European Journal of Cancer 192 (2023) 113258

Available online at www.sciencedirect.com

j o u rn a l h o mep a ge : w ww.e j cance r .c om

Original Research

Efficacy and safety outcomes of darolutamide in patients

with non-metastatic castration-resistant prostate cancer ]]
]]]]]]
]]

with comorbidities and concomitant medications from

the randomised phase 3 ARAMIS trial
⁎
Karim Fizazi a, , Neal D. Shore b, Matthew Smith c, Rodrigo Ramos d,
Robert Jones e, Günter Niegisch f, Egils Vjaters g, Yuan Wang h,
Shankar Srinivasan h, Toni Sarapohja i, Frank Verholen j

a
Institut Gustave Roussy, University of Paris Saclay, Villejuif, France
b
Carolina Urologic Research Center/Genesis Care, Myrtle Beach, South Carolina, USA
c
Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center and Harvard Medical School,
Boston, Massachusetts, USA
d
Departamento de Cirurgia, Instituto Português de Oncologia, Lisboa, Portugal
e
University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK
f
Department of Urology, University Hospital and Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
g
Urological Center, P. Stradins Clinical University Hospital, Riga, Latvia
h
Global Medical Affairs, Oncology, Bayer Healthcare, Whippany, New Jersey, USA
i
Clinical Operations and Data Science, Orion Corporation, Espoo, Finland
j
Global Medical Affairs, Oncology, Bayer Consumer Care AG, Basel, Switzerland

Received 23 May 2023; Received in revised form 18 July 2023; Accepted 22 July 2023
Available online 27 July 2023

KEYWORDS Abstract Purpose: In patients with non-metastatic castration-resistant prostate cancer

Darolutamide; (nmCRPC) in the Androgen Receptor Antagonizing Agent for Metastasis-free Survival
Non-metastatic (ARAMIS) trial, darolutamide significantly improved median metastasis-free survival by
castration-resistant nearly 2 years and reduced the risk of death by 31% versus placebo, with a favourable safety/
prostate cancer; tolerability profile. This post hoc analysis of ARAMIS evaluated efficacy and safety in pa­
Comorbidities; tients by number of comorbidities and concomitant medications.
Concomitant Methods: Patients with nmCRPC were randomised 2:1 to darolutamide (n = 955) or placebo
medications; (n = 554) while continuing androgen-deprivation therapy. Overall survival (OS) and
Survival; treatment-emergent adverse events (TEAEs) were evaluated in subgroups by median numbers
Adverse events

⁎
Correspondence to: Department of Cancer Medicine, Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France.
E-mail address: [email protected] (K. Fizazi).

https://doi.org/10.1016/j.ejca.2023.113258
0959-8049/© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creative­
commons.org/licenses/by-nc-nd/4.0/).
2 K. Fizazi et al. / European Journal of Cancer 192 (2023) 113258

of ongoing comorbidities and concomitant medications. HRs were determined from uni­
variate analysis using Cox regression.
Findings: Median numbers of comorbidities and concomitant medications were 6 and 10,
respectively, with 41.6% of patients having > 6 comorbidities and 48.8% taking > 10 con­
comitant medications. For patients with ≤ 6 and > 6 comorbidities, darolutamide increased
OS versus placebo (hazard ratio [HR] 0.65 and 0.73, respectively), and this benefit was con­
sistent for cardiovascular, metabolic, and other comorbidities (HR range: 0.39–0.88). For
patients taking ≤ 10 and > 10 concomitant medications, increased OS was also observed with
darolutamide versus placebo (HR 0.76 and 0.66, respectively), and the benefit was consistent
across medication classes (HR range: 0.45–0.80). Incidences of TEAEs and TEAEs leading to
treatment discontinuation with darolutamide were similar to placebo across subgroups by
numbers of comorbidities and concomitant medications.
Conclusions: The OS benefit and safety of darolutamide remained consistent with that ob­
served in the overall ARAMIS population, even in patients with high numbers of co­
morbidities or concomitant medications.
ClinicalTrials.gov registration: NCT02200614.
Tweetable abstract: Darolutamide increased overall survival versus placebo, and incidences of
most adverse events were similar between treatments in patients with ≤ 6 or > 6 comorbidities
and those taking ≤ 10 or > 10 concomitant medications.
© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction ARAMIS evaluated efficacy and safety outcomes of dar­

