PMID- 31571095
OWN - NLM
STAT- MEDLINE
DCOM- 20200403
LR  - 20231014
IS  - 1776-260X (Electronic)
IS  - 1776-2596 (Print)
IS  - 1776-2596 (Linking)
VI  - 14
IP  - 5
DP  - 2019 Oct
TI  - Evaluation of Clinically Relevant Drug-Drug Interactions and Population 
      Pharmacokinetics of Darolutamide in Patients with Nonmetastatic 
      Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc 
      Analyses of the Phase III ARAMIS Trial.
PG  - 527-539
LID - 10.1007/s11523-019-00674-0 [doi]
AB  - BACKGROUND: Darolutamide, an androgen receptor antagonist with a distinct 
      molecular structure, significantly prolonged metastasis-free survival versus 
      placebo in the phase III ARAMIS study in men with nonmetastatic 
      castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy 
      for age-related comorbidities is common and may increase drug-drug interaction 
      (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI 
      potential-other than breast cancer resistance protein/organic anion transporter 
      protein substrates (e.g., statins), no clinically relevant effect on 
      comedications is expected. OBJECTIVE: Our objective was to evaluate the effect of 
      commonly administered drugs on the pharmacokinetics of darolutamide and the 
      effect of comedications potentially affected by darolutamide on safety in 
      patients with nmCRPC. PATIENTS AND METHODS: Comorbidities and comedication use in 
      the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or 
      placebo were assessed. A population pharmacokinetic analysis evaluated whether 
      comedications affected the pharmacokinetics of darolutamide in a subset of 388 
      patients. A subgroup analysis of adverse events (AEs) in statin users versus 
      nonusers was conducted. RESULTS: Most participants (median age 74 years) had at 
      least one comorbidity (98.4% in both arms) and used at least one comedication 
      (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study 
      arms. Despite frequent use of comedications with DDI potential, no significant 
      effects on darolutamide pharmacokinetics were identified. Comedications included 
      lipid-modifying agents (34.5%), beta-blockers (29.7%), antithrombotics (42.8%), and 
      systemic antibiotics (26.9%). AE incidence was similar across study arms in 
      statin users and nonusers. Study limitations include the small sample size for 
      sub-analyses. CONCLUSIONS: These analyses suggest the pharmacokinetic profile of 
      darolutamide is not affected by a number of commonly administered drugs in 
      patients with nmCRPC. Although pharmacokinetic data have indicated that 
      darolutamide has the potential to interact with rosuvastatin, used to assess DDI 
      in these studies, this finding did not seem to translate into increased AEs due 
      to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614.
FAU - Shore, Neal
AU  - Shore N
AUID- ORCID: 0000-0001-5767-0548
AD  - Carolina Urologic Research Center, 823 82nd Parkway, Suite B, Myrtle Beach, SC, 
      29572, USA. NShore@gsuro.com.
FAU - Zurth, Christian
AU  - Zurth C
AD  - Bayer AG, Berlin, Germany.
FAU - Fricke, Robert
AU  - Fricke R
AD  - Bayer AG, Berlin, Germany.
FAU - Gieschen, Hille
AU  - Gieschen H
AD  - Bayer AG, Berlin, Germany.
FAU - Graudenz, Kristina
AU  - Graudenz K
AD  - Bayer AG, Berlin, Germany.
FAU - Koskinen, Mikko
AU  - Koskinen M
AD  - Orion Corporation Orion Pharma, Espoo, Finland.
FAU - Ploeger, Bart
AU  - Ploeger B
AD  - Bayer AG, Berlin, Germany.
FAU - Moss, Jonathan
AU  - Moss J
AD  - BAST Inc. Ltd., Loughborough, UK.
FAU - Prien, Olaf
AU  - Prien O
AD  - Bayer AG, Berlin, Germany.
FAU - Borghesi, Gustavo
AU  - Borghesi G
AD  - Bayer AG, Berlin, Germany.
FAU - Petrenciuc, Oana
AU  - Petrenciuc O
AD  - Bayer AG, Berlin, Germany.
FAU - Tammela, Teuvo L
AU  - Tammela TL
AD  - Tampere University Hospital and Tampere University, Tampere, Finland.
FAU - Kuss, Iris
AU  - Kuss I
AD  - Bayer AG, Berlin, Germany.
FAU - Verholen, Frank
AU  - Verholen F
AD  - Bayer AG, Berlin, Germany.
FAU - Smith, Matthew R
AU  - Smith MR
AD  - Massachusetts General Hospital Cancer Center, Boston, USA.
FAU - Fizazi, Karim
AU  - Fizazi K
AD  - Institut Gustave Roussy, Universite Paris-Sud, Villejuif, France.
