A phase Ib, open-label study evaluating the safety and efficacy of ipatasertib + rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC).

Abstract

95 Background: mCRPC remains an incurable disease with unmet need for improved therapies. PARP inhibition has demonstrated antitumor activity, and preclinical studies suggest synergy between PARP and AKT inhibition. This phase Ib trial (NCT03840200) sought to determine the maximum tolerated dose of PARP inhibitor rucaparib (ruca) with AKT inhibitor ipatasertib (ipat) and explore early safety and efficacy in patients (pts) with mCRPC. Methods: The study had 2 parts: a part 1 dose-escalation phase (cohort [C]1: ipat 300 mg QD + ruca 400 mg BID; C2a: ipat 300 mg QD + ruca 600 mg BID; C2b ipat 400 mg QD + ruca 400 mg BID; C3: ipat 400 mg QD + ruca 600 mg BID) in unselected pts with mCRPC or advanced breast or ovarian cancer, and a Part 2 dose-expansion phase in pts with mCRPC whose previous androgen deprivation therapy failed. The primary safety endpoints were AEs and dose-limiting toxicities, with the goal of identifying a recommended phase II dose (RP2D). The primary efficacy endpoint was prostate-specific antigen (PSA) response (PSA reduction of ≥ 50%) in pts with mCRPC. Secondary efficacy endpoints included ORR per RECIST 1.1, radiographic PFS (rPFS) per Prostate Cancer Working Group 3 and OS in pts with mCRPC. We assessed homologous recombination deficiency (HRD), PIK3CA/ AKT1/ PTEN status and other alterations by next-generation sequencing. Results: Part 1 enrolled 21 pts: 17 with mCRPC, 3 with ovarian cancer and 1 with breast cancer (C1 [n=8], C2a [n=6] and C2b [n=7], C3 [not opened]). Ipat 400 mg QD + ruca 400 mg BID was the selected RP2D. 30 pts enrolled in Part 2, so 37 pts with mCRPC (C2b + Part 2) received the RP2D (median follow-up 93 days). All grade AEs occurred in 37 pts (100%), serious AEs in 8 pts (22%) and AEs leading to treatment modification in 26 pts (70%). The most frequent AEs (all grade and grade 3, respectively) were diarrhea (35 [95%] and 2 [5%]); asthenia (24 [65%] and 4 [11%]); and nausea (24 [65%] and 2 [5%]). There was 1 grade 4 AE (anemia) and no grade 5 AEs. See the table for efficacy data. In biomarker subgroups, the PSA response rate was 50% (3/6) in pts with HRD tumors vs 25% (4/16) in pts with HR-proficient tumors, and 14% (1/7) vs 40% (6/15) in pts with PIK3CA/ AKT1/ PTEN–altered or intact tumors, respectively. Conclusions: The combination of ipat and ruca was well tolerated but did not show clinically relevant antitumor activity in pts with mCRPC, including in predefined biomarker subpopulations. Clinical trial information: NCT03840200. [Table: see text]