Safety of Approved Rucaparib Starting Dose Confirmed from Pooled Analysis

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The goal of the analysis was to evaluate correlations between pharmacokinetic exposure and clinical parameters in patients with recurrent ovarian cancer receiving rucaparib (Rubraca). Rucaparib exposure was dose proportional and not associated with baseline platelet counts or patient weight.

Among patients enrolled in Study 10 (a phase 1/2 study of oral rucaparib in patients with a solid tumor or with germline BRCA-mutated ovarian cancer) and ARIEL2 (a phase 2 study of rucaparib in patients with platinum-sensitive, relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer), in which patients received 40 mg a day to 840 mg twice-daily starting dosages, “rucaparib was well tolerated overall,” with high Cmax associated with more frequent adverse events, according to data presented by Gottfried E. Konecny, MD, Lead Clinician, Gynecologic Oncology, University of California Los Angeles, and colleagues in a poster during the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.

In Study 10, 56 patients in part 1 received escalating doses of oral rucaparib (40-500 mg once daily and 240-840 mg twice daily), and 42 patients with germline BRCA1/2-mutated high-grade ovarian cancer received 600 mg twice daily.

In ARIEL2, 204 patients began treatment with oral rucaparib at 600 mg twice daily for continuous 28-day cycles until disease progression or study discontinuation.

Researchers sought to evaluate the side effects associated with exposure to rucaparib, using a published population pharmacokinetic model to estimate the actual dose-normalized average steady-state area under the plasma drug concentration-time curve (AUCss) and Cmax. Safety was evaluated in patients who received ≥1 rucaparib dose, and efficacy was assessed in patients who had a deleterious BRCA mutation or who had loss of heterozygosity-high tumors.

“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,” reported Dr Konecny.

Cmax was significantly correlated with grade ≥2 increases in serum creatinine concentration and grade ≥3 increases in the levels of alanine aminotransferase and aspartate transaminase, 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 the 75 patients with platinum-sensitive disease (P = .017), but not in the 27 patients with platinum-resistant recurrent ovarian cancer who had received ≥2 previous lines of chemotherapy (P = .661).

Researchers concluded that the analysis supported the approved rucaparib starting dose of 600 mg twice daily with dose reductions if necessary due to treatment-emergent side effects.

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