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Presidential Symposium II

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

Date

20 Sep 2020

Session

Presidential Symposium II

Presenters

Johann de Bono

Citation

Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325

Authors

J.S. de Bono1, S. Bracarda2, C.N. Sternberg3, K.N. Chi4, D. Olmos5, S. Sandhu6, C. Massard7, N. Matsubara8, B. Alekseev9, R. Gafanov10, F. Parnis11, G.L. Buchschacher Jr12, L. Corrales13, M. Borre14, G. Vasconcelos Alves15, J. Garcia16, M. Harle-Yge16, G. Chen17, M.J. Wongchenko17, C. Sweeney18

Author affiliations

  • 1 Drug Development Unit, The Institute of Cancer Research and the Royal Marsden Hospital, SM2 5PT - London/GB
  • 2 Medical Oncology, Azienda Ospedaliera Santa Maria, 05100 - Terni/IT
  • 3 Medical Oncology And Hematology, Englander Institute for Precision Medicine, Weill Cornell Medicine, NewYork-Presbyterian, 10021 - New York/US
  • 4 Medical Oncology Department, BC Cancer Agency, Vancouver, V5Z 4E6 - Vancouver/CA
  • 5 Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Center (CNIO), Madrid/ES
  • 6 Medical Oncology, Peter MacCallum Cancer Centre, Melbourne/AU
  • 7 Drug Development Department, Institut Gustave Roussy, 94805 - Villejuif/FR
  • 8 Department Of Breast And Medical Oncology, National Cancer Center Hospital East, 277-8577 - Chiba/JP
  • 9 Oncourology, P.A. Herzen Research Institute, Moscow/RU
  • 10 Department Of Urology, Russian Scientific Center of Roentgenoradiology, Moscow/RU
  • 11 Medical Oncology, Adelaide Cancer Centre, Adelaide/AU
  • 12 Medical Oncology Department, Southern California Permanente Medical Group, Los Angeles Medical Center, Los Angeles/US
  • 13 Department Of Medical Oncology, Centro de Investigación y Manejo del Cáncer CIMCA, San José/CR
  • 14 Department Of Urology, Aarhus University Hospital, Aarhus/DK
  • 15 Hematogy-oncology Division, Hospital Nossa Senhora da Conceicao, Porto Alegre/BR
  • 16 Clinical Oncology, F. Hoffmann-La Roche, Ltd., Basel/CH
  • 17 Oncology Biomarker Development, Genentech, Inc., South San Francisco/US
  • 18 Medical Oncology, Dana Farber Cancer Institute, 02215 - Boston/US
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Abstract LBA4

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

PTEN Loss by IHC n = 521 ITTN = 1101
Pbo + abi Ipat + abi Pbo + abi Ipat + abi
Time to PSA progression, n 261 260 554 547
Median (95% CI), mo 7.6 (6.4, 9.3) 12.6 (10.2, 15.3) 8.4 (7.4, 9.3) 12.9 (10.3, 15.1)
Stratified HR (95% CI) 0.69 (0.55, 0.87) 0.73 (0.62, 0.85)
PSA response, n/N, % 187/261, 72 217/260, 84 418/554, 76 444/546, 81
P 0.0012a 0.0183a
Time to pain progression, n/N, % 95/261, 36 73/260, 28 187/554, 34 156/547, 29
HR (95% CI) 0.77 (0.56, 1.04) 0.87 (0.70, 1.08)
Confirmed ORR, n/N 37/96 60/99 98/225 122/201
% 39 61 44 61
Difference (95% CI), % 22 (7, 37) 17 (7, 27)
rPFS in PTEN loss by NGS, n 103 105
Median (95% CI), mo 14.2 (10.9, 18.7) 19.1 (13.9, NE)
HR (95% CI) 0.65 (0.45, 0.95)

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.

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