Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial.

Background: The PI3K/AKT and androgen-receptor pathways are dysregulated in metastatic castration-resistant prostate cancers (mCRPCs); tumours with functional PTEN-loss status have hyperactivated AKT signalling. Dual pathway inhibition with AKT inhibitor ipatasertib plus abiraterone might have greater benefit than abiraterone alone. We aimed to compare ipatasertib plus abiraterone with placebo plus abiraterone in patients with previously untreated mCRPC with or without tumour PTEN loss.
Methods: We did a randomised, double-blind, phase 3 trial at 200 sites across 26 countries or regions. Patients aged 18 years or older with previously untreated asymptomatic or mildly symptomatic mCRPC who had progressive disease and Eastern Collaborative Oncology Group performance status of 0 or 1 were randomly assigned (1:1; permuted block method) to receive ipatasertib (400 mg once daily orally) plus abiraterone (1000 mg once daily orally) and prednisolone (5 mg twice a day orally) or placebo plus abiraterone and prednisolone (with the same dosing schedule). Patients received study treatment until disease progression, intolerable toxicity, withdrawal from the study, or study completion. Stratification factors were previous taxane-based therapy for hormone-sensitive prostate cancer, type of progression, presence of visceral metastasis, and tumour PTEN-loss status by immunohistochemistry. Patients, investigators, and the study sponsor were masked to the treatment allocation. The coprimary endpoints were investigator-assessed radiographical progression-free survival in the PTEN-loss-by-immunohistochemistry population and in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03072238.
Findings: Between June 30, 2017, and Jan 17, 2019, 1611 patients were screened for eligibility and 1101 (68%) were enrolled; 554 (50%) were assigned to the placebo-abiraterone group and 547 (50%) to the ipatasertib-abiraterone group. At data cutoff (March 16, 2020), median follow-up duration was 19 months (range 0-33). In the 521 (47%) patients who had tumours with PTEN loss by immunohistochemistry (261 in the placebo-abiraterone group and 260 in the ipatasertib-abiraterone group), median radiographical progression-free survival was 16·5 months (95% CI 13·9-17·0) in the placebo-abiraterone group and 18·5 months (16·3-22·1) in the ipatasertib-abiraterone group (hazard ratio [HR] 0·77 [95% CI 0·61-0·98]; p=0·034; significant at α=0·04). In the intention-to-treat population, median progression-free survival was 16·6 months (95% CI 15·6-19·1) in the placebo-abiraterone group and 19·2 months (16·5-22·3) in the ipatasertib-abiraterone group (HR 0·84 [95% CI 0·71-0·99]; p=0·043; not significant at α=0·01). Grade 3 or higher adverse events occurred in 213 (39%) of 546 patients in the placebo-abiraterone group and in 386 (70%) of 551 patients in the ipatasertib-abiraterone group; adverse events leading to discontinuation of placebo or ipatasertib occurred in 28 (5%) in the placebo-abiraterone group and 116 (21%) in the ipatasertib-abiraterone group. Deaths due to adverse events deemed related to treatment occurred in two patients (<1%; acute myocardial infarction [n=1] and lower respiratory tract infection [n=1]) in the placebo-abiraterone group and in two patients (<1%; hyperglycaemia [n=1] and chemical pneumonitis [n=1]) in the ipastasertb-abiraterone group.
Interpretation: Ipatasertib plus abiraterone significantly improved radiographical progression-free survival compared with placebo plus abiraterone among patients with mCRPC with PTEN-loss tumours, but there was no significant difference between the groups in the intention-to-treat population. Adverse events were consistent with the known safety profiles of each agent. These data suggest that combined AKT and androgen-receptor signalling pathway inhibition with ipatasertib and abiraterone is a potential treatment for men with PTEN-loss mCRPC, a population with a poor prognosis.
Funding: F Hoffmann-La Roche and Genentech.
