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. 2023 Sep 17:195:113342.
doi: 10.1016/j.ejca.2023.113342. Online ahead of print.

Effect of crossover from placebo to darolutamide on overall survival in men with non-metastatic prostate cancer: sensitivity analyses from the randomised phase 3 ARAMIS study

Neal D Shore  1 , Karim Fizazi  2 , Teuvo L J Tammela  3 , Murilo Luz  4 , Manuel Philco Salas  5 , Paul Ouellette Jr  6 , Sérgio Lago  7 , Diogo Assed Bastos  8 , G Kenneth Jansz  9 , Flavio Mavignier Cárcano  10 , Lívia Andrade  11 , Marc Pliskin  12 , Nicolas Lazaretti  13 , Larissa Arruda  14 , José Jaime Correa Ochoa  15 , Iris Kuss  16 , Christian Kappeler  16 , Toni Sarapohja  17 , Matthew Smith  18
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Free article

Effect of crossover from placebo to darolutamide on overall survival in men with non-metastatic prostate cancer: sensitivity analyses from the randomised phase 3 ARAMIS study

Neal D Shore et al. Eur J Cancer. .
Free article

Abstract

Background: In the phase 3 ARAMIS study (NCT02200614), darolutamide significantly improved metastasis-free survival in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Following the primary analysis, the study was unblinded, and placebo recipients were permitted to cross over to open-label darolutamide. Despite crossover, darolutamide significantly improved overall survival (OS). We conducted sensitivity analyses to estimate the effect of placebo-darolutamide crossover on OS.

Methods: Patients with nmCRPC were randomised to oral darolutamide 600 mg twice daily (n = 955) or placebo (n = 554). Prespecified (rank-preserving structural failure time [RPSFT] and iterative parameter estimation [IPE]) and post hoc (OS-adjusted censoring and inverse probability of censoring weighting [IPCW], with weightings for baseline testosterone and prostate-specific antigen) sensitivity analyses were conducted.

Results: After unblinding, 170 of 554 placebo recipients (30.7%) crossed over to darolutamide. At the final OS intention-to-treat analysis (median 11.2 months after unblinding), darolutamide significantly improved OS by 31% versus placebo (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.53-0.88; P = 0.003). The benefit increased in the analyses adjusting for crossover is as follows: RPSFT HR 0.68, 95% CI 0.51-0.90; P = 0.007; IPE HR 0.66, 95% CI 0.51-0.84; P < 0.001; OS-adjusted censoring HR 0.59, 95% CI 0.45-0.76; IPCW HR 0.63, 95% CI 0.48-0.81. The favourable safety profile of darolutamide was maintained, including in crossover patients.

Conclusions: After adjusting for crossover, darolutamide reduced the risk of death by up to 41% in patients with nmCRPC. The effect of darolutamide on OS may have been underestimated in the original intention-to-treat analysis.

Keywords: Castration resistant; Cross-over; Crossover; Darolutamide; Prostatic neoplasms; Sensitivity analysis; Survival analysis.

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Conflict of interest statement

Declaration of Competing Interest All authors received support for medical writing and article processing charges from Bayer HealthCare Pharmaceuticals, Inc. N.D.S. reports consulting fees from AbbVie, Akido, Alessa Therapeutics, Amgen, Arquer, Asieris, Astellas, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Clarity, Clovis, Cold Genesys, Dendreon, Eli Lilly, Exact Images, Exact Sciences, FerGene, Ferring, FIZE Medical, Foundation Medicine, GConcology, GenesisCare, Genetech, Guardant, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, MDX, Merck, Minomic, Myovant, Myriad, NGM, Nonagen, Novartis, NYMOX, Pacific Edge, Photocure, Pfizer, PlatformQ, Profound, Promaxo, Propella, Protara, Sanofi, SesenBio, Speciality Networks, Telix, Tolmar, Urogen, Vaxiion and Vessi; payment for expert testimony from Ferring; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, with Photocure. K.F. reports participation in advisory boards for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer and Sanofi (honoraria paid to institution), and Arvinas, CureVac, Macrogenics and Orion (honoraria paid to self). T.L.J.T. reports grants or contracts from Astellas Pharma, Bayer and Pfizer; consulting fees from Astellas Pharma and Bayer; and participation on a data safety monitoring board or advisory board for Bayer. M.L. reports grants or contracts for research funding from Bayer, Janssen, Medivation, Myovant Sciences, Pfizer and Roche/Genentech; consulting fees from Astellas Pharma, Bayer and Janssen; payment or honoraria for speaker bureau participation from Astellas Pharma, Bayer and Janssen; and support for attending meetings and/or travel from Astellas Pharma, Bayer, Janssen, Pfizer and Zodiac. M.P.S. reports grants or contracts from Astellas Pharma, Bayer, Merck and Roche; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Bayer; payment for expert testimony from Pfizer and Roche; and support for attending meetings and/or travel from Pfizer and Roche. P.O. Jr., S.L., G.K.J., N.L. and La.A. have no other conflicts to declare. D.A.B. reports grants or contracts from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen and Merck; consulting fees from Astellas Pharma, Bayer, Janssen and Merck; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Astellas Pharma, Bayer and Janssen; and support for attending meetings and/or travel from Astellas Pharma, Bayer and Janssen. F.M.C. reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Zodiac (Adium); and support for attending meetings and/or travel from Zodiac, Bayer, Janssen and Pfizer. Lí.A. reports support for attending meetings and/or travel from Bayer. M.P. reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Myovant; and participation on a data safety monitoring board or advisory board for Pfizer. J.J.C.O. reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from AstraZeneca, Bayer and Janssen; and support for attending meetings and/or travel from Janssen. I.K. has stock or stock options in Bayer and is an employee of Bayer. C.K. is an employee of Bayer. T.S. is an employee of Orion Corporation. M.S. reports grants or contracts for research funding paid to his institution from Bayer, Eli Lilly, ESSA, Janssen Oncology and ORIC Pharmaceuticals; consulting fees from Amgen, Astellas Pharma, Bayer, Eli Lilly, Janssen Oncology, Novartis and Pfizer; and participation on a data safety monitoring board or advisory board for Amgen, Astellas Pharma, Bayer, Eli Lilly, Janssen Oncology, Novartis and Pfizer.

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