olutamide in patients by number of ongoing comorbidities
Patients with non-metastatic castration-resistant prostate and use of concomitant medications.
cancer (nmCRPC) are usually elderly and have co­
morbidities that are treated with various medications [1,2]. 2. Methods
As a result, some of these patients have an increased health
care and drug burden that may lead to diminished physical The study design and methodology of ARAMIS have
function, attention, and concentration [3]. Polypharmacy been previously published [7]. Briefly, this global, mul­
is typically defined as use of 5 or more daily medications ticentre, double-blind, phase 3 trial randomised (2:1)
and is associated with an increased risk of adverse events adult patients with nmCRPC to darolutamide 600 mg
and drug–drug interactions (DDIs) [4]. DDIs with clinical twice daily (n = 955) or placebo (n = 554), in addition to
relevance may manifest as an increase in adverse events or ongoing androgen-deprivation therapy (ADT). Key in­
a decline in therapeutic activity, potentially leading to clusion criteria were baseline prostate-specific antigen
compromised clinical outcomes [2,5]. Minimising risks (PSA) level ≥ 2 ng/mL, a PSA doubling time ≤ 10
associated with DDIs from polypharmacy is an important months, and an Eastern Cooperative Oncology Group
component of optimal care for patients with nmCRPC. performance status (ECOG PS) of 0 or 1. Assessment
Thus, treatment selection for these patients should con­ visits occurred every 16 weeks, and patients continued
sider treatment efficacy as well as the safety, tolerability, treatment until protocol-defined progression, dis­
and DDI profile of medications [1,2]. Currently, limited continuation due to TEAEs, or withdrawal of consent.
data are available on the effects of underlying comorbid­ The trial protocol is available at https://clinicaltrials.
ities and concomitant medications on outcomes for pa­ gov/ProvidedDocs/14/NCT02200614/Prot_002.pdf.
tients with nmCRPC [6]. For this post hoc analysis, the end-points were overall
In the phase 3 Androgen Receptor Antagonizing Agent survival (OS) and TEAEs, defined as adverse events that
for Metastasis-free Survival (ARAMIS) trial in patients occurred after the start of treatment and graded ac­
with nmCRPC, the androgen receptor inhibitor (ARi) cording to the National Cancer Institute Common
darolutamide improved median metastasis-free survival by Terminology Criteria for Adverse Events (v4.03). These
almost 2 years and reduced the risk of death by 31% end-points were analysed for subgroups of patients based
compared with placebo [7,8]. Darolutamide also demon­ on median numbers of comorbidities and concomitant
strated a favourable safety and tolerability profile with medications ongoing at baseline. The frequencies of in­
similar discontinuation rates due to treatment-emergent dividual comorbidities were reported and grouped by
adverse events (TEAEs) in the darolutamide and placebo preferred terms from the most common (occurring in
groups (8.9% and 8.7%, respectively). Darolutamide is > 5% of the total ARAMIS population) ongoing co­
structurally distinct and a highly potent ARi, with low morbid conditions by Shore et al using the Medical
blood–brain barrier penetration and a limited potential for Dictionary for Regulatory Activities (MedDRA) [5].
clinically relevant DDIs [5,9–12]. This post hoc analysis of Cardiovascular comorbidities included hypertension,
 K. Fizazi et al. / European Journal of Cancer 192 (2023) 113258 3

cardiac arrhythmias, and coronary artery disorders, in­ receiving darolutamide and 11 patients receiving pla­
cluding myocardial ischaemia. Metabolic comorbidities cebo. Among patients assigned to darolutamide and
included obesity, lipid metabolism disorders, and various placebo, the most common concomitant medication
forms of diabetes mellitus. Other comorbidities included subgroups were antihypertensive medications (70.3%
renal insufficiency, joint disorders, and gastrointestinal and 67.1%, respectively), medications for pain and
mobility and defecation disorders (gastroesophageal re­ inflammation (67.5% and 65.7%, respectively), and
flux disease and constipation). non-antihypertensive medications for cardiovascular
Using all recorded medications ongoing at baseline of disease (64.1% and 65.7%, respectively). Medications for
ARAMIS, concomitant medications subgroups were de­ gastrointestinal and metabolic disorders were reported
fined by classes and subclasses of medications per Shore in 52.5% and 54.0% and medications for urologic dis­
et al [5]. Cardiovascular medications were divided into orders were reported in 32.0% and 32.9% of patients in
antihypertensives, including agents acting on the the darolutamide and placebo groups, respectively.
renin–angiotensin system, beta-blockers, calcium-channel Demographics and baseline characteristics were
blockers, and diuretics, and non-antihypertensives, in­ generally consistent across patient subgroups by median
cluding antithrombotics (antiplatelet agents and numbers of comorbidities and concomitant medications
anticoagulants), lipid-modifying agents, cardiac therapy (Table 1). For patients with > 6 comorbidities or > 10
(glycosides, antiarrhythmics, and antianginals), and vaso­ concomitant medications, median time from diagnosis
protectives. Medications used for pain and inflammation to study treatment was longer and more patients re­
included analgesics, anti-inflammatory and disease-mod­ ceived bone-sparing agents compared with those with
ifying antirheumatic products, and systemic corticoster­ fewer comorbidities or concomitant medications. More
oids. Medications for gastrointestinal and metabolic patients with > 6 comorbidities had an ECOG PS of 1
disorders included drugs for acid-related disorders, anti­ versus those with ≤ 6 comorbidities.
diabetics, antidiarrhoeals, intestinal anti-inflammatory and Darolutamide increased OS compared with placebo
anti-infective agents, and drugs for constipation. Medica­ with similar HRs in terms of reduction in risk of death
tions for urologic disorders included drugs for erectile in patients with ≤ 6 comorbidities (HR 0.65; 95% CI
dysfunction, benign prostatic hyperplasia, and overactive 0.45–0.93) and in patients with > 6 comorbidities
bladder; medications used for ADT were not included. (HR 0.73; 95% CI 0.51–1.04; Fig. 1). The survival
benefit of darolutamide versus placebo was generally
2.1. Statistical analysis consistent in patients with cardiovascular disorders
(hypertension HR 0.67; arrhythmias HR 0.49; coronary
Data used for this analysis were from the final data cutoff artery disorders HR 0.51), metabolic disorders (obesity
date of 15th November 2019, for the double-blind period, HR 0.65; lipid disorders HR 0.65; diabetes HR 0.88),
which was defined as the time from randomisation to the and other comorbidities (renal insufficiency HR 0.67;
start date of the open-label period. The data cutoff date joint disorders HR 0.70; gastrointestinal disorders
for the Shore et al [5] publication was 17th January 2019. HR 0.39) (Fig. 2). Overall survival results for darolutamide
Forest plots of OS were generated with hazard ratios versus placebo were also comparable among patients re­
(HRs) and 95% confidence intervals (CIs) determined ceiving ≤ 10 concomitant medications (HR 0.76; 95% CI
from univariate analysis using Cox regression. The 95% 0.52–1.11) and patients receiving > 10 concomitant medi­
CIs were not controlled for multiple comparisons. cations (HR 0.66; 95% CI, 0.47–0.92; Fig. 1). Patients re­
ceiving various classes of medications achieved a consistent
3. Results trend of OS benefit with darolutamide versus placebo, with
HRs ranging from 0.45 to 0.80 (Fig. 3).
In the ARAMIS study population, the median number The incidences of TEAEs, grade 3/4 TEAEs, and
of comorbidities was 6 and the median number of serious TEAEs were higher in both arms for patients with
concomitant medications was 10, excluding ADT. > 6 comorbidities and for patients with > 10 concomitant
Overall, 42.4% of patients receiving darolutamide and medications compared with patients with fewer co­
40.1% of patients receiving placebo had > 6 comorbid­ morbidities and concomitant medications (Table 2). In­
ities, and 48.6% of patients receiving darolutamide and cidences of most TEAEs, grade 3/4 TEAEs, and serious
49.3% of patients receiving placebo had > 10 con­ TEAEs were similar between darolutamide and placebo
comitant medications. Eleven patients receiving dar­ for each subgroup of patients based on the median
olutamide and 6 patients receiving placebo had no numbers of comorbidities and concomitant medications.
comorbidities. Cardiovascular and metabolic co­ Among TEAEs commonly associated with ARi therapy,
morbidities (including diabetes) were most common, incidences of hypertension, fracture, fall, and mental
occurring in 73.3% and 73.2% of patients receiving impairment were similar between darolutamide and pla­
darolutamide, respectively, and 71.5% and 74.2% of cebo in patient subgroups by comorbidities and con­
patients receiving placebo, respectively. Data on con­ comitant medications. Incidences of rash and fatigue
comitant medications were missing for 10 patients were generally comparable to the overall study
 4

