Abstract CT124: Evaluation of rucaparib in Japanese patients (pts) with a previously treated advanced solid tumor

Abstract

Abstract Background: The PARP inhibitor rucaparib is approved in the US for pts with recurrent ovarian or metastatic castration-resistant prostate cancer. This phase 1 study (NCT03499444) evaluated safety, pharmacokinetics (PK), and antitumor activity (per RECIST v1.1) of rucaparib in Japanese pts. Methods: Pts were enrolled in a 3+3 dose-escalation phase to establish the recommended dose (RD) in Japanese pts; dose-limiting toxicities (DLTs) were assessed in the first 21 days. Pts must have had an advanced solid tumor that had progressed on standard treatment. A dose-expansion phase enrolled pts at the RD to further assess safety, PK, and efficacy. Results: The visit cutoff was Oct 20, 2020; 29 pts received rucaparib, including 15 in the dose-escalation phase (400 mg BID, n=3; 500 mg BID, n=6; and 600 mg BID, n=6) and 14 in the dose-expansion phase at the RD of 600 mg BID. Median (range) time on treatment was 5.1 (1.3-16.4) months overall and 5.3 (1.4-16.4) months for 600 mg BID pts (n=20).One DLT was reported (treatment interruption >7 days due to grade 1/2 nausea, vomiting, diarrhea, fatigue; 500 mg BID cohort). Across all doses, the most frequent any-grade treatment-emergent adverse events (TEAEs) were alanine aminotransferase/aspartate aminotransferase increased (82.8%), anemia (82.8%), and nausea (69.0%); the most frequent grade ≥3 TEAE was anemia (51.7%). Among 600 mg BID pts, 25.0% (5/20) had a TEAE leading to treatment interruption or dose reduction, most commonly due to anemia (20.0%; 4/20).Steady-state PK was evaluated for the 400, 500, and 600 mg BID cohorts (Table).Most pts with measurable disease had a best response of stable disease (63.0%; 17/27); the confirmed objective response rate was 18.5% (5/27) overall and 21.1% (4/19) among 600 mg BID pts (Table).Conclusions: Rucaparib 600 mg BID had a manageable safety profile for Japanese pts with advanced solid tumors, with a PK profile similar to that of Western pts. These results support further exploration of rucaparib in Japanese pts. 400 mg BID(n=3)500 mg BID(n=6)600 mg BID(n=20)Overall(N=29)Baseline characteristicsAge, median (range), years67.0 (45.0-68.0)61.5 (44.0-73.0)59.5 (43.0-74.0)61.0 (43.0-74.0)Female, n (%)3 (100)6 (100)16 (80.0)25 (86.2)ECOG PS 0, n (%)a3 (100)4 (66.7)15 (75.0)22 (75.9)Tumor type, n (%)Ovarian2 (66.7)1 (16.7)9 (45.0)12 (41.4)Primary peritoneal1 (33.3)2 (33.3)2 (10.0)5 (17.2)Pancreatic004 (20.0)4 (13.8)Breast02 (33.3)1 (5.0)3 (10.3)Other01 (16.7)4 (20.0)5 (17.2)Steady-state PK dataCmax, mean (CV%), ng/mL1,690 (38.7)3,650 (61.9)b2,800 (37.0)cNCtmax, median (range), h1.48 (1.47-2.45)3.95 (2.47-9.95)b2.50 (0.93-9.83)cNCCmin, mean (CV%), ng/mL1,590 (38.7)2,380 (78.5)2,130 (44.4)NCAUClast, mean (CV%), h × ng/mL14,400 (36.6)30,200 (64.7)b23,800 (39.9)cNCCL/F, mean (CV%), L/h26.1 (45.2)22.1 (68.5)d24.3 (34.6)eNCAUC0-12, mean (CV%), h × ng/mL17,200 (35.8)33,900 (78.9)d28,100 (40.8)eNCEfficacy dataORR, n/N (%) [95% CI]1/3 (33.3) [0.8-90.6]0/5 (0) [0.0-52.2]4/19 (21.1) [6.1-45.6]5/27 (18.5) [6.3-38.1]aAll other pts had ECOG PS 1.bn=5.cn=18.dn=3.en=13.AUC0-12, area under the concentration-time curve up to 12 h; AUClast, area under the concentration-time curve up to last time point (10 h) with a quantifiable concentration; CL/F, apparent total clearance of drug after oral administration; Cmax, maximum concentration; CV, coefficient of variation; ECOG PS, Eastern Cooperative Oncology Group performance status; NC, not calculated; ORR, objective response rate; PK, pharmacokinetics; tmax, time to maximum concentration. Citation Format: Kenji Tamura, Koji Matsumoto, Kan Yonemori, Kosei Hasegawa, Jenn Habeck, Eric Jones, Jim Xiao, Aaron Enke, Keiichi Fujiwara. Evaluation of rucaparib in Japanese patients (pts) with a previously treated advanced solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT124.