Darolutamide: First Approval

Anthony Markham1 · Sean Duggan1

© Springer Nature Switzerland AG 2019

Abstract
Darolutamide (NUBEQA™) is a structurally distinct non-steroidal androgen receptor antagonist being developed by Orion and Bayer as a treatment for prostate cancer. Based on positive results in the phase III ARAMIS trial, darolutamide was recently approved in the USA for the treatment of men with non-metastatic castration-resistant prostate cancer. This article summarizes the milestones in the development of darolutamide leading to this first approval.

Darolutamide (NUBEQA™): Key points

A non-steroidal androgen receptor antagonist being developed by Orion and Bayer for the treatment of pros- tate cancer
Received its first approval on 30 July 2019 in the USA Approved for use in non-metastatic castration-resistant
prostate cancer

1Introduction

Darolutamide (NUBEQA™) is a structurally distinct andro- gen receptor antagonist being developed by Orion and Bayer for the treatment of prostate cancer. On the basis that andro- gen receptors drive the expression of genes involved in the growth, differentiation and survival of prostate cancer cells, androgen deprivation therapy (ADT) to reduce serum
testosterone levels to castration levels is a common initial therapeutic intervention for localised disease. However, approximately one third of patients will develop disease pro- gression with standard ADT, leading to castration-resistant prostate cancer [1], thereby prompting research into alterna- tive therapies. Darolutamide competitively inhibits andro- gen binding, androgen receptor nuclear translocation, and androgen-mediated transcription. The drug is approved for the treatment of non-metastatic castration-resistant prostate cancer in the USA [2] and is under regulatory review in the EU [3] and Japan [4]. Darolutamide is also undergoing phase III investigation for the treatment of metastatic hor- mone-sensitive prostate cancer. The recommended dose of darolutamide is 600 mg administered orally twice daily [5].

1.1Company Agreements

Darolutamide was discovered by Finnish pharmaceutical company Orion Corporation [6]. In June 2014 Orion entered into a partnership with Bayer for the global development and commercialisation of darolutamide. Under the terms of the agreement, the companies will co-develop the product, with Bayer providing a major share of future development

Enhanced material for this AdisInsight Report can be found at https://doi.org/10.6084/m9.figshare.9926909 .

This profile has been extracted and modified from the AdisInsight database. AdisInsight tracks drug development worldwide through the entire development process, from discovery, through pre- clinical and clinical studies to market launch and beyond.

*
[email protected]
1 Springer Nature, Private Bag 65901, Mairangi Bay, Auckland 0754, New Zealand
costs. Bayer will have global commercialisation rights, with Orion retaining an option to co-promote the product in sev- eral European countries. Orion will maintain responsibility for manufacturing [7]. This agreement was expanded in June 2016 to include the development of darolutamide for meta- static hormone-sensitive prostate cancer [8].

Phase I trials commenced (Mar 2011)

Granted Fast Track designation in the USA (Oct)
Rolling NDA completed in USA (Feb)
Preregistration in the EU and Japan (Mar)
Granted Priority Review in the USA (Apr)
Approved in the USA for non-metastatic castration-resistant prostate cancer (Jul)

2014 2015 2016 2017 2018 2019 2020 2021 2022

ARAMIS (NCT02200614)
ARASENS (NCT02799602)
Non-metastatic castration-resistant prostate cancer Metastatic hormone-sensitive prostate cancer

Key milestones in the development of darolutamide, focussing on its use in the treatment of non-metastatic castration-resistant prostate cancer. NDA New Drug Application

