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Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.

Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ - Sci Rep (2015)

Bottom Line: Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR.In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice.In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs.

View Article: PubMed Central - PubMed

Affiliation: Orion Corporation, Orion Pharma, Finland.

ABSTRACT
Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.

No MeSH data available.


Related in: MedlinePlus

Regulation of testosterone levels.A. Serum testosterone levels (nmol/L, ±SEM) of individual intact nude mice bearing orthotopic VCaP tumors after the oral treatment with vehicle, enzalutamide (20 mg/kg, qd), or ODM-201 (50 mg/kg, bid) for 3 weeks (n = 8). *p < 0.05 vs. vehicle. B. Brain penetrance. Brain/plasma ratios (%) were calculated based on plasma and brain exposures (AUC0–24) after the oral dosing of ODM-201 (25, 50, or 100 mg/kg, bid for 7 days), enzalutamide (20 mg/kg, qd for 7 days) (n = 5), or ARN-509 (a single dose of 10 mg/kg) (n = 3). Data represent mean brain/plasma ratios. *Brain/plasma ratios of ORM-15341 were evaluated in mice treated with different concentrations of ODM-201. Qd = once daily, bid = twice daily.
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f5: Regulation of testosterone levels.A. Serum testosterone levels (nmol/L, ±SEM) of individual intact nude mice bearing orthotopic VCaP tumors after the oral treatment with vehicle, enzalutamide (20 mg/kg, qd), or ODM-201 (50 mg/kg, bid) for 3 weeks (n = 8). *p < 0.05 vs. vehicle. B. Brain penetrance. Brain/plasma ratios (%) were calculated based on plasma and brain exposures (AUC0–24) after the oral dosing of ODM-201 (25, 50, or 100 mg/kg, bid for 7 days), enzalutamide (20 mg/kg, qd for 7 days) (n = 5), or ARN-509 (a single dose of 10 mg/kg) (n = 3). Data represent mean brain/plasma ratios. *Brain/plasma ratios of ORM-15341 were evaluated in mice treated with different concentrations of ODM-201. Qd = once daily, bid = twice daily.

Mentions: Serum testosterone levels can increase due to central nervous system stimulation of luteinizing hormone (LH) signaling by the antiandrogen therapy31. In an experiment where orthotopic VCaP tumor-bearing intact nude mice were treated orally with enzalutamide (20 mg/kg, qd) or ODM-201 (50 mg/kg,bid) for 3 weeks, enzalutamide increased significantly serum testosterone concentrations (p < 0.05), whereas ODM-201 did not affect the testosterone levels in serum (Fig. 5A). Also in this xenograft model, ODM-201 inhibited tumor growth significantly compared to the control group (Supplementary Fig. S4).


Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.

Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ - Sci Rep (2015)

Regulation of testosterone levels.A. Serum testosterone levels (nmol/L, ±SEM) of individual intact nude mice bearing orthotopic VCaP tumors after the oral treatment with vehicle, enzalutamide (20 mg/kg, qd), or ODM-201 (50 mg/kg, bid) for 3 weeks (n = 8). *p < 0.05 vs. vehicle. B. Brain penetrance. Brain/plasma ratios (%) were calculated based on plasma and brain exposures (AUC0–24) after the oral dosing of ODM-201 (25, 50, or 100 mg/kg, bid for 7 days), enzalutamide (20 mg/kg, qd for 7 days) (n = 5), or ARN-509 (a single dose of 10 mg/kg) (n = 3). Data represent mean brain/plasma ratios. *Brain/plasma ratios of ORM-15341 were evaluated in mice treated with different concentrations of ODM-201. Qd = once daily, bid = twice daily.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490394&req=5

f5: Regulation of testosterone levels.A. Serum testosterone levels (nmol/L, ±SEM) of individual intact nude mice bearing orthotopic VCaP tumors after the oral treatment with vehicle, enzalutamide (20 mg/kg, qd), or ODM-201 (50 mg/kg, bid) for 3 weeks (n = 8). *p < 0.05 vs. vehicle. B. Brain penetrance. Brain/plasma ratios (%) were calculated based on plasma and brain exposures (AUC0–24) after the oral dosing of ODM-201 (25, 50, or 100 mg/kg, bid for 7 days), enzalutamide (20 mg/kg, qd for 7 days) (n = 5), or ARN-509 (a single dose of 10 mg/kg) (n = 3). Data represent mean brain/plasma ratios. *Brain/plasma ratios of ORM-15341 were evaluated in mice treated with different concentrations of ODM-201. Qd = once daily, bid = twice daily.
Mentions: Serum testosterone levels can increase due to central nervous system stimulation of luteinizing hormone (LH) signaling by the antiandrogen therapy31. In an experiment where orthotopic VCaP tumor-bearing intact nude mice were treated orally with enzalutamide (20 mg/kg, qd) or ODM-201 (50 mg/kg,bid) for 3 weeks, enzalutamide increased significantly serum testosterone concentrations (p < 0.05), whereas ODM-201 did not affect the testosterone levels in serum (Fig. 5A). Also in this xenograft model, ODM-201 inhibited tumor growth significantly compared to the control group (Supplementary Fig. S4).

Bottom Line: Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR.In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice.In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs.

View Article: PubMed Central - PubMed

Affiliation: Orion Corporation, Orion Pharma, Finland.

ABSTRACT
Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.

No MeSH data available.


Related in: MedlinePlus