Table 1
Demographic and baseline characteristics for subgroups of patients by median numbers of comorbidities and concomitant medications.
Variable Comorbiditiesa Concomitant medicationsb Overall ARAMIS population
≤6 >6 ≤ 10 > 10
DARO PBO DARO PBO DARO PBO DARO PBO DARO PBO
(n = 539) (n = 326) (n = 405) (n = 222) (n = 481) (n = 270) (n = 464) (n = 273) (n = 955) (n = 554)
Age, y 73 (51–94) 72 (50–92) 76 (48–95) 75.5 (57–91) 74 (52–94) 72 (50–92) 75 (48–95) 75 (52–91) 74 (48–95) 74 (50–92)
Time from diagnosis, mo 82.9 75.0 92.4 (2.6–302.3) 105.0 82.1 73.1 92.3 96.1 86.2 84.2
(4.8–337.5) (1.3–266.6) (0.5–344.7) (2.9–337.5) (1.3–239.1) (2.6–302.3) (0.5–344.7) (2.6–337.5) (0.5–344.7)
Lymph nodes on central 61 (11.3) 47 (14.4) 39 (9.6) 18 (8.1) 48 (10.0) 34 (12.6) 51 (11.0) 31 (11.4) 100 (10.5) 66 (11.9)
imaging, n (%)
Serum PSA, ng/mL 8.6 (1.2–858.3) 9.5 (1.5–885.2) 10.2 (0.3–240.0) 9.8 (1.6–310.2) 9.8 (1.1–858.3) 9.6 (1.5–885.2) 8.7 (0.3–240.0) 9.4 (1.6–310.2) 9.0 (0.3–858.3) 9.7 (1.5–885.2)
PSA doubling time, mo 4.3 (0.9–11.0) 4.4 (0.7–12.0) 4.5 (0.7–10.4) 4.7 (0.9–13.2) 4.3 (0.7–10.4) 4.3 (0.7–13.2) 4.6 (0.9–11.0) 4.9 (0.9–10.2) 4.4 (0.7–11.0) 4.7 (0.7–13.2)
ECOG PS = 1, n (%) 130 (24.1) 78 (23.9) 172 (42.5) 85 (38.3) 140 (29.1) 73 (27.0) 163 (35.1) 86 (31.5) 305 (31.9) 163 (29.4)
Use of bone-sparing 6 (1.1) 12 (3.7) 25 (6.2) 19 (8.6) 9 (1.9) 12 (4.4) 22 (4.7) 20 (7.3) 31 (3.2) 32 (5.8)
agent, n (%)
Prior hormonal therapy,
n (%)
1 110 (20.4) 69 (21.2) 65 (16.0) 32 (14.4) 96 (20.0) 58 (21.5) 80 (17.2) 43 (15.8) 178 (18.6) 103 (18.6)
≥2 294 (73.1) 237 (72.7) 325 (80.2) 179 (80.6) 353 (73.4) 193 (71.5) 369 (79.5) 220 (80.6) 726 (76.0) 420 (75.8)
Not applicablec 35 (6.5) 20 (6.1) 15 (3.7) 11 (5.0) 32 (6.7) 19 (7.0) 15 (3.2) 10 (3.7) 51 (5.3) 31 (5.6)
DARO, darolutamide; ECOG PS, Eastern Cooperative Oncology Group performance status; PBO, placebo; PSA, prostate-specific antigen.
Values are median (range) unless otherwise indicated.
Data for “Overall ARAMIS population” are from K. Fizazi, et al., Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide, Volume No 383, Page No 1040-9
Copyright © 2020 Massachusetts Medical Society, reprinted with permission, except for the presence of lymph nodes on central imaging and prior hormonal therapy, which were updated at the final
K. Fizazi et al. / European Journal of Cancer 192 (2023) 113258