2Scientific Summary

2.1Pharmacodynamics

Darolutamide, its (S,R)- and (S,S)-diastereomers, and keto-darolutamide (the primary metabolite in vivo) had IC50 values of 60–100 nmol/L against wild type andro- gen receptor after stimulation with the agonist R1881 at a concentration of 1 nmol/L, and 5670–7650 nmol/L after stimulation with R1881 10 nmol/L. Darolutamide, its diastereomers and keto-darolutamide also had strong activity against W742C and W742L androgen recep- tor mutants, and darolutamide had IC50 values of less than ≈ 200 nmol/L against most other androgen receptor mutants tested after stimulation with R1881 0.1 nmol/L. The drug potently antagonised androgen receptor F877L, which is resistant to enzalutamide and apalutamide, and had marked activity against M896T and M896V. However, the antagonistic activity of the drug was reduced in the presence of the T878A mutation [9].
Darolutamide, its two diastereomers and keto-darolu- tamide inhibited VCaP and LAPC-4 prostate cancer cells in vitro with IC50 values of 250–500 and 440–840 nmol/L, respectively, but were less potent against LNCaP cells (IC50 3210–5260 nmol/L), which harbour the androgen
treatment with oral darolutamide significantly reduced the growth of tumour cells compared with enzalutamide [10]. Negligible penetration of darolutamide into the blood- brain barrier was observed, while serum testosterone lev- els did not increase relative to vehicle [10].

2.2Pharmacokinetics

Darolutamide had a steady-state mean Cmax and AUC12 of 4.79 mg/L and 52.82 h·μg/mL, respectively, after adminis- tration of repeated 600 mg twice daily doses; steady-state was achieved after 2–5 days, with ≈ 2-fold accumulation. After administration of a single 600 mg oral dose of the drug, the time to reach Cmax (tmax) was ≈ 4 h. The bioavail- ability of darolutamide was increased 2.0–2.5-fold when given with food. Darolutamide and keto-darolutamide are 92% and 99.8% protein bound, respectively [5].
Darolutamide is predominantly metabolized by CYP3A4 and, to a lesser extent UGT1A9 and UGT1A1 [5, 11]. It has also been identified as a substrate for P-gp and BCRP, according to preclinical data [11]. The total exposure of keto-darolutamide in plasma is 1.7-fold higher than that of darolutamide [5].

receptor T878A mutation [9].
In vivo oral administration of darolutamide to mice

O

N

NH

bearing LAPC-4 and KuCaP-1 (harbouring the androgen receptor W742C mutation) tumours was associated with reductions in tumour volume compared to vehicle control [9].
In an in vivo model in mice bearing VCaP tumours (characterised by androgen receptor over-expression),

Cl

NC

N
N
(S) NH
(S/R)

HO

Chemical structure of darolutamide

In patients, the effective half-life of darolutamide and keto-darolutamide is ≈ 20 h; the clearance (%CV) of daro- lutamide following intravenous administration is 116 mL/
min (39.7%). After administration of a single oral radiola- beled dose of darolutamide, 63.4% of radioactivity was recovered from urine (≈ 7% as unchanged drug) and 32.4% from faeces (≈ 30% as unchanged drug) [5].
In patients with non-metastatic castration-resistant pros- tate cancer, the pharmacokinetic profile of darolutamide was not significantly altered by age, race, mild to moder- ate renal impairment (eGFR 30–89 mL/min/1.73 m2), or mild hepatic impairment. However, darolutamide expo- sure was increased in volunteers with severe renal impair- ment (eGFR 15–29 mL/min/1.73 m2) not receiving dialy- sis (≈ 2.5-fold increase) or moderate hepatic impairment (Child-Pugh Class B, ≈ 1.9-fold increase) [5].
Darolutamide plasma exposure is decreased (by 72%) when co-administered with the strong CYP3A4 and P-gp inducer rifampicin and is increased (by 1.7-fold) when co-administered with the combined P-gp and strong CYP3A4 inhibitor itraconazole [11]. No clinically sig- nificant effects on the pharmacokinetics of midazolam (CYP3A4 substrate) or dabigatran (P-gp substrate) were seen when co-administered with darolutamide. Concomi- tant administration of darolutamide increased the plasma exposure of rosuvastatin (a BCRP substrate) by ≈ 5-fold [11]. In a prespecified analysis of the phase III ARAMIS trial in patients with non-metastatic castration-resistant prostate cancer, the pharmacokinetic profile of daroluta- mide was not significantly affected by concomitant drugs commonly administered in this patient population [12]. The interaction between darolutamide and rosuvastatin observed in preclinical and phase I studies [11] did not

