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Clinical Trial
. 2024 Jul 5;29(7):581-588.
doi: 10.1093/oncolo/oyae019.

Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS

Neal D Shore  1 , Christian Gratzke  2 , Susan Feyerabend  3 , Patrick Werbrouck  4 , Joan Carles  5 , Egils Vjaters  6 , Teuvo L J Tammela  7 , David Morris  8 , Jeanny B Aragon-Ching  9 , Raoul S Concepcion  8 , Urban Emmenegger  10   11 , Neil Fleshner  12 , Markus Grabbert  2 , Vilnis Lietuvietis  13 , Hakim Mahammedi  14 , Felipe M Cruz  15 , Adriano Paula  16 , Christopher Pieczonka  17 , Antti Rannikko  18 , Martin Richardet  19 , Glauco Silveira  20 , Iris Kuss  21 , Marie-Aude Le Berre  22 , Frank Verholen  23 , Toni Sarapohja  24 , Matthew R Smith  25 , Karim Fizazi  26
Affiliations
Clinical Trial

Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS

Neal D Shore et al. Oncologist. .

Abstract

Background: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment.

Patients and methods: Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period.

Results: Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months.

Conclusion: Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment.

Trial number: ClinicalTrials.gov identifier NCT02200614.

Keywords: adverse events; androgen receptor inhibitor; darolutamide; nonmetastatic castration-resistant prostate cancer; safety; tolerability.

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Conflict of interest statement

