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Safety profile of darolutamide versus placebo: a systematic review and meta-analysis

Prostate Cancer and Prostatic Diseases (2023)Cite this article

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Abstract

Background

Darolutamide is an androgen receptor pathway inhibitor (ARPI) used in patients with prostate cancer (PC). In pivotal trials, it has demonstrated a favorable toxicity profile. There are no head-to-head comparison studies between the different ARPIs, but the efficacy of these drugs seems to be similar making the toxicity profile a key element for treatment selection.

Methods

We conducted a systematic review of all clinical trials assessing treatment with darolutamide for patients with PC using placebo as the control using the PubMed/Medline and Cochrane library databases. We also performed a meta-analysis to compare the safety of darolutamide versus placebo evaluating adverse events (AE) leading to treatment discontinuation and the rate of the AE reported as “AE of interest” in the ARAMIS trial. The comparison among darolutamide and the placebo group in terms of safety and tolerability was performed using odds ratio (OR) as meta-analytic outcome.

Results

We identified three articles comprising 2902 patients for the systematic review and meta-analysis (1652 treated with darolutamide and 1250 with placebo). Darolutamide did not increase AE leading to treatment discontinuation compared to placebo (pooled OR: 1.176, 95% CI 0.918–1.507, p = 0.633). Regarding the “AE of interest” there was no difference between darolutamide and placebo in terms of asthenia, cardiac arrhythmia, cardiac disorder, coronary artery disorder, depression mood disorder, falls, fatigue, heart failure, hot flushes, hypertension, mental-impairment disorder, rash, seizure and weight loss. The only “AE of interest” with a statistically significant difference in favor of placebo was bone fractures (pooled OR: 1.523, 95% CI 1.081–2.146).

Conclusions

In our systematic review and meta-analysis, darolutamide showed a toxicity profile comparable to placebo with the exception of bone fractures. In the absence of head-to-head comparison studies between the different ARPIs, the results of our research suggest a preferred use of darolutamide in the approved settings.

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Fig. 1: PRISMA flowchart on the literature selection based on the review question. From Page et al. [15].
Fig. 2: Forest plot of adverse events leading to treatment discontinuation obtained using random-effects.
Fig. 3: Forest plot of bone fractures obtained using random-effects.

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Authors and Affiliations

  1. Istituto Oncologico della Svizzera Italiana, EOC, Bellinzona, Switzerland

    Fabio Turco, Silke Gillessen & Ursula M. Vogl

  2. Department of Oncology, University of Torino at S. Luigi Hospital, Orbassano (Torino), Italy

    Fabio Turco & Consuelo Buttigliero

  3. Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland

    Silke Gillessen & Giorgio Treglia

  4. Division of Nuclear Medicine, Imaging Institute of Southern Switzerland, EOC, Bellinzona, Switzerland

    Giorgio Treglia

  5. Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland

    Giorgio Treglia

  6. Institut Gustave Roussy, University of Paris Saclay, Villejuif, France

    Karim Fizazi

  7. Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Matthew R. Smith

  8. Cliniques universitaires Saint Luc, Brussels, Belgium

    Bertrand Tombal

  9. Division of Oncology/Hematology, Kantonsspital Graubünden, Chur, Switzerland

    Richard Cathomas

  10. Department of Oncology, University of Turin, at Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10028, Turin, Italy

    Massimo Di Maio

  11. Department of Medical Oncology, Cardinal Massaia Hospital, 14100, Asti, Italy

    Marcello Tucci

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Contributions

FT: conception and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis, supervision. SG: conception and design, acquisition of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, supervision. GT: conception and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis, supervision. KF: critical revision of the manuscript for important intellectual content. MRS: critical revision of the manuscript for important intellectual content. BT: critical revision of the manuscript for important intellectual content. RC: critical revision of the manuscript for important intellectual content. CB: critical revision of the manuscript for important intellectual content. MDM: critical revision of the manuscript for important intellectual content. MT: critical revision of the manuscript for important intellectual content. UV: conception and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis, supervision.

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Correspondence to Fabio Turco.

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Competing interests

FT: travel grant: Bayer. SG: (last 3 years) personal honoraria advisory boards from Amgen, MSD; invited speaker ESMO, Swiss group for Clinical Cancer Research (SAKK), German-speaking European School of Oncology (DESO), Swiss Academy of Multidisciplinary oncology (SAMO); travel grant from AstraZeneca, Bayer. Institutional honoraria advisory boards or in Independent Data Monitoring-/Steering Committees from AAA International, Amgen, AstraZeneca, Astellas Pharma, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, DAIICHI Sankyo, Innomedia, Ipsen, Modra Pharmaceuticals, MSD, Myriad Genetic, Novartis, Orion, Pfizer, Roche, Telixpharma; invited speaker SAKK, ASCO GU, ESMO, PeerVoice, Silvio Grasso Consulting, WebMD-Medscape. Patent for a research method for biomarker WO2009138392. GT: no conflicts of interest. KF: participation in advisory boards and talks for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, Sanofi Honoraria go to Gustave Roussy, my institution. Participation to advisory boards with personal honorarium for Arvinas, CureVac, Macrogenics and Orion. MRS: consultant to Ambrx, Astellas, Bayer, Pfizer, Janssen, Lilly. BT: consultant and advisor for Amgen, Astellas, AstraZeneca, Bayer, Ferring, Janssen, Myovant, Novartis, Pfizer. RC: consultation or participation at advisory boards (institutional): AstraZeneca, Astellas, Bayer, Janssen, Roche, Pfizer, Novartis, MSD, BMS, Ipsen, Debiopharm, Accord, Merck; honoraria (institutional): Ipsen, Astellas, Janssen, Merck Travel support (institutional): Ipsen. CB: no conflicts of interest. MDM: honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, GlaxoSmithKline, Amgen, Merck, Takeda for consultancy or participation to advisory boards; institutional research funding from Tesaro/GlaxoSmithKline; institutional funding for work in clinical trials/contracted research from Beigene, Exelixis, MSD, Pfizer and Roche. MT: no conflicts of interest. UV: grant: Fond’Action; Institutional: Pfizer, Astellas, Janssen, Sanofi, Merck, MSD, BMS, Ipsen, Health Book, Novartis, Bayer Private: Health Book, SAMO, Inselspital Bern, Kantonsspital Chur, Kantonsspital Baden, Ipsen; Travel Grant: AstraZeneca, Janssen.

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Turco, F., Gillessen, S., Treglia, G. et al. Safety profile of darolutamide versus placebo: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis (2023). https://doi.org/10.1038/s41391-023-00775-y

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