Features and properties of darolutamide

appear to translate into an increase in adverse events in patients receiving statins in ARAMIS [12].
In men with metastatic castration-resistant prostate can- cer participating in the phase I component of the ARADES trial, oral darolutamide at doses of 100–900 mg twice daily, exposure to darolutamide at steady-state was linear with increasing doses up to 700 mg twice daily before plateauing [13].
In the ARAFOR trial in men with metastatic chemother- apy-naive castration-resistant prostate cancer, administration of a single 600 mg dose of darolutamide after a high-calorie, high-fat breakfast increased AUC and Cmax values ≈ 2-fold [14].

2.3Therapeutic Trials

2.3.1Non‑metastatic Castration‑Resistant Prostate Cancer Metastasis-free survival was significantly longer with daro-
lutamide compared with placebo in men with non-metastatic castration-resistant prostate cancer participating in the phase III ARAMIS trial (NCT02200614) [15]. The primary end- point of median metastasis-free survival was 40.4 months with darolutamide compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41; p < 0.001). The secondary endpoint of overall survival showed a positive trend in favour of darolutamide that was associated with a lower risk of death. Additional endpoints, such as time to pain progression, time to first cytotoxic chemo- therapy and time to a symptomatic skeletal event also favoured darolutamide. In ARAMIS, patients with a baseline prostate- specific antigen (PSA) level of ≥ 2 ng/mL, a PSA doubling

Alternative names NUBEQA™, BAY-1841788, darramamide, ODM-201
Class Amides, anti-androgens, anti-neoplastics, pyrazoles, small molecules
Mechanism of action Androgen receptor antagonist
Route of administration Oral
Pharmacodynamics IC50 6560 nmol/L for wild type androgen receptor treated with R1881 10 nmol/L

Pharmacokinetics Adverse events
Cmax 4.79 mg/L, AUC12 52.82 h·μg/mL, tmax ≈ 4 h after multiple 600 mg twice daily doses

Most frequent Fatigue, pain in extremity, rash
Occasional Ischaemic heart disease, heart failure, hypertension, diarrhoea, nausea

Rare ATC codes
Death, general deterioration in physical health, pneumonia, pulmonary embolism

WHO ATC code L02B-B (anti-androgens)
EphMRA ATC code L2B2 (cytostatic anti-androgens)

Chemical name
N-[(2S)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-5-(1-hydroxyethyl)-1H-pyrazole-3-carbox- amide

time of ≤ 10 months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomized to treatment with darolutamide 600 mg twice daily (n=955) or placebo (n = 554) until disease progression or discontinuation of treatment because of adverse events or withdrawal of con- sent. At data cutoff (3 September 2018) median follow-up was 17.9 months and treatment duration was 14.8 and 11.0 months in the darolutamide and placebo groups, respectively [15]. Health-related quality of life outcomes were generally similar between darolutamide and placebo treatment groups; some outcome scores favoured darolutamide [BPI-SF (pain severity and pain interference scores), FACT-P (Physical Well-Being, Emotional Well-Being, PCS, General, FACT-P total, and Trial Outcome Index), and the EORTC-QLQPR25 urinary symp- toms subscale]; although these differences were statistically significant, they were not considered clinically meaningful [15].