analysis data cutoff of 15th November 2019.

a
Not including data for patients without comorbidities (DARO, n = 11; PBO, n = 6).
b
Data on concomitant medications missing for 10 patients receiving DARO and 11 patients receiving PBO.
c
Patients who underwent surgical castration.
 K. Fizazi et al. / European Journal of Cancer 192 (2023) 113258 5

Number of Number of
HR (D/P) [95% CI] HR (D/P) [95% CI]
comorbidities: concomitant medications:
0.650 [0.456–0.925] 0.757 [0.516–1.111]
≤6 (n=865, D=125)a ≤10 (n=751, D=112)b

Number of Number of
comorbidities: 0.729 [0.512–1.038] concomitant medications: 0.661 [0.473–0.924]
>6 (n=627, D=129)a >10 (n=737, D=139)b

Overall Overall
0.683 [0.532–0.876] 0.683 [0.532–0.876]
(N=1509, D=254) (N=1509, D=254)

0.400 0.500 0.600 0.700 0.800 0.900 1.000 1.100 0.400 0.500 0.600 0.700 0.800 0.900 1.000 1.100 1.200
Hazard Ratio Hazard Ratio

Fig. 1. Forest plots for HRs of overall survival for subgroups of patients by median numbers of comorbidities and concomitant medi­
cations. D, number of patients with an event (death); D/P, darolutamide/placebo; HR, hazard ratio. aDoes not include data for patients
without comorbidities (darolutamide, n = 11; placebo, n = 6); bData on concomitant medications were missing for 10 patients receiving
darolutamide and 11 patients receiving placebo.
Cardiovascular

HR (D/P) [95% CI]

Vascular hypertensive disorders (n=977, D=176) 0.673 [0.498–0.909]

Cardiac arrhythmias (n=307, D=63) 0.486 [0.287–0.823]

Coronary artery disorders (n=208, D=62) 0.507 [0.298–0.864]

Metabolic

Obesity (n=901, D=155) 0.651 [0.473–0.895]

Lipid metabolism disorders (n=453, D=78) 0.650 [0.414–1.021]

Glucose metabolism disorders
0.881 [0.499–1.553]
(including diabetes mellitus) (n=298, D=50)

Baseline eGFR <90 mL/min/1.73 m2 (n=867, D=176) 0.666 [0.493–0.899]

Other

Joint disorders (n=343, D=58) 0.699 [0.401–1.219]

Gastrointestinal mobility and 0.387 [0.156–0.964]

defecation conditions (n=172, D=20)

Overall (N=1509, D=254) 0.683 [0.532–0.876]

0.000 0.200 0.400 0.600 0.800 1.000 1.200 1.400 1.600

Hazard Ratio

Fig. 2. Forest plots of overall survival for darolutamide versus placebo by comorbidity groups. D, number of patients with an event
(death); D/P, darolutamide/placebo; eGFR, estimated glomerular filtration rate.

population of ARAMIS (Table 2). Notably, TEAEs overall population. Incidences of most TEAEs, except
leading to permanent discontinuation of study drug were fatigue and rash, as well as the incidences of grade 3/4
similar between darolutamide and placebo, even in pa­ TEAEs, serious TEAEs, and TEAEs leading to dis­
tients with > 10 concomitant medications (10.8% and continuation, were similar between darolutamide and
10.6%, respectively). placebo in each subgroup, including patients with high
numbers of comorbidities and concomitant medications.
4. Discussion The results of this post hoc analysis add to available
information regarding the treatment benefit, toler­
The ARAMIS population consisted of patients with ability, and safety profile of darolutamide in various
nmCRPC with a median age of 74 years, a median of 6 patient subgroups [13]. Darolutamide had a consistently
comorbidities, and a median of 10 concomitant medica­ favourable impact on OS in prespecified subgroup
tions. In this post hoc analysis of ARAMIS, the OS analyses of ARAMIS [8], which included various age
benefit and safety of darolutamide compared with pla­ groups and ECOG performance status. The survival
cebo were consistent across subgroups by numbers of benefit of darolutamide was also similar among patients
comorbidities and concomitant medications and with the with a PSA doubling time of ≤ 6 months (HR 0.55;
6 K. Fizazi et al. / European Journal of Cancer 192 (2023) 113258

HR (D/P) [95% CI]

Antihypertensives
Antihypertensives (n=1043, D=186) 0.678 [0.506–0.910]
Agents acting on the renin–angiotensin
0.803 [0.562–1.148]
system (n=811, D=132)

