be carefully monitored, particularly for haematological toxicities [12], and the tablet dose should be adjusted to 200 mg bid (2 × 100 mg).…”

“…Population pharmacokinetic-pharmacodynamic analyses of olaparib in a patient population showed a significant exposure-safety relationship with the haemoglobin level, where increased exposure to olaparib was associated with a reduction in the haemoglobin level [12]. Population pharmacokinetic-pharmacodynamic simulations have suggested that for patients with an AUC > 100 µg h/mL, a clinically significant decrease in haemoglobin may occur, particularly in patients with low baseline haemoglobin.…”