Mechanism Of Action
Darolutamide is an androgen receptor (AR) inhibitor.
Darolutamide competitively inhibits androgen binding, AR nuclear translocation,
and AR-mediated transcription. A major metabolite, keto-darolutamide, exhibited
similar in vitro activity to darolutamide. In addition, darolutamide functioned
as a progesterone receptor (PR) antagonist in vitro (approximately 1% activity
compared to AR). Darolutamide decreased prostate cancer cell proliferation in
vitro and tumor volume in mouse xenograft models of prostate cancer.
Darolutamide exposure at 600 mg twice daily results in
PSA mean reduction of more than 90% from baseline.
The effect of darolutamide (600 mg twice daily) on the
QTc interval was evaluated in a subgroup of 500 patients in the ARAMIS study.
No large mean increase in QTc (i.e., > 20 ms) was detected.
Following administration of 600 mg twice daily,
darolutamide mean (%CV) steady-state peak plasma concentration (Cmax) is 4.79
mg/L (30.9%) and area under the plasma concentration-time curve from time 0 to
12 hours (AUC12h) is 52.82 h•μg/mL (33.9%). Steady-state is reached 2–5
days after repeated dosing with food, with an approximate 2-fold accumulation.
The exposure (Cmax and AUC12) of the darolutamide and the
active metabolite keto-darolutamide increase in a nearly dose-proportional
manner in the dose range of 100 to 700 mg (0.17 to 1.17 times the approved
recommended dosage). No further increase in darolutamide exposure was observed
at 900 mg twice daily (1.5 times the approved recommended dosage).
Darolutamide Cmax is reached approximately 4 hours after
administration of a single 600 mg oral dose.
The absolute bioavailability is approximately 30%
following oral administration of a NUBEQA tablet containing 300 mg darolutamide
under fasted conditions.
Bioavailability of darolutamide increased by 2.0 to
2.5-fold when administered with food. A similar increase of exposure was
observed for the active metabolite keto-darolutamide.
The apparent volume of distribution of darolutamide after
intravenous administration is 119 L.
Protein binding is 92% for darolutamide and 99.8% for the
active metabolite, keto-darolutamide. Serum albumin is the main binding protein
for darolutamide and keto-darolutamide.
The effective half-life of darolutamide and
keto-darolutamide is approximately 20 hours in patients. The clearance (%CV) of
darolutamide following intravenous administration is 116 mL/min (39.7%).
Darolutamide is primarily metabolized by CYP3A4, as well
as by UGT1A9 and UGT1A1. Keto-darolutamide total exposure in plasma is 1.7-fold
higher compared to darolutamide.
After a single radiolabeled dose as an oral solution, a
total of 63.4% of darolutamide-related material is excreted in the urine
(approximately 7% unchanged) and 32.4% (approximately 30% unchanged) in the
feces. More than 95% of the dose was recovered within 7 days after
In nmCRPC patients, no clinically significant differences
in the pharmacokinetics of darolutamide were observed based on age (48-95
years), race (White, Japanese, non-Japanese Asian, Black or African American),
mild to moderate renal impairment (eGFR 30–89 mL/min/1.73m²), or mild hepatic
In non-cancer subjects with severe renal impairment (eGFR
15–29 mL/min/1.73 m²) not receiving dialysis or with moderate hepatic
impairment (Child-Pugh Class B), NUBEQA exposure increased by about 2.5-and
1.9-fold, respectively, compared to healthy subjects.
The effect of end-stage renal disease (eGFR <15
mL/min/1.73 m²) or severe hepatic impairment (Child-Pugh C) on darolutamide
pharmacokinetics has not been studied.
Drug Interaction Studies
Combined P-gp And Strong CYP3A4 Inducers
Concomitant use of rifampicin (a combined P-gp and strong
CYP3A4 inducer) decreased mean darolutamide AUC0-72 by 72% and Cmax by 52%. The
decrease of darolutamide exposure by moderate CYP3A4 inducers is expected to be
in the range of 36% – 58 %.
Combined P-gp And Strong CYP3A4 Inhibitors
Itraconazole (a strong combined CYP3A4 and P-gp
inhibitor) increased mean darolutamide AUC0-72 by 1.7-and Cmax by 1.4-fold.
Concomitant use of darolutamide decreased the mean AUC
and Cmax of midazolam (CYP3A4 substrate) by 29% and 32%, respectively. No
clinically significant differences in the pharmacokinetics of midazolam were
observed when used concomitantly with darolutamide.