2.3.2Metastatic Castration‑Resistant Prostate Cancer Extended treatment with darolutamide was associated
with durable disease control in patients with metastatic

castration-resistant prostate cancer after extended follow- up in the open-label phase I/II ARADES (NCT01429064) and phase I ARAFOR (NCT01784757) trials [16].
The phase II component of the ARADES trial included patients treated with darolutamide 100 (n = 38), 200 (n = 37) or 700 mg (n = 35) twice daily. PSA response (≥ 50% decrease in PSA from baseline at week 12) was observed at all doses but was less frequent in patients previously treated with CYP17 inhibitors than in those who had received chem- otherapy other than CYP17 inhibitors. The highest response rate (86%) was observed in chemotherapy-naive patients who received darolutamide 700 mg twice daily (n = 7) [13].
In the extension phase of the phase I ARAFOR trial patients (n = 30) were treated with darolutamide 600 mg twice daily until disease progression. The PSA response rate (as per ARADES) was 83%, and 30% of patients had a reduction in PSA levels of ≥ 90%. The median time to PSA progression was 54 weeks and the median time to radiographic progression was 66 weeks. At 12 weeks median serum testosterone was 0.60 nmol/L compared with 0.80 nmol/L at baseline [14].

Key clinical trials of darolutamide (Orion, Bayer)

Drug(s) Indication Phase Status Location(s) Identifier
Darolutamide Castration resistant prostate cancer I/II Completed Multinational NCT01317641
Darolutamide Castration resistant prostate cancer (extension study) II Completed Multinational NCT01429064
(ARADES)

Darolutamide Bioavailability in pts with metastatic chemotherapy-
naive castration-resistant prostate cancer
I Ongoing Latvia NCT01784757
(ARAFOR)

Darolutamide, placebo High-risk non-metastatic castration-resistant prostate
cancer
III Ongoing Multinational NCT02200614
(ARAMIS)

Darolutamide Dose escalation study in Japanese pts with metastatic
castration-resistant prostate cancer
ICompleted Japan NCT02363855

Darolutamide Pharmacokinetics in male volunteers I Completed UK NCT02418650
(ARIADME) Darolutamide, rosuvastatin Drug-drug interaction study I Completed Germany NCT02671097
Darolutamide Effect of hepatic and renal impairment I Completed Germany NCT02894385

Darolutamide, standard ADT, docetaxel, placebo
Metastatic castration sensitive prostate cancer III Ongoing Multinational NCT02799602
(ARASENS)

Darolutamide, itraconazole, rifampicin
Drug-drug interaction study I Completed Germany NCT03048110

Darolutamide, placebo Metastatic castration-resistant prostate cancer II Recruiting Italy NCT02933801

Darolutamide, dabigatran etexilate, midazolam
Drug-drug-interaction study
I
Completed Germany
NCT03237416

Darolutamide, enzalutamide Metastatic castration-resistant prostate cancer II Recruiting France NCT03314324
(ODENZA) Darolutamide, standard ADT Hormone naive prostate cancer II Recruiting Belgium, Spain NCT02972060

Darolutamide, AZD1775, savolitinib, CFI-400945
Prostate cancer biomarker enrichment and treatment
selection
IIRecruiting Canada NCT03385655

ADT androgen deprivation therapy, pts patients

2.4Adverse Events

In patients with non-metastatic, castration-resistant prostate cancer, darolutamide was generally well tolerated, with a safety and tolerability profile similar to that of placebo. The majority of adverse reactions seen with darolutamide were grade 1 or 2. In the ARAMIS trial, adverse reactions in patients receiv- ing darolutamide (n = 954) occurring with a ≥ 2% absolute increase in frequency compared to placebo (n= 554) included fatigue (occurring in 16% of darolutamide vs. 11% of placebo recipients), pain in extremity (6% vs. 3%) and rash (3% vs. 1%). Serious adverse reactions of any grade occurred in 25% of daro- lutamide recipients versus 20% of placebo recipients; serious adverse reactions occurring in≥1% of patients receiving daro- lutamide included urinary retention, pneumonia and haematu- ria. In the darolutamide and placebo arms, 3.9% and 3.2% of patients, respectively, were reported by the investigators to have died from adverse reactions and 9% of patients in both treatment arms required permanent discontinuation of treatment because of adverse reactions. Dosage interruptions because of adverse reactions were required in 13% of patients treated with darolu- tamide, most frequently due to hypertension (0.6%), diarrhoea (0.5%), and pneumonia (0.5%). Dosage reductions because of adverse reactions were necessary in 6% of patients receiving darolutamide, most frequently because of fatigue (0.7%), hyper- tension (0.3%), and nausea (0.3%). Adverse reactions considered clinically significant that occurred in ≥ 2% of patients treated with darolutamide included ischemic heart disease (4.0% of darolutamide vs. 3.4% of placebo recipients) and heart failure (2.1% vs. 0.9%). Laboratory test abnormalities of any grade included decreased neutrophil count (occurring in 20% of daro- lutamide vs. 9% of placebo recipients), increased AST levels (23% vs. 14%) and increased bilirubin (16% vs. 7%) [5].
Darolutamide was also generally well tolerated in the open-label phase I/II ARADES [13] and phase I ARAFOR [14] trials in patients with metastatic castration-resistant prostate cancer, with a tolerability profile generally similar to that seen in studies with non-metastatic castration-resist- ant prostate cancer [5]. The majority of adverse reactions seen with darolutamide were grade 1 or 2; the most com- mon adverse reactions of any grade seen with darolutamide treatment were fatigue or asthenia, back pain and arthralgia in ARADES [13] and fatigue and nausea in ARAFOR [14].

