ESMO 2017: Randomized phase III trial of ipatasertib vs. placebo, plus abiraterone and prednisone/prednisolone, in men with asymptomatic or mildly symptomatic previously untreated metastatic castrate-resistant prostate cancer (mCRPC)

Madrid, Spain (UroToday.com) Dr. De Bono and colleagues presented their phase III trial design for assessing ipatasertib vs. placebo + abiraterone and prednisone/prednisolone for men with previously untreated metastatic castrate-resistant prostate cancer (mCRPC).

mCRPC commonly has hyperactivated PI3K/Akt signaling via PTEN loss, and subsequently androgen receptor blockade activates Akt supporting mCRPC cell survival. Dr. De Bono and colleagues have previously shown in a phase Ib/II study that the small-molecule AKT inhibitor ipatasertib in combination with abiraterone and prednisone/prednisolone improves radiographic progression free survival (rPFS) vs abiraterone and prednisone/prednisolone alone, with greater benefit in patients with phosphatase and tensin homolog (PTEN)–loss tumors [1]. As such, the objective of this randomized phase III trial is to evaluate the efficacy, safety and pharmacokinetics of ipatasertib vs placebo (both combined with abiraterone and prednisone/prednisolone) in patients with previously untreated mCRPC.

Trial Design: Inclusion criteria for this trial will be men with previously 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 performance status 0 or 1. Key exclusion criteria include treatment with second-generation CYP450 inhibitors or androgen-receptor blockers and untreated or active central nervous system metastases. Prior chemotherapy for hormone-sensitive disease is permitted. Stratification factors will include prior taxane based therapy in the hormone-sensitive setting, progression factor (PSA only vs other), presence of liver or lung metastasis, tumor PTEN status by immunohistochemistry (loss vs non-loss) and geographic region. Eligible patients will then be randomized 1:1 to receive abiraterone 1000 mg QD + prednisone/prednisolone 5 mg BID plus ipatasertib 400 mg QD or placebo. Crossover between treatment arms is not allowed. The primary efficacy endpoint is investigator-assessed rPFS (intent-to-treat population and patients with PTEN-loss tumors). Additional secondary endpoints include overall survival, additional patient-reported outcomes, safety, pharmacokinetics, and time to: pain progression, next cytotoxic chemotherapy, first opioid use, and PSA progression. The authors plan on enrolling approximately 850 patients at ∼200 centers worldwide. Clinical trial identification: NCT03072238.

Reference:

1. De Bono JS, De Giorgi U, Massard C, et al. Randomized phase II study of AKT blockade with ipatasertib (GDC-0068) and abiraterone (Abi) vs. Abi alone in patients with metastatic castration-resistant prostate cancer (mCPRC) after docetaxel chemotherapy. J Clin Oncol May 2016;34(15_suppl): 5017.

Speaker: Johann De Bono, The Institutde of Cancer Research, London, United Kingdom

Co-Authors: S. Bracarda (Arezzo, Italy) K. Chi (Vancouver, British Columbia, Canada) C. Massard (Villejuif, France) D. Olmos Hidalgo (Madrid, Spain) S. Sandhu (Melbourne, Australia)

C. N. Sternberg (Roma, Italy) S. Gendreau (South San Francisco, United States of America)

N. Xu (South San Francisco, United States of America) T. Baney (South San Francisco, United States of America) D. Maslyar (South San Francisco, United States of America) C. J. Sweeney (Boston, United States of America)

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
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