Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study

Massard, Christophe; Penttinen, Heidi; Vjaters, Egils; Bono, Petri; Lietuvietis, Vilnis; Tammela, Teuvo L.J.; Vuorela, Annamari; Nykänen, Pirjo; Pohjanjousi, Pasi; Snapir, Amir; Fizazi, Karim

doi:10.1016/j.eururo.2015.09.046

Cited by 58 publications

(66 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

supporting

confidence: 57%

“…Darolutamide administered as a single 300-or 600-mg once-daily dose (with and without food) or as multiple doses of 300 mg BID or 600 mg BID for a median treatment duration of 84 days (range 31-328) was well tolerated in this heavily treated population, and overall toxicities were consistent with the known safety profile of darolutamide in a previously reported phase 1 trial in a Western study population [13,17]. Our results show that there are no remarkable differences in PK parameters between Japanese and Western patients with mCRPC [13,17]. For example, Western patients in the ARAFOR study who were administered a single dose of darolutamide 600 mg had C max and AUC 0-48 values approximately twofold greater in the fed versus fasted state compared with 2.8-and 2.5-fold greater in Japanese patients, and fed-state t max values of 4.0 versus 6.3 h, respectively [17].…”

supporting

confidence: 57%

“…In addition, darolutamide is different from other new-generation nonsteroidal AR antagonists with respect to its negligible blood-brain barrier penetration [14][15][16]. In early-phase clinical trials with Western mCRPC patients, darolutamide has shown a good safety profile and significant reductions in PSA levels [13,[17][18][19].…”

mentioning

confidence: 99%

See 2 more Smart Citations

Erratum to: Phase 1 study of darolutamide (ODM-201), a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer

Matsubara

Mukai

Hosono

et al. 2017

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

supporting

confidence: 57%

supporting

confidence: 57%

See 1 more Smart Citation

Erratum to: Phase 1 study of darolutamide (ODM-201), a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer

Matsubara

Mukai

Hosono

et al. 2017

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

“…Then, ice water (300 mL) was added and the mixture was stirred for 5 min and then separated. The organic layer was dried over anhydrous Na 2 …”

Section: Methodsmentioning

confidence: 99%

“…1,2) ODM-201 ( Fig. 1) is structurally distinct from any known antiandrogens including the second-generation antiandrogens enzalutamide and ARN-509.…”

mentioning

confidence: 99%

Chemical Synthesis of the ODM-201’s Diastereomers through an Efficient Intramolecular 1,3-Dipolar Cycloaddition

Pan

Xia²,

Jiang

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

Key words ODM-201; diastereomer; synthesis; intramolecular 1,3-dipolar cycloaddition ODM-201 (1) is a novel androgen receptor (AR) inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with castration-resistant prostate cancer (CRPC).1,2) ODM-201 ( Fig. 1) is structurally distinct from any known antiandrogens including the second-generation antiandrogens enzalutamide and ARN-509. In contrast to other antiandrogens, ODM-201 displays negligible brain penetrance and does not increase serum testosterone levels in mice.3)As demonstrated in Fig. 1, ODM-201 is a synthetic compound comprising a mixture (1 : 1) of diastereomers, namely 1a and b. Although both compounds 1a and b are claimed to be pharmacologically active, 4) the specific data was not disclosed. We believe that more bioactivity studies are necessary to clarify the action mechanism, which requires substantial supply of diastereomerically pure 1a and b. There are two methods have been reported for the synthesis of 1a and b. 5)In the first method, special enzymes (KREDs) were used for the selective reduction which limited the extensive application. The second one only gave a very low yield (0.025%) in the synthesis of (R)-ethyl-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxylate or (S)-ethyl-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxylate, which is hard for practical production.As well known, 1,3-dipolar cycloaddition has been widely employed in construction of 5-membered heterocyclic systems. 6) In the present work, we devoted to developing an efficient synthetic route for the synthesis of ODM-201's diastereomers through intramolecular 1,3-dipolar cycloaddition. Results and DiscussionAs displayed in Figs. 2 and 3, we initiated our synthesis from commercially available enantiopure (R)-methyl 3-hydroxybutanoate (2a) and (S)-methyl 3-hydroxybutanoate (2b). We firstly tried to protect the 3-OH in 2a and b with trimethyl silyl (TMS) group, the following transformation, however, only resulted in poor yield. Considering that tert-butyldimethylsilyl (TBS) is more stable than TMS in most cases, we thereof prepared TBS protected intermediates (R)-methyl 3-((tert-butyldimethylsilyl) oxy) butanoate (3a) and (S)-methyl 3-((tert-butyldimethylsilyl) oxy) butanoate (3b) in 94-97% yield. Following diisobutylaluminium hydride (DIBAL)-H reduction of 3a and b gave aldehydes 4a and b correspondingly in 88-92% yield.With aldehydes 4a and b available, we explored the conditions for preparation of 5a and b through condensation with ethyl diazoacetate. We found that when strong bases such as lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (LiHMDS) were employed, target compounds 5a and b were prepared in 73-75% yield. 7,8) The yield of this method is acceptable, but low temperature of −78°C and absolutely anhydrous conditions are required, which limited its application. Further optimization revealed that when ethyl diazoacetate treated with milder base tetrabutylammonium hydroxide (TBAOH) using dimethyl sulfoxide (DMSO) ...

show abstract

Androgen Receptor Function and Androgen Receptor–Targeted Therapies in Breast Cancer

et al. 2017

View full text Add to dashboard Cite

Androgen receptor-targeted treatments for breast cancer are in development and have shown promising preliminary results. In-depth understanding of AR and AR-related signaling pathways would improve the treatment strategies for AR-positive breast cancer. Further preclinical and clinical studies of AR-targeted drugs alone and in combination with other drugs are justified and warranted to clarify the biology of AR and inform the development of AR-targeted therapies to improve survival outcome in patients with breast cancer.

show abstract

Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study

Cited by 58 publications

References 12 publications

Erratum to: Phase 1 study of darolutamide (ODM-201), a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer

Erratum to: Phase 1 study of darolutamide (ODM-201), a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer

Chemical Synthesis of the ODM-201’s Diastereomers through an Efficient Intramolecular 1,3-Dipolar Cycloaddition

Androgen Receptor Function and Androgen Receptor–Targeted Therapies in Breast Cancer

Contact Info

Product

Resources

About