Beta-blocking agents (n=445, D=92) 0.452 [0.296–0.690]

Cardiovascular

Calcium-channel blockers (n=350, D=58) 0.548 [0.326–0.919]

Diuretics (n=329, D=74) 0.558 [0.344–0.906]

antihypertensives

Non-antihypertensives (n=976, D=175) 0.575 [0.427–0.775]

Antithrombotic agents (n=646, D=129) 0.494 [0.349–0.699]

Non-

Lipid-modifying agents (n=559, D=94) 0.642 [0.427–0.965]

Cardiac therapy (n=343, D=62) 0.643 [0.386–1.070]

Vasoprotectives (n=312, D=66) 0.562 [0.344–0.918]

Pain/Inflammation

Pain and inflamation (n=1009, D=193) 0.631 [0.474–0.841]

Analgesics or anti-inflammatory
0.647 [0.481–0.870]
and antirheumatic products (n=958, D=182)

Analgesics (n=834, D=160) 0.650 [0.473–0.891]

Anti-inflammatory and
0.801 [0.496–1.294]
antirheumatic products (n=395, D=73)

Corticosteroids for systemic use (n=224, D=53) 0.704 [0.405–1.227]

GI and metabolic disorders (n=800, D=144) 0.626 [0.451–0.870]

GI/Metabolic

Drugs for acid-related disorders (n=462, D=81) 0.792 [0.508–1.234]

Drugs for diabetes (n=299, D=47) 0.794 [0.442–1.426]

Antidiarrhoeals, intestinal anti-inflammatory/
0.657 [0.384–1.124]
anti-infective agents (n=260, D=54)

Drugs for constipation (n=240, D=46) 0.674 [0.374–1.213]

Urologic

Urologic disorders (n=488, D=91) 0.662 [0.437–1.001]

Overall (N=1509, D=254) 0.683 [0.532–0.876]

0.200 0.400 0.600 0.800 1.000 1.200 1.400 1.600

Hazard Ratio

Fig. 3. Forest plots of overall survival for darolutamide versus placebo by class and subclass of concomitant medications. D, number of
patients with an event (death); D/P, darolutamide/placebo; GI, gastrointestinal.

95% CI 0.35–0.88) and those with a PSA doubling time The observed number of concomitant medications in
of ≥ 6 months (HR 0.74; 95% CI 0.55–0.99) [8,14]. In the ARAMIS population is consistent with other reports
addition, darolutamide maintained health-related of older patients with cancer, in whom the mean or
quality of life in patients with nmCRPC by significantly median number of reported concomitant medications was
(P < 0.01) delaying the time to deterioration in prostate 11 [4,17]. One of these studies evaluated 105 patients re­
cancer-specific quality of life and urinary and bowel ceiving enzalutamide for metastatic CRPC and found that
symptoms versus placebo [15,16]. The effects of dar­ 85% of patients were using at least 1 concomitant medi­
olutamide on local symptom control were also evident cation that interacted with enzalutamide and required
in fewer prostate cancer–related invasive procedures and treatment modification [17]. In another study of 86 pa­
similar incidences of urinary and bowel TEAEs versus tients with metastatic CRPC who received enzalutamide,
placebo [16]. These outcomes offer important informa­ 93% of patients had a potential DDI, with the highest risk
tion for treatment selection in this population of pa­ of interactions occurring with drugs acting on the cardi­
tients who are generally asymptomatic and may receive ovascular and nervous systems [18]. DDIs may lead to
treatment for prolonged periods of time. increased TEAEs, as shown in a retrospective review of
 K. Fizazi et al. / European Journal of Cancer 192 (2023) 113258 7

Table 2
Treatment-emergent adverse events for subgroups of patients by median numbers of comorbidities and concomitant medications.
AE, n (%) Comorbiditiesa Concomitant medicationsb Overall ARAMIS
population
≤6 >6 ≤ 10 > 10
DARO PBO DARO PBO DARO PBO DARO PBO DARO PBO
(n = 538) (n = 326) (n = 405) (n = 222) (n = 481) (n = 270) (n = 464) (n = 273) (n = 954c) (n = 554)
Any 447 (83.1) 242 (74.2) 366 (90.4) 195 (87.8) 371 (77.1) 184 (68.1) 442 (95.3) 248 (90.8) 818 (85.7) 439 (79.2)
Grade 3/4 127 (23.6) 58 (17.8) 124 (30.6) 61 (27.5) 67 (13.9) 36 (13.3) 183 (39.4) 82 (30.0) 251 (26.3) 120 (21.7)
Serious 118 (21.9) 59 (18.1) 131 (32.3) 61 (27.5) 65 (13.5) 33 (12.2) 183 (39.4) 85 (31.1) 249 (26.1) 121 (21.8)
AE leading to 43 (8.0) 20 (6.1) 42 (10.4) 28 (12.6) 35 (7.3) 17 (6.3) 50 (10.8) 29 (10.6) 85 (8.9) 48 (8.7)
permanent study
drug discontinuation
AEs of interest
Fatigue 49 (9.1) 19 (5.8) 76 (18.8) 27 (12.2) 42 (8.7) 12 (4.4) 84 (18.1) 33 (12.1) 126 (13.2) 46 (8.3)
Hypertension 43 (8.0) 23 (7.1) 30 (7.4) 13 (5.9) 29 (6.0) 15 (5.6) 44 (9.5) 21 (7.7) 74 (7.8) 36 (6.5)
Fracture 29 (5.4) 8 (2.5) 23 (5.7) 12 (5.4) 21 (4.4) 5 (1.9) 31 (6.7) 15 (5.5) 52 (5.5) 20 (3.6)
Fall 23 (4.3) 14 (4.3) 27 (6.7) 13 (5.9) 13 (2.7) 7 (2.6) 36 (7.8) 18 (6.6) 50 (5.2) 27 (4.9)
Rash 15 (2.8) 2 (0.6) 15 (3.7) 4 (1.8) 7 (1.5) 2 (0.7) 23 (5.0) 4 (1.5) 30 (3.1) 6 (1.1)
Mental 9 (1.7) 4 (1.2) 10 (2.5) 6 (2.7) 7 (1.5) 3 (1.1) 12 (2.6) 7 (2.6) 19 (2.0) 10 (1.8)
impairment
AE, adverse event; ARAMIS, Androgen Receptor Antagonizing Agent for Metastasis-free Survival; DARO, darolutamide; PBO, placebo.
a
Not including data for patients without comorbidities (DARO, n = 11; PBO, n = 6).
b
Data on concomitant medications missing for 10 patients receiving DARO and 11 patients receiving PBO.
c
One patient randomised to DARO did not receive treatment and was excluded from the safety analysis.

