LBA4 - IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC)

Background

PI3K/AKT and androgen receptor (AR) signalling are dysregulated in mCRPC. PTEN loss (40%-50% of mCRPC) results in activation of AKT, the ipat target, and worse outcomes. Preclinically, dual pathway inhibition has greater antitumor activity than AR inhibition. IPATential150 is a phase III, randomised, double-blind study evaluating the efficacy and safety of adding ipat to abi in asymptomatic or mildly symptomatic pts previously untreated for mCRPC.

Methods

Pts with mCRPC were randomised 1:1 to receive ipat (400 mg/d) + abi (1000 mg/d) + prednisone (5 mg bid) or pbo + abi + prednisone. Coprimary endpoints were investigator-assessed radiographic (r) PFS by PCWG3 criteria in pts with PTEN-loss tumours by immunohistochemistry (IHC; PTEN-loss in ≥ 50% of tumour cells) and in the overall ITT. Secondary endpoints included time to PSA progression, PSA response rate, confirmed ORR (per RECIST 1.1 + PCWG3) in ITT pts and pts with PTEN-loss tumours by IHC, and rPFS in pts with PTEN-loss tumours by next-generation sequencing (NGS).

Results

1101 pts were randomised: 547 to ipat + abi and 554 to pbo + abi. Median follow-up was 19 mo. In PTEN loss by IHC pts, median rPFS was 18.5 mo (95% CI: 16.3, 22.1) with ipat and 16.5 mo (95% CI: 13.9, 17.0) with pbo (HR: 0.77; 95% CI: 0.61, 0.98; P = 0.0335); in ITT pts, rPFS was 19.2 mo (95% CI: 16.5, 22.3) with ipat and 16.6 mo (95% CI: 15.6, 19.1) with pbo (HR: 0.84; 95% CI: 0.71, 0.99; P = 0.0431). Secondary endpoints favoured the combination arm (Table). Serious adverse events (AEs) occurred in 40% and 23% of ipat and pbo pts, respectively; AEs leading to discontinuation of ipat/pbo occurred in 21% and 5%.

Conclusions

In this primary endpoint analysis, ipat + abi as first-line treatment for mCRPC resulted in significantly improved rPFS and antitumor activity vs pbo + abi in pts with PTEN-loss mCRPC, but not in the ITT. The safety profile was in line with known and potential risks. Table: LBA4

NE, not evaluable. ^a Descriptive.

Clinical trial identification

NCT03072238.

Editorial acknowledgement

Medical writing support was provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

J.S. de Bono: Advisory/Consultancy, Research grant/Funding (institution), Olaparib in BRCA cancers and Investigator Initiated Trial: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Translational studies: Sanofi; Advisory/Consultancy, Research grant/Funding (institution), Translational studies: Astellas Pharma; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (institution), Preclinical studies: Genentech/Roche; Advisory/Consultancy, Translational studies: Janssen Oncology; Advisory/Consultancy: Menarini Silicon Biosystems; Advisory/Consultancy, Research grant/Funding (institution), Preclinical studies: Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution), Preclinical studies: Sierra Oncology; Advisory/Consultancy, Research grant/Funding (institution), Preclinical studies: Bayer; Advisory/Consultancy, Research grant/Funding (institution), Preclinical studies: Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution), Preclinical studies: Merck Serono; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution), Preclinical studies: Celgene; Advisory/Consultancy, Research grant/Funding (institution), Preclinical studies: Taiho Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution), Translational studies: Genmab; Advisory/Consultancy, Research grant/Funding (institution), Preclinical studies: GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution), Preclinical studies: Orion Pharma; Advisory/Consultancy: Eisai; Advisory/Consultancy: Bioxcel Therapeutics; Advisory/Consultancy, Preclinical studies: Astex Pharmaceuticals; Research grant/Funding (institution), Preclinical studies: Cellcentric; Research grant/Funding (institution), Preclinical studies: MedImmune; Research grant/Funding (institution), Preclinical studies: Medivation; Research grant/Funding (institution), Investigator initiated trial: Terumo; Non-remunerated activity/ies, I am the Principal Investigator on multiple trials and have been PI on more than 100 trials with multiple Pharma and Biotech partners: Multiple Pharma and Biotech Partners. S. Bracarda: Advisory/Consultancy: Bayer; Advisory/Consultancy: Astellas; Advisory/Consultancy: Janssen; Advisory/Consultancy: Pfizer; Advisory/Consultancy: BMS; Advisory/Consultancy: Roche; Advisory/Consultancy: Ipsen; Advisory/Consultancy: MSD; Advisory/Consultancy: Merck; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: AAA. C.N. Sternberg: Advisory/Consultancy: Pfizer; Advisory/Consultancy: MSD; Advisory/Consultancy: Merck; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Astellas; Advisory/Consultancy: Sanofi/Genzyme; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: Incyte; Advisory/Consultancy: Clovis. K.N. Chi: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Astellas; Honoraria (self), Research grant/Funding (institution): Janssen; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self): Daiichi Sanyo; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Research grant/Funding (institution): Roche. D. Olmos: Honoraria (institution), Travel/Accommodation/Expenses: Astellas Pharma ; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Clovis Oncology; Research grant/Funding (institution): Astellas Medivation; Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Pfizer; Travel/Accommodation/Expenses: Tokai Pharmaceuticals; Travel/Accommodation/Expenses: Ipsen. S. Sandhu: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Amgen; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution): Merck; Honoraria (self): Merck Serono; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche/Genentech; Research grant/Funding (institution): AstraZeneca. C. Massard: Advisory/Consultancy: Amgen; Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: BeiGene; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy: BMS; Advisory/Consultancy: Celgene; Advisory/Consultancy: Debiopharm Group; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy: Innate Pharma; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Janssen; Advisory/Consultancy: Lilly; Advisory/Consultancy: MSD; Advisory/Consultancy: Novartis; Advisory/Consultancy: Orion; Advisory/Consultancy: Pfizer; Advisory/Consultancy: PharmaMar; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Tahio. N. Matsubara: Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy: Astellas; Advisory/Consultancy: Janssen; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Bayer; Advisory/Consultancy: Eisai; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Pierre Fabre. B. Alekseev: Speaker Bureau/Expert testimony: Astellas; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Bayer; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony: Ferring; Speaker Bureau/Expert testimony: Janssen; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: MSD; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Sanofi. R. Gafanov: Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy: Astellas; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Bayer; Advisory/Consultancy: Eisai; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Pierre Fabre. M. Borre: Advisory/Consultancy: Ferring; Advisory/Consultancy: MSD; Advisory/Consultancy: Bayer; Advisory/Consultancy: Astellas; Research grant/Funding (institution): AstraZeneca. G. Vasconcelos Alves: Research grant/Funding (institution): MSD; Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Merck-Serono; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Beigene; Research grant/Funding (institution): Ipsen; Advisory/Consultancy: Janssen. J. Garcia: Full/Part-time employment: Roche. M-L. Harle-Yge: Full/Part-time employment: Roche. G. Chen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Genentech. M.J. Wongchenko: Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche/Genentech. C. Sweeney: Advisory/Consultancy, Research grant/Funding (institution): Astellas; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy, Research grant/Funding (institution): Dendreon; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Sanofi; Advisory/Consultancy: Genentech; Advisory/Consultancy: GlaxoSmithKline. All other authors have declared no conflicts of interest.