In a Phase Ib/II study, the small-molecule AKT inhibitor ipatasertib in combination with abiraterone and prednisone/prednisolone demonstrated an improved radiographic progression-free survival (rPFS) vs abiraterone and prednisone/prednisolone alone, with greater benefit in patients with phosphatase and tensin homolog (PTEN)–loss tumors. This randomized Phase III trial will evaluate the efficacy, safety and pharmacokinetics (PK) of ipatasertib vs placebo (both combined with abiraterone and prednisone/prednisolone) in patients with previously untreated mCRPC.
Eligible patients must have untreated asymptomatic or mildly symptomatic mCRPC with progressive disease by Prostate Cancer Clinical Trials Working Group 3 criteria, ongoing androgen deprivation therapy or castrated state and ECOG PS 0 or 1. Treatments with second-generation CYP450 inhibitors or androgen-receptor blockers and untreated or active central nervous system metastases are not allowed; however, prior chemotherapy for hormone-sensitive disease is permitted. Eligible cases will be randomized 1:1 to abiraterone 1000 mg QD + prednisone/prednisolone 5 mg BID plus ipatasertib 400 mg QD or placebo. Crossover between treatment arms is not allowed. Stratification factors are prior taxane-based therapy in the hormone-sensitive setting, progression factor (prostate-specific antigen [PSA] only vs other), presence of liver or lung metastasis, tumor PTEN status by immunohistochemistry (loss vs non-loss) and geographic region. The primary efficacy endpoint is investigator-assessed rPFS (intent-to-treat population and patients with PTEN-loss tumors). Additional endpoints include time to pain progression, time to next cytotoxic chemotherapy, overall survival, additional patient-reported outcomes, time to first opioid use, time to PSA progression, safety and PK. Approximately 850 patients will be enrolled at ∼200 centers worldwide.
Clinical trial identification
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd
F. Hoffmann-La Roche Ltd
J. de Bono: Scientific advisor: Genentech/Roche Advisory boards: AstraZeneca/MedImmune, Boehringer Ingelheim, GenMab, Glaxo-Smith Kline, Medivation, Merck, Novartis, Pfizer, Sanofi, Vertex, Taiho and Daiichi. S. Bracarda: Advisory Board Member for: Pfizer, Novartis, BMS, Roche, Genentech, MSD, IPSEN, Eusa Pharma, Astellas; Honoraria from: Pfizer, Astellas, Jannsen, Novartis, BMS Travel Reimbursement: Bayer, BMS, Astellas, Jannsen, Ipsen. K. Chi: Adviser and honoraria from Roche/Genetech. C. Massard: Advisory boards, speaker or investigator for: Amgen, Astellas, AstraZeneca, Bayer, Celgene, Genentech, Ipsen, Jansen, Lilly, Novartis, Pfizer, Roche, Sanofi Orion. D. Olmos Hidalgo: Advisory boards for Gentech/Roche (Ipasertib - international - and in local advisory boards of atezolizumab), advisory boards of Janssen, research funding from Janssen. C.N. Sternberg: Research funding to department or consulted: Astellas, Bayer, Janssen, Roche/Genentech, Sanofi, Novartis. S. Gendreau: Employee of Genentech. N. Xu: Employee of Roche and own Roche stocks. T. Baney, D. Maslyar: Employee at Genentech and own stock. C.J. Sweeney: Consultant with compensation: Astellas, Bayer, Genentech, Janssen, Pfizer, Sanofi Research Funding: Astellas, Janssen, Sotio, Sanofi. All other authors have declared no conflicts of interest.