Researchers evaluated the connections between safety and efficacy and rucaparib pharmacokinetic exposure in patients with recurrent ovarian cancer.
In patients with recurrent ovarian carcinoma, pooled data from 2 clinical trials confirmed the safety of rucaparib at the recommended starting dose of 600 mg, with subsequent dose reductions after the occurrence of any treatment-emergent adverse events. These findings were presented in a poster by Gottfried E. Konecny, MD, lead clinician for gynecologic oncology in the Department of Medicine at the University of California at Los Angeles, at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.
This study aimed to evaluate the correlations between rucaparib pharmacokinetic exposure and safety/efficacy in patients with recurrent ovarian cancer using data from Study 10 (a study of oral rucaparib in patients with a solid tumor or with germline BRCA-mutated ovarian cancer) and ARIEL2 (a study of rucaparib in patients with platinum-sensitive, relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer).
In phase 1, patients received escalating doses of rucaparib followed by the recommended starting dose of 600 mg rucaparib twice per day in phase 2. According to the study authors, a published population pharmacokinetic model was used to estimate the actual dose-normalized average steady-state area under the plasma drug concentration-time curve (AUCss) and Cmax. AUC and Cmax are pharmacokinetic measures that determine the level of exposure to a drug. The researchers sought to evaluate the side effects associated with exposure to rucaparib. AUC is a method to measure absorption of a drug, and Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given.
Safety was evaluated in patients who received ≥1 doses of rucaparib, and efficacy was assessed in patients with a deleterious BRCA mutation or had tumors with high genomic loss of heterozygosity. In this analysis, rucaparib pharmacokinetic exposure was dose-proportional and not associated with baseline patient weight or baseline platelet counts.
In the exposure-safety analysis of 375 patients, most patients received a starting dose of 600 mg twice daily, with 27% and 21% of patients receiving 1 or ≥2 dose reductions, respectively. “Rucaparib was well tolerated overall,” Dr Konecny reported. Cmax was significantly correlated with grade ≥2 serum creatinine increase and grade ≥3 increases in liver enzymes (ALT/AST), platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease.
In the exposure-efficacy analysis of 102 patients with BRCA mutations, AUCss was positively associated with an independent radiologist reviewer–assessed objective response rate in 75 patients with platinum-sensitive disease. However, this was not the case in the 27 patients with platinum-resistant recurrent ovarian cancer who had received ≥2 prior lines of chemotherapy, the investigators reported.
Based on these data, Dr Konecny and colleagues maintain that “high Cmax was associated with more frequent clinical safety events, but was not associated with low patient weight or baseline platelet counts. Additionally, higher rucaparib AUCss was associated with improved independent radiologist reviewer–assessed response in platinum-sensitive, BRCA-mutated recurrent ovarian cancer.”
Source: Konecny G, et al. Gynecol Oncol. 2020;159(1_suppl). Abstract 190.