Neal D. Shore: Consulting or advisory role: AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb/Sanofi, CG Oncology, Clarity Pharmaceuticals, Clovis Oncology, Dendreon, Exact Imaging, Exact Sciences, FerGene, Ferring, Foundation Medicine, Genesis Cancer Care, Genzyme, Invitae, Janssen Scientific Affairs, Lantheus Medical Imaging, Lilly, Mdxhealth, Medivation/Astellas Pharma, Merck, Myovant Sciences, Myriad Genetics, Nymox, Pacific Edge Biotechnology, PeerView, Pfizer, Phosphorus, Photocure, Propella Therapeutics, Sanofi, Sema4, Sesen Bio, Specialty Networks, Telix Pharmaceuticals, Tempus, Tolmar, UroGen Pharma, Vaxiion; speakers’ bureau: Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Foundation Medicine, Guardant Health, Janssen, Merck, Pfizer; expert testimony: Ferring; other relationship: Alessa Therapeutics, Photocure; research funding: AbbVie, Advantagene, Amgen, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Boston Scientific, CG Oncology, Clovis Oncology, Dendreon, DisperSol, Endocyte, Exact Imaging, Exelixis, Ferring, FKD Therapies, FORMA Therapeutics, Foundation Medicine, Genentech, Guardant Health, Invitae, Istari Oncology, Janssen, Jiangsu Yahong Meditech, Mdxhealth, Medivation, Merck, MT Group, Myovant Sciences, Myriad Genetics, Novartis, Nymox, OncoCell MDx, ORIC Pharmaceuticals, Pacific Edge, Palette Life Sciences, Pfizer, Plexxikon, POINT Biopharma, Propella Therapeutics, RhoVac, Sanofi, Seattle Genetics, Sesen Bio, Steba Biotech, Theralase, Tolmar, UroGen Pharma, Urotronic, US Biotest, Vaxiion, Veru, Zenflow. Christian Gratzke: No conflicts. Susan Feyerabend: Advisory boards: Astellas, Aventis, Bayer, Janssen; honorarium: Janssen; travel, accommodation, expenses: Aventis. Patrick Werbrouck: No conflicts. Joan Carles: Consulting and scientific advisory board attendee role: Amgen, Astellas, Bayer, Bristol-Myers Squibb, Johnson & Johnson, Merck Sharp & Dohme, Pfizer, Sanofi; speakers’ bureau: Asofarma, Astellas, Bayer, Johnson & Johnson, Sanofi. Egils Vjaters: No conflicts. Teuvo L. Tammela: Consultant: Astellas Pharma; investigator: Bayer, Laboratórios Pfizer Ltda. David Morris: Consulting or advisory role: Astellas Pharma, AstraZeneca, Bayer, Decipher Biosciences, Dendreon, Janssen Oncology, Myovant Sciences, Myriad Genetics, Pfizer/EMD Serono, UroGen Pharma, UroGRO; speakers’ bureau: AstraZeneca, Astellas/Medivation, Clovis Oncology, Janssen, Merck; research funding: Merck. Jeanny B. Aragon-Ching: Consulting or advisory role: AZD, Bayer, Exelixis, Immunomedics, Janssen Oncology, Merck, Pfizer/EMD Serono, Pfizer/Myovant; speaker honorarium: Astellas/Seagen, Bristol-Myers Squibb, Pfizer/EMD Serono. Raoul S. Concepcion: Speakers’ bureau: Amgen, Astellas, Pfizer, Sun Pharma; consultant: AZ, Blue Earth, Curium, Dendreon, GoPath, Immunity Bio, Janssen, Sun Pharma. Urban Emmenegger: Consulting or advisory role: Amgen Canada, Astellas Pharma Canada, AstraZeneca Canada, Bayer, Janssen Biotech, Knight Inc Canada, Merck, Novartis, Pfizer Canada Inc; research support: Clovis Oncology, Merck, Novartis, Point Biopharma. Neil Fleshner: Grants/sponsorship support: Astellas, Bayer, Janssen; honorarium/consulting fees/speaker fees: AbbVie, Astellas, Bayer, Janssen, Sanofi; and is the co-founder of Point Biopharma and Verity. Markus Grabbert: Consulting or advisory role: Ipsen, MSD; travel, accommodation, expenses: Astellas, Janssen, MSD; honoraria: Bristol-Myers Squibb, Janssen, Medac, MSD. Vilnis Lietuvietis: No conflicts. Hakim Mahammedi: Consulting or advisory role: 3A, Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck/Pfizer, MSD, Novartis, Pfizer; travel, accommodation, expenses: Astellas, Ipsen, Janssen, Pfizer. Felipe M. Cruz: No conflicts. Adriano Paula: No conflicts. Christopher Pieczonka: Employment: Associated Medical Professionals of New York; consulting or advisory role: AstraZeneca, Bayer, Bristol-Myers Squibb, Dendreon, Janssen Oncology, Merck, Pfizer/Astellas, Sun Pharma, Tolmar; leadership: Associated Medical Professionals of New York; speakers’ bureau: Astellas Pharma, Bayer, Dendreon, Janssen Oncology, Pfizer, Merck, Myovant Sciences, Sun Pharma, Tolmar; stock ownership: US Urology Partners; honoraria: AstraZeneca, Bayer, Bristol-Myers Squibb, Dendreon, Janssen, Merck, Myovant Sciences, Pfizer/Astellas, Sun Pharma, Tolmar; research funding: Advantagene, Astellas Pharma, AstraZeneca, Bayer, Dendreon, Innocrin Pharma, Janssen Oncology, Merck, Pfizer. Antti Rannikko: Board member: the Ida Montin Foundation and Orion Research Foundation; advisory board member: Bayer, Janssen, Orion Pharma; stockholder and clinical advisor: Aqsens Health; clinical investigator: Astellas Pharma Inc., Bayer, Janssen, Orion Pharma, RhoVac; receiving competitive state research funding: HUS Helsinki University Hospital, Finnish Cancer Organizations, the Jane and Aatos Erkko Foundation. Martin Richardet: No conflicts. Glauco Silveira: No conflicts. Iris Kuss: Employment: Bayer. Marie-Aude Le Berre: Employment: Bayer. Frank Verholen: Employment: Bayer. Toni Sarapohja: Employment: Orion Pharma. Matthew R. Smith: Consulting or advisory role: Amgen, Astellas Pharma, Bayer, Janssen Oncology, Lilly, Novartis, Pfizer; research funding: Bayer (Inst), ESSA (Inst), Janssen Oncology (Inst), Lilly (Inst), ORIC Pharmaceuticals (Inst). Karim Fizazi: Honoraria: Astellas Pharma (Inst), Bayer (Inst), Bristol-Myers Squibb (Inst), Janssen (Inst), Sanofi (Inst); consulting or advisory role: Amgen (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bayer, Clovis Oncology (Inst), ESSA (Inst), Novartis (Inst), Janssen Oncology (Inst), Pfizer (Inst), Orion Pharma, Sanofi (Inst); travel, accommodation, expenses: AstraZeneca, Janssen, MSD.

Figures

Figure 1.
Figure 1.
Dose modifications and re-escalation to full dose of darolutamide or placebo equivalent. The safety population excluded one patient in the darolutamide group who did not receive any dose of study drug. Abbreviations: DB: double-blind; OL: open-label.
Figure 2.
Figure 2.
Cumulative incidence of treatment-emergent adverse events associated with androgen receptor inhibitors and hormone treatments (>1%) at 24 months during the double-blind treatment period. Acute myocardial infarction occurred in >1% of patients assigned to darolutamide (1.2% vs. 0.7% in patients assigned to placebo) and is included under coronary artery disorders.
Figure 3.
Figure 3.
Cumulative incidences of grade 3/4 treatment-emergent adverse events (A) and serious treatment-emergent adverse events (B) over 24 months.
Figure 4.
Figure 4.
Exposure-adjusted incidence rates for treatment-emergent adverse events of interest during the double-blind and open-label periods. Abbreviations: DB: double-blind; OL: open-label.
Figure 5.
Figure 5.
Time interval–specific new event rates of fatigue (A), hot flushes (B), falls (C), fractures (D), and rash (E). Abbreviation: Wk: week.
See this image and copyright information in PMC

References

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