Competing Interests: Declaration of interests All authors report editorial assistance from F Hoffmann-La Roche. CS reports grants or personal fees, or both from Janssen, F Hoffmann-La Roche and Genentech, Sanofi, Astellas, Pfizer, Bayer, and Lilly, during the conduct of the study; and has a patent abiraterone plus cabozantinib issued to Exelixis, a patent parthenolide as treatment for cancer licensed to Indiana University, and a patent dimethylaminoparthenolide as treatment for cancer licensed to Leuchemix, outside of the submitted work. SB reports serving as advisory board member for Astellas, Janssen, Pfizer, BMS, F Hoffmann-La Roche, Ipsen, MSD, Merck, AAA, and AstraZeneca, outside of the submitted work. CNS reports grants and non-financial support from F Hoffmann-La Roche during the conduct of the study; and personal fees from Pfizer, MSD, Merck, AstraZeneca, Astellas, Sanofi and Genzyme, F Hoffmann-La Roche and Genentech, Incyte, and Clovis, outside of the submitted work. KNC reports grants from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees, or both from Astellas, AstraZeneca, Constellation Pharma, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Point Biopharma, F Hoffmann-La Roche, and Sanofi, outside of the submitted work. DO reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants, personal fees, or non-financial support from Astellas Pharma, Bayer, Janssen, AstraZeneca, Clovis Oncology, Astellas Medivation, F Hoffmann-La Roche and Genentech, Pfizer, Tokai Pharmaceuticals, Ipsen, MSD, and Daiichi Sankyo, outside of the submitted work. SS reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees, or both from Amgen, MSD, Merck Serono, F Hoffmann-La Roche and Genentech, AstraZeneca, and Novartis, outside of the submitted work. CM reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and personal fees from Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, BMS, Celgene, Debiopharm Group, F Hoffmann-La Roche and Genentech, Innate Pharma, Ipsen, Janssen, Lilly, MSD, Novartis, Orion, Pfizer, PharmaMar, Sanofi, and Taiho, outside of the submitted work. NM reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees, or both from Janssen, MSD, Chugai, Astellas, Eli Lilly, Taiho, Pfizer, and Sanofi, outside of the submitted work. BA reports grants from F Hoffmann-La Roche, during the conduct of the study; and grants, personal fees, or non-financial support from Astellas, AstraZeneca, Bayer, BMS, Eisai, Ferring, Ipsen, Janssen, MSD, Pfizer, F Hoffmann-La Roche, and Sanofi, outside of the submitted work. RG reports grants from F Hoffmann-La Roche, during the conduct of the study; and grants, personal fees, or non-financial support from Astellas, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen, MSD, Pfizer, F Hoffmann-La Roche, Sanofi, and Pierre Fabre, outside of the submitted work. LC reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study. GVA reports grants from MSD, BMS, Merck-Serono, F Hoffmann-La Roche, Pfizer, AstraZeneca, Beigene, Ipsen, and Janssen, outside of the submitted work. EB reports personal fees from Sanofi Aventis, Astellas Pharmaceuticals, Roche Hellas, Bayer, Janssen Pharmaceuticals, GlaxoSmithKline, Pierre Fabre, and Merck, outside of the submitted work. JP reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees from Astellas Pharma, AstraZeneca, Bayer, BMS, Eisai, EUSA Pharma, Ipsen, Janssen-Cilag, MSD Oncology, Pierre Fabre, F Hoffmann-La Roche, Sanofi, Clovis Oncology, and MSD, and grants, personal fees, and non-financial support from Pfizer, outside of the submitted work. M-LH-Y, JGal, and JGar are employees of F Hoffmann-La Roche. GC, JH, and MJW are employees of Genentech. JSdB reports personal fees and grants from F Hoffmann-La Roche and Genentech, during the conduct of the study; grants, personal fees, or travel expenses from AstraZeneca, GlaxoSmithKline, Pfizer, Taiho, Daiichi, Bayer, Orion Pharma, F Hoffmann-La Roche and Genentech, Merck Serono, Sierra Oncology, MSD, Astellas, Cellcentric, Sanofi Aventis, and Vertex Pharmaceuticals, and personal fees or travel expenses from Terumo, Menarini and Silicon Biosystems, Bioexcel Therapeutics, Eisai, and Qiagen, outside of the submitted work; and has a patent for DNA damage repair inhibitors for treatment of cancer (patent number WO 2005 053662 licensed to AstraZeneca) and a patent for 17-substituted steroids useful in cancer treatment (patent number US 5604213 licensed to Janssen). All other authors declare no competing interests.
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