A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer

Abstract

Purpose: To report the safety and efficacy of ipatasertib (AKT inhibitor) combined with rucaparib (PARP inhibitor) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with second-generation androgen-receptor inhibitors. Patients and Methods: In this two-part phase Ib trial (NCT03840200), patients with advanced prostate, breast, or ovarian cancer received ipatasertib (300 or 400mg daily [QD]) plus rucaparib (400 or 600mg twice daily [BID]) to assess safety and identify a recommended phase 2 dose (RP2D). A Part 1 dose-escalation phase was followed by a Part 2 dose-expansion phase in which only patients with mCRPC received the RP2D. The primary efficacy endpoint was prostate-specific antigen (PSA) response (≥50% reduction) in patients with mCRPC. Patients were not selected on tumor mutational status. Results: Fifty-one patients were enrolled (Part 1=21; Part 2=30). Ipatasertib 400mg QD plus rucaparib 400mg BID was the selected RP2D, received by 37 patients with mCRPC. Grade 3/4 adverse events occurred in 46% (17/37) of patients, with one grade 4 adverse event (anemia, deemed related to rucaparib) and no deaths. Adverse events leading to treatment modification occurred in 70% (26/37). The PSA response rate was 26% (9/35), and the objective response rate per RECIST 1.1 was 10% (2/21). Median radiographic progression-free survival per Prostate Cancer Working Group 3 criteria was 5.8 months (95% CI, 4.0-8.1), and median overall survival was 13.3 months (95% CI, 10.9-not evaluable). Conclusion: Ipatasertib plus rucaparib was manageable with dose modification but did not demonstrate synergistic or additive antitumor activity in previously treated patients with mCRPC.