Concomitant use of darolutamide increased the mean AUC
and Cmax of rosuvastatin (BCRP substrate) by approximately 5-fold.
No clinically significant differences in the
pharmacokinetics of dabigatran (P-gp substrate) were observed when used
concomitantly with darolutamide.
In Vitro Studies
In vitro, darolutamide inhibits OATP1B1 and OATP1B3.
Darolutamide did not inhibit the major CYP enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9,
2C19, 2D6, 2E1, and 3A4) or transporters (MRP2, BSEP, OATs, OCTs, MATEs,
OATP2B1, and NTCP) at clinically relevant concentrations.
ARAMIS (NCT02200614) was a multicenter, double-blind,
placebo-controlled clinical trial in 1509 patients with non-metastatic
castration resistant prostate cancer with a prostate-specific antigen doubling
time (PSADT) of ≤ 10 months. Randomization was stratified by PSADT and
use of bone-targeted therapy at study entry. Patients with pelvic lymph nodes
less than 2 cm in short axis below the aortic bifurcation were allowed to enter
the study. Patients with a history of seizures were not excluded. Absence or
presence of metastasis was assessed by blinded independent central review
(BICR). PSA results were not blinded and were not used for treatment
Patients were randomized 2:1 to receive either 600 mg
darolutamide orally twice daily (n=955) or matching placebo (n=554). Treatment
continued until radiographic disease progression as assessed by CT, MRI, 99mTc
bone scan by BICR, unacceptable toxicity or withdrawal. All patients received a
gonadotropin-releasing hormone (GnRH) analog concurrently or had a bilateral
The following patient demographics and disease
characteristics were balanced between treatment arms. The median age was 74
years (range 48–95) and 9% of patients were 85 years of age or older. The
racial distribution was 79% White, 13% Asian, and 3% Black. A majority of
patients (73%) had a Gleason score of 7 or higher at diagnosis. The median
PSADT was 4.5 months. Forty-two percent of patients in both treatment arms had
prior surgery or radiotherapy to the prostate. Eleven percent of patients had
enlarged pelvic lymph nodes less than 2 cm at study entry. Six percent of
patients were retrospectively identified by BICR as having metastases at
baseline. Seventy-three percent of patients received prior treatment with an
anti-androgen (bicalutamide or flutamide). All patients had an Eastern
Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at
study entry. There were 12 patients enrolled on the NUBEQA arm with a history
of seizure. At baseline, 47% of patients reported no pain on the Brief Pain
Inventory-Short Form (a 7-day diary average of the daily worst pain item).
The major efficacy endpoint was metastasis free survival
(MFS), defined as the time from randomization to the time of first evidence of
BICR-confirmed distant metastasis or death from any cause within 33 weeks after
the last evaluable scan, whichever occurred first. Distant metastasis was
defined as new bone or soft tissue lesions or enlarged lymph nodes above the
aortic bifurcation. Overall survival (OS) and time to pain progression were
additional efficacy endpoints.
The efficacy results for MFS from ARAMIS are summarized
in Table 3 and Figure 1. Treatment with NUBEQA resulted in a statistically
significant improvement in MFS compared to placebo. MFS results were consistent
across patient subgroups for PSADT (≤ 6 months or > 6 months) or prior
use of bone-targeting agents (yes or no). OS data were not mature at the time
of final MFS analysis (57% of the required number of events). Locoregional-only
progression occurred in 6% of patients overall.
Table 3: Efficacy Results from the ARAMIS Study
|Number of Events (%)
|Median, months (95% CI)1
||40.4 (34.3, NR)
||18.4 (15.5, 22.3)
|Hazard Ratio (95% CI)2
||0.41 (0.34, 0.50)
|NR: not reached
1 Based on Kaplan-Meier estimates
2 Hazard ratio is based on a Cox regression model (with treatment as
the only covariate) stratified by PSADT (≤ 6 months vs. > 6 months)
and use of osteoclast-targeted therapy (yes vs. no). Hazard ratio < 1 favors
3 P-value is based on a stratified log-rank test by PSADT (≤ 6
months vs. > 6 months) and use of osteoclast-targeted therapy (yes vs. no)
Figure 1: Kaplan-Meier Curve Metastasis Free Survival
The MFS result was supported by a delay in time to pain
progression, defined as at least a 2-point worsening from baseline of the pain
score on Brief Pain Inventory-Short Form or initiation of opioids, in patients
treated with NUBEQA as compared to placebo. Pain progression was reported in
28% of all patients on study.