404 older patients with cardiovascular disease, in whom treatment groups, suggesting minimal effect of these DDIs
the most common potential interactions were drugs with [5,7]. Darolutamide inhibits the breast cancer resistance
an additive central nervous system–depressant effect [19]. protein (BCRP) transporter, leading to a potential increase
A meta-analysis and systematic literature review of older in exposure of BCRP substrates, such as rosuvastatin,
patients with cancer found an association between poly­ which should be taken into consideration. In contrast, en­
pharmacy and falls in 3 studies [20]. The risk of falls and zalutamide and apalutamide have been shown to induce
other central nervous system–related adverse events in key enzymes responsible for drug metabolism, including
patients with polypharmacy should be considered when cytochrome P 450 3A4, 2C8, 2C9, and 2C19, and apalu­
selecting anticancer drugs that will be given over extended tamide has the potential to interact with drug transporters
periods of time. This is especially relevant for drugs such [25–27]. The effect of enzyme or transporter induction may
as enzalutamide and apalutamide that have higher in­ result in lower concentrations of the coadministered drug
cidences of central nervous system side effects, such as (e.g. omeprazole, warfarin, and rosuvastatin), potentially
falls and mental impairment disorders compared with leading to suboptimal clinical outcomes for related co­
placebo, and a higher potential for clinically relevant morbid conditions.
DDIs [21–23]. By contrast, the incidence of these TEAEs The results of this analysis are limited by their post
of interest were similar between patients receiving dar­ hoc nature, potential for selection bias, and small po­
olutamide and those receiving placebo and darolutamide pulations for certain comorbidities and concomitant
has been shown to have limited potential for DDIs in the medications. Patients were grouped by the number of
ARAMIS study [5,7,8]. comorbidities and concomitant medications without
These findings highlight the importance of considering considering their potential prognostic implications. The
the impact of polypharmacy on the choice of drugs used for ongoing PEACE-6 Vulnerable trial (NCT04916613)
treatment of patients with nmCRPC [5,24]. The results of may add to the evidence regarding use of darolutamide
this post hoc analysis of ARAMIS suggest that the efficacy in patients with limited functional ability and co­
and safety of darolutamide are not impacted by commonly morbidities who are not considered candidates for
used concomitant medications in this population [5,11]. docetaxel or other androgen receptor pathway in­
Darolutamide has been previously shown to have a low hibitors. This international, multicentre, phase 3, ran­
potential to interact with medications commonly used to domised, double-blind, placebo-controlled trial will
treat comorbidities in the nmCRPC population, such as assess the effect of darolutamide versus placebo, in ad­
calcium-channel blockers and anticoagulants [5,11]. A dition to ADT, on standard disease-related endpoints,
subgroup analysis of ARAMIS patients who used statins including radiographic and clinical progression-free
versus non-users found no imbalance in treatment effects survival, time to CRPC, and OS, as well as health-re­
and the incidence of adverse events was similar between lated quality of life and geriatric status in patients with
8 K. Fizazi et al. / European Journal of Cancer 192 (2023) 113258