2.5Ongoing Clinical Trials

In addition to the ongoing phase III ARAMIS (NCT02200614) and phase I ARAFOR (NCT01784757) studies, the efficacy of darolutamide as treatment for newly diagnosed metastatic, hormone-sensitive prostate cancer is being studied in the placebo-controlled multinational phase III ARASENS trial (NCT02799602). Patients have been ran- domized to oral darolutamide 600 mg twice daily or placebo

in conjunction with 6 cycles of standard androgen depriva- tion therapy plus docetaxel [17].
A double-blind, placebo-controlled phase II trial (NCT02933801) is being conducted in patients with meta- static castration-resistant prostate cancer previously treated with abiraterone or enzalutamide with no evidence of dis- ease progression on docetaxel or cabazitaxel. Patients will be randomized to darolutamide 600 mg or placebo twice daily in conjunction with best supportive care until disease progression [18].
The efficacy, safety and tolerability of darolutamide as an alternative to LHRH analogues in men requiring androgen deprivation therapy is being assessed in the EORTC-1532- GUCG study (NCT02972060). Patients with hormone-naive prostate cancer and up to 4 metastases will be randomized to darolutamide 600 mg twice daily or a LHRH agonist or antagonist [19].
A randomized phase II ARACOG trial (AFT-47) is being conducted to compare the cognitive effects of darolutamide compared with enzalutamide in men with advanced pros- tate cancer receiving undergoing treatment with androgen deprivation therapy [20, 21]. The phase II ODENZA study (NCT03314324) is also underway, which is assessing patient preference between darolutamide and enzalutamide in men with metastatic castration-resistant prostate cancer.

3Current Status

Darolutamide received its first approval on 30 July 2019 for non-metastatic castration-resistant prostate cancer in the USA.

Compliance with Ethical Standards

Funding The preparation of this review was not supported by any external funding.

Conflict of interest During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. A. Markham, a contracted employee of Adis International Ltd/Springer Nature, and S. Duggan, a salaried employee of Adis International Ltd/
Springer Nature, are responsible for the article content and declare no relevant conflicts of interest.

References

1.Fizazi K, Smith MR, Tombal B. Clinical development of darolu- tamide: a novel androgen receptor antagonist for the treatment of prostate cancer. Clin Genitourin Cancer. 2018;16(5):332–40.
2.US Food & Drug Administration. FDA approves darolutamide for non-metastatic castration-resistant prostate cancer [media release]. 1 Aug 2019. https://www.fda.gov/drugs/resources-infor