LA  - eng
SI  - ClinicalTrials.gov/NCT02200614
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - France
TA  - Target Oncol
JT  - Targeted oncology
JID - 101270595
RN  - 0 (Androgen Receptor Antagonists)
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Placebos)
RN  - 0 (Pyrazoles)
RN  - 0 (darolutamide)
RN  - 83MVU38M7Q (Rosuvastatin Calcium)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Androgen Receptor Antagonists/pharmacokinetics/*therapeutic use
MH  - Anticholesteremic Agents/therapeutic use
MH  - Antineoplastic Agents/*therapeutic use
MH  - Castration
MH  - Comorbidity
MH  - Double-Blind Method
MH  - *Drug Interactions
MH  - Drug-Related Side Effects and Adverse Reactions/*epidemiology
MH  - Humans
MH  - Incidence
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Metastasis
MH  - Neoplasm Recurrence, Local
MH  - Placebos
MH  - Polypharmacy
MH  - Prostatic Neoplasms/*drug therapy/epidemiology
MH  - Pyrazoles/pharmacokinetics/*therapeutic use
MH  - Rosuvastatin Calcium/*therapeutic use
PMC - PMC6797643
OAB - BACKGROUND: Darolutamide is a medicine used to treat men with prostate cancer 
      that has not spread to other parts of the body (nonmetastatic). Often, these 
      patients are taking other medicines for common age-related illnesses. Taking more 
      than one medicine at the same time increases the chances of what is known as 
      drug-drug interactions. Drug-drug interactions can decrease how well the 
      medicines work or may sometimes increase side effects. STUDY AIM: To test for 
      possible drug-drug interactions in men with prostate cancer who take darolutamide 
      alongside other medicines. STUDY PARTICIPANTS: Men with nonmetastatic prostate 
      cancer who were being treated with a medicine that lowers testosterone, a 
      chemical in the body that causes prostate cancer tumors to grow. Participants 
      took two darolutamide 300 mg tablets, or an inactive placebo, twice a day. WHAT 
      DID THE RESEARCHERS MEASURE? The researchers documented the number of medicines 
      taken by each participant and the number of other medical conditions that they 
      had. Tests were done to find out whether other medicines affected the way that 
      darolutamide works in the body and whether patients taking darolutamide alongside 
      other medicines experienced more side effects. RESULTS: As would be expected, 
      based on the typical age of patients with prostate cancer, more than 90% of 
      participants in this study used medicines other than darolutamide to manage 
      common age-related illnesses or medical conditions. Taking medicines alongside 
      darolutamide did not impact how darolutamide worked in the body and did not 
      increase the number of side effects experienced by patients. Darolutamide is 
      known to interact with rosuvastatin, a cholesterol-lowering drug. However, in 
      this study, there was no overall increase in side effects among 
      darolutamide-treated patients who took this type of drug compared with in those 
      who did not. CONCLUSION: In this study of patients with nonmetastatic prostate 
      cancer, limited drug-drug interactions were seen when taking darolutamide 
      alongside other medicines given to these patients to manage age-related medical 
      conditions.
OABL- eng
COIS- Dr. Shore reports personal fees from Ferring, Bayer, Amgen, Janssen, Dendreon, 
      Tolmar, Astellas, Pfizer, AstraZeneca, Genentech/Roche, Myovant Sciences, Merck, 
      AstraZeneca, Bristol Meyers Squibb, and Nymox outside the submitted work. Drs. 
      Zurth, Fricke, Gieschen, Graudenz, Ploeger, Prien, Borghesi, Petrenciuc, and Kuss 
      report employment by and stock ownership in Bayer. Dr. Koskinen reports 
      employment by and stock ownership in Orion. Dr. Moss reports personal fees from 
      Akari, AstraZeneca, Bayer, Carrick Therapeutics, Debiopharm, Orphazym, Proveca, 
      Richmond Pharmacology, and the University of Leicester outside the submitted 
      work. Dr. Tammela reports personal fees from Janssen, and grants and personal 
      fees from Bayer, Lidds AB, and Astellas, outside the submitted work. Dr. Verholen 
      reports employment by Bayer. Dr. Smith reports personal fees from Amgen, 
      Astellas, Bayer, Clovis, Gilead, Janssen, Lilly, Novartis, and Pfizer, outside 
      the submitted work. Dr. Fizazi reports personal fees from Amgen, Astellas, 
      AstraZeneca, Bayer, Clovis, Curevac, ESSA, Janssen, Orion Pharma, 
      Roche/Genentech, and Sanofi outside the submitted work.
EDAT- 2019/10/02 06:00
MHDA- 2020/04/04 06:00
PMCR- 2019/09/30
CRDT- 2019/10/02 06:00
PHST- 2019/10/02 06:00 [pubmed]
PHST- 2020/04/04 06:00 [medline]
PHST- 2019/10/02 06:00 [entrez]
PHST- 2019/09/30 00:00 [pmc-release]
AID - 10.1007/s11523-019-00674-0 [pii]
AID - 674 [pii]
AID - 10.1007/s11523-019-00674-0 [doi]
PST - ppublish
SO  - Target Oncol. 2019 Oct;14(5):527-539. doi: 10.1007/s11523-019-00674-0.