decreased functional ability, chronic illnesses, and me­ Guardant Health, Merck, Foundation Medicine. Expert
tastatic prostate cancer. testimony: Ferring. Other relationship: Photocure, Alessa
The results from this subgroup analysis of ARAMIS, Therapeutics. Research funding: AbbVie, Amgen,
even among patients with a high number of comorbid­ Astellas Pharma, AstraZeneca, Bayer, Bristol Myers
ities and patients with a high number of concomitant Squibb/Pfizer, Boston Scientific, Clovis Oncology,
medications, are consistent with the overall ARAMIS Dendreon, Exact Imaging, Ferring, Foundation
population, showing improved OS with darolutamide Medicine, InVitae, Janssen, MDxHealth, Merck,
versus placebo and a favourable safety and tolerability Myovant Sciences, Myriad Genetics, Nymox, Pfizer,
profile of darolutamide. A plain-language summary of Sanofi, Sesen Bio, Tolmar, CG Oncology, DisperSol,
this report is available in the online Supplementary FORMA Therapeutics, Guardant Health, Jiangsu
Material. Yahong Meditech, Novartis, Pacific Edge, POINT
Biopharma, Propella Therapeutics, Seattle Genetics, MT
Funding statement Group, Theralase, Veru, Zenflow, Advantagene, Aragon
Pharmaceuticals, Endocyte, Exelixis, FKD Therapies,
This study was funded by Bayer AG and Orion Genentech, ISTARI Oncology, Medivation,
Corporation. OncoCellMDx, ORIC Pharmaceuticals, Palette Life
Sciences, Plexxikon, RhoVac, Steba Biotech, Urogen
CRediT authorship contribution statement Pharma, Urotronic, US Biotest, Vaxiion. Matthew
Smith: Consulting or advisory role: Bayer, Janssen
Karim Fizazi, Neal D. Shore, Matthew Smith, Rodrigo Oncology, Amgen, Pfizer, Lilly, Novartis, Astellas
Ramos, Robert Jones, Günter Niegisch, Egils Vjaters: Pharma. Research funding: Janssen Oncology (Inst),
Investigation, Data Curation, Resources, Supervision, Bayer (Inst), Lilly (Inst), ESSA (Inst), ORIC
Visualisation, Writing – original draft, review & editing. Pharmaceuticals (Inst). Rodrigo Ramos: Honoraria:
Yuan Wang: Conceptualisation, Funding Acquisition, Astellas Pharma, Bayer, Janssen-Cilag, Pfizer.
Methodology, Project Administration, Visualisation, Consulting or advisory roles: Astellas Pharma, Bayer,
Writing – original draft, review & editing. Shankar Janssen-Cilag; Travel, accommodations, expenses:
Srinivasan: Methodology, Formal Analysis, Software, Janssen-Cilag. Robert Jones: Honoraria: Astellas
Visualisation, Writing – original draft, review & Pharma, AstraZeneca, Bayer, Bristol Myers Squibb,
editing. Toni Sarapohja: Visualisation, Writing – ori­ Clovis Oncology, Eisai, EUSA Pharma, Ipsen, Janssen,
ginal draft, review & editing. Frank Verholen: Merck Serono, MSD Oncology, Novartis. Fizer,
Methodology, Visualisation, Writing – original draft, Pharmacyclics, Roche/Genentech, Sanofi, Seagen.
review & editing. Consulting or advisory roles: Clovis Oncology. Research
funding: Astellas Pharma (Inst), AstraZeneca (Inst),
Declaration of Competing Interest Bayer (Inst), Clovis Oncology (Inst), Exelixis (Inst),
Novartis (Inst), Pfizer (Inst), Roche (Inst). Travel, ac­
Karim Fizazi: Honoraria: Janssen (Inst), Sanofi (Inst), commodations, expenses: Astellas Pharma, Bayer, Ipsen,
Astellas Pharma (Inst), Bayer (Inst). Consulting or ad­ Janssen, MSD. Günter Niegisch: Honoraria:
visory role: Janssen Oncology (Inst), Bayer, Astellas AstraZeneca, Medac, Roche Pharma AG. Consulting or
Pharma (Inst), Sanofi (Inst), Orion, AstraZeneca (Inst), advisory roles: Bristol Myers Squibb, Ipsen, Janssen
ESSA (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Oncology, Merck/Pfizer, Pfizer, Roche Pharma AG,
Clovis Oncology (Inst), Curevac, Novartis (Inst), Pfizer Sanofi-Aventis. Travel, accommodations, expenses:
(Inst). Travel, accommodations, expenses: Janssen, Bristol Myers Squibb/Celgene, Roche Pharma AG. Egils
MSD, AstraZeneca. Neal D. Shore: Consulting or ad­ Vjaters: Consulting or advisory roles: Bayer, Ipsen,
visory roles: Bayer, Janssen Scientific Affairs, Dendreon, Janssen. Yuan Wang: Employment: Bayer. Stock and
Tolmar, Ferring, Medivation/Astellas, Amgen, Pfizer, other ownership interests: Bayer. Shankar Srinivasan:
AstraZeneca, Myovant Sciences, Astellas Pharma, Employment: Bayer. Stock and other ownership inter­
AbbVie, Merck, Bristol Myers Squibb/Sanofi, Clovis ests: Bayer. Toni Sarapohja: Employment: Orion. Frank
Oncology, Exact Imaging, FerGene, Foundation Verholen: Employment: Bayer.
Medicine, CG Oncology, InVitae, MDxHealth, Myriad
Genetics, Nymox, Propella Therapeutics, Genzyme, Acknowledgements
Sanofi, Sesen Bio, CG Oncology, Exact Sciences, Genesis
Cancer Care, Pacific Edge Biotechnology, Phosphorus, We thank the patients, their families, and all of the in­
Urogen Pharma, Specialty Networks, Peerview, Clarity vestigators involved in this study. The ARAMIS study
Pharmaceuticals, Lantheus Medical Imaging, Lilly, was sponsored by Bayer HealthCare and Orion
Photocure, Sema4, Telix Pharmaceuticals, Tempus, Corporation. The statistical analyses were supported by
Vaxiion. Speakers’ bureau: Janssen, Bayer, Dendreon, Kevin Clark (MPH, MS, PT) of Bayer, and Lei Li
Astellas Pharma, AstraZeneca, Clovis Oncology, Pfizer, (M.Sc) and Jessica Abramowski (M.Sc) of CHRESTOS
 K. Fizazi et al. / European Journal of Cancer 192 (2023) 113258 9