mation-approved-drugs/fda-approves-darolutamide-non-metas tatic-castration-resistant-prostate-cancer.
3.Bayer. Bayer submits European marketing authorization applica- tion for darolutamide [media release]. 8 Mar 2019. http://www. bayer.com.
4.Orion. Darolutamide submitted for marketing authorization in Japan [media release]. 5 Mar 2019. http://www.orion.fi .
5.Bayer HealthCare Pharmaceuticals Inc. Nubeqa™ (daroluta- mide): US prescribing information. 2019. https://www.acces sdata.fda.gov/drugsatfda_docs/label/2019/212099Orig1s000lbl. pdf. Accessed 19 Aug 2019.
6.Orion. Orion group interim report January-September 2013 [media release]. 22 Oct 2013. http://www.orion.fi .
7.Bayer. Bayer and Orion Corporation to develop and commercial- ize novel prostate cancer treatment [media release]. 2 Jun 2014. http://www.bayerpharma.com.
8.Bayer. Bayer and Orion expand clinical development program for BAY-1841788 (ODM-201) in prostate cancer [media release]. 3 Jun 2016. http://www.bayer.us.
9.Sugawara T, Baumgart SJ, Nevedomskaya E, et al. Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models. Int J Cancer. 2019;145(5):1382–94.
10.Moilanen AM, Riikonen R, Oksala R, et al. Discovery of ODM- 201, a new-generation androgen receptor inhibitor targeting resist- ance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5:12007.
11.Zurth C, Koskinen M, Fricke R, et al. Drug–drug interaction potential of darolutamide: in vitro and clinical studies. Eur J Drug Metab Pharmacokinet. 2019. https://doi.org/10.1007/s13318-019- 00577-5.
12.Shore N, Zurth C, Fricke R, et al. Evaluation of clinically rel- evant 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. Target Oncol. 2019. https://doi. org/10.1007/s11523-019-00674-0.
13.Fizazi K, Massard C, Bono P, et al. Activity and safety of ODM- 201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation

and randomised phase 2 dose expansion trial. Lancet Oncol. 2014;15(9):975–85.
14.Massard C, Penttinen HM, Vjaters E, et al. Pharmacokinetics, antitumor activity, and safety of ODM-201 in patients with chem- otherapy-naive metastatic castration-resistant prostate cancer: an open-label phase 1 study. Eur Urol. 2016;69(5):834–40.
15.Fizazi K, Shore N, Tammela TL, et al. Darolutamide in non- metastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235–46.
16.Shore ND, Tammela TL, Massard C, et al. Safety and antitumour activity of ODM-201 (BAY-1841788) in chemotherapy-naive and CYP17 inhibitor-naive patients: follow-up from the ARADES and ARAFOR trials. Eur Urol Focus. 2018;4(4):547–53.
17.Smith MR, Saad F, Hussain M, et al. ARASENS: a phase 3 trial of darolutamide in combination with docetaxel for men with meta- static hormone-sensitive prostate cancer (mHSPC) [abstract no. TPS383]. J Clin Oncol. 2018;36(6 Suppl).
18.Gillessen S, Hayoz S, Fuhrer AC, et al. A phase 2 trial of ODM- 201 maintenance therapy in patients with metastatic castration resistant prostate cancer (mCRPC) previously treated with a AR targeting agent and nonprogressive on a second line taxane (SAKK 08/16) [abstract no. TPS393]. J Clin Oncol. 2018;36(6 Suppl).
19.Tombal BF, Gillessen S, Loriot Y, et al. Intergroup study EORTC- 1532-gucg: a phase 2 randomized open-label study of oral darolu- tamide (ODM-201) vs. androgen deprivation therapy (ADT) with LHRH agonists or antagonist in men with hormone naive pros- tate cancer (PCa) [abstract no. TPS406]. J Clin Oncol. 2018;36(6 Suppl).
20.Alliance for Clinical Trials in Oncology. ARACOG: Phase II study of androgen receptor and cognitive function in patients treated with darolutamide or enzalutamide. 2019. https://www. allianceforclinicaltrialsinoncology.org. Accessed 30 Sep 2019.
21.Us TOO International. August 2019 Hot Sheet. 2019. https://www. ustoo.org/Read-the-HotSheet-Newsletter. Accessed 30 Sept 2019.