Concept GmbH and Co. KG. Jorge Ortiz (MD) of [4] Ramsdale E, Lemelman T, Loh KP, Flannery M, Kehoe L,
Bayer provided review of the manuscript. Writing and Mullaney T, et al. Geriatric assessment-driven polypharmacy
discussions between oncologists, older patients, and their care­
editorial support in the development of this manuscript givers. J Geriatr Oncol 2018;9:534–9.
were provided by Michelle McDermott (PharmD) and [5] Shore N, Zurth C, Fricke R, Gieschen H, Graudenz K, Koskinen
Lauren Gallagher (RPh, PhD) of OPEN Health M, et al. Evaluation of clinically relevant drug-drug interactions
Communications (London, UK), with financial support and population pharmacokinetics of darolutamide in patients
from Bayer Healthcare. The authors retained full edi­ with nonmetastatic castration-resistant prostate cancer: results of
pre-specified and post hoc analyses of the phase III ARAMIS
torial control over the content of the manuscript and the trial. Target Oncol 2019;14:527–39.
decision to publish. [6] Vogl UM, Beer TM, Davis ID, Shore ND, Sweeney CJ, Ost P, et al.
Lack of consensus identifies important areas for future clinical re­
Data sharing statement search: Advanced Prostate Cancer Consensus Conference (APCCC)
2019 findings. Eur J Cancer 2022;160:24–60.
[7] Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S,
Availability of the data underlying this publication will be et al. Darolutamide in nonmetastatic, castration-resistant pros­
determined according to Bayer’s commitment to the tate cancer. N Engl J Med 2019;380:1235–46.
EFPIA/PhRMA “Principles for responsible clinical trial [8] Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S,
data sharing”. This pertains to scope, timepoint, and et al. Nonmetastatic, castration-resistant prostate cancer and
process of data access. As such, Bayer commits to sharing survival with darolutamide. N Engl J Med 2020;383:1040–9.
[9] Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E,
upon request from qualified scientific and medical re­ Wohlfahrt G, et al. Discovery of ODM-201, a new-generation
searchers patient-level clinical trial data, study-level clinical androgen receptor inhibitor targeting resistance mechanisms to
trial data, and protocols from clinical trials in patients for androgen signaling-directed prostate cancer therapies. Sci Rep
medicines and indications approved in the United States 2015;5:12007.
(US) and European Union (EU) as necessary for con­ [10] Zurth C, Sandman S, Trummel D, Seidel D, Nubbemeyer R,
Gieschen H. Higher blood–brain barrier penetration of [14C]
ducting legitimate research. This applies to data on new apalutamide and [14C]enzalutamide compared to [14C]dar­
medicines and indications that have been approved by the olutamide in rats using whole-body autoradiography [abstract]. J
EU and US regulatory agencies on or Clin Oncol 2019;37(7 suppl):156.
after 1st January 2014. Interested researchers can [11] Zurth C, Graudenz K, Denner K, Korjamo T, Fricke R,
use www.vivli.org to request access to anonymised Wilkinson G, et al. Drug-drug interaction (DDI) of darolutamide
with cytochrome P450 (CYP) and P-glycoprotein (P-gp) sub­
patient-level data and supporting documents from clinical strates: results from clinical and in vitro studies [abstract 297]. J
studies to conduct further research that can help advance Clin Oncol 2019;37:297.
medical science or improve patient care. Information on [12] Williams S, Mazibuko N, O.’Daly O, Zurth C, Patrick F,
the Bayer criteria for listing studies and other relevant Wooldridge C, et al. Significant localized reduction in cerebral
information is provided in the member section of the blood flow in regions relevant to cognitive function with en­
zalutamide (ENZA) compared to darolutamide (DARO) and
portal. Data access will be granted to anonymised patient- placebo (PBO) in healthy volunteers [poster]. Annual
level data, protocols and clinical study reports after ap­ Genitourinary Cancers Symposium. San Francisco, CA; 2020.
proval by an independent scientific review panel. Bayer is [13] Fizazi K, Smith MR, Tombal B. Clinical development of
not involved in the decisions made by the independent darolutamide: a novel androgen receptor antagonist for the
review panel. Bayer will take all necessary measures to treatment of prostate cancer. Clin Genitourin Cancer
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ensure that patient privacy is safeguarded. [14] Bögemann M, Shore ND, Smith MR, Tammela TLJ, Ulys A,
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Appendix A. Supporting material nonmetastatic castration-resistant prostate cancer stratified by
prostate-specific antigen doubling time: planned subgroup analysis
of the phase 3 ARAMIS trial. Eur Urol 2023;83(3):212–21.
Supplementary data associated with this article can be [15] Smith MR, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov
found in the online version at doi:10.1016/j.ejca.2023. S, et al. Darolutamide and health-related quality of life in patients
113258. with non-metastatic castration-resistant prostate cancer: an ana­
lysis of the phase 3 ARAMIS trial. Eur J Cancer
2021;154:138–46.
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