Androgen receptor inhibitors for the treatment of non-metastatic castration-resistant prostate cancer in subjects with severe hepatic impairment

Patent metadata

Field	Value
Publication number	US-11723898-B2
Application number	US-202017089393-A
Country	US
Kind code	B2
Filing date	Nov 4, 2020
Priority date	Nov 4, 2019
Publication date	Aug 15, 2023
Grant date	Aug 15, 2023

Abstract

Described herein are methods of treating non-metastatic castration-resistant prostate cancer in subjects with severe hepatic impairment with androgen receptor inhibitors, including but not limited to, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide.

First claim

What is claimed:

1. A method for treating non-metastatic castration-resistant prostate cancer (nmCRPC) in a male human comprising administering apalutamide at a dose of about 30 mg per day to about 480 mg per day to a male human in need of such treatment who has severe hepatic impairment.

2. The method of claim 1 , wherein the male human has normal cardiac condition and function.

3. The method of claim 2 , wherein the normal cardiac condition and function comprises sinus rhythm, a heart rate between about 50 and about 100 beats per minutes, and a QTc interval of less than or equal to about 480 ms.

4. The method of any one of the preceding claims, wherein the male human has a creatinine clearance of less than or equal to about 45 mL/min/17.3 m 2 .

5. The method of any one of claims 1 to 4 , wherein the male human has stable hepatic impairment.

6. The method of any one of claims 1 to 4 , wherein the male human has a blood pressure of between about 90 and about 170 mmHg systolic.

7. The method of any one of claims 1 to 4 , wherein the male human has a blood pressure of less than about 100 mmHg diastolic.

8. The method of any one of claims 1 to 4 , the male human receives concomitant therapy for the severe hepatic impairment.

9. The method of claim 8 , wherein the concomitant therapy comprises one or more of antihypertensive agents, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor-antagonists, diuretics, cholesterol-lowering drugs, oral antidiabetics, and electrolyte substitution.

10. The method of any one of claims 1 to 4 , wherein the male human is not administered a strong inhibitor or inducer of CYP2C8 or CYP3A4.

11. The method of any one of claims 1 to 4 , wherein administration of apalutamide is accompanied by an increased risk of adverse events relative to a male human with nmCRPC who is not receiving treatment with apalutamide.

12. The method of any one of claims 1 to 4 , wherein the nmCRPC is a high-risk nmCRPC.

13. The method of any one of claims 1 to 4 , wherein administration of the apalutamide provides an increase in the metastasis-free survival of the male human relative to the metastasis-free survival rate of a population of male humans with nmCRPC who are not receiving treatment with apalutamide.

14. The method of any one of claims 1 to 4 , wherein the male human has a prostate-specific antigen doubling time (PSADT) that is less than or equal to 10 months.

15. The method of any one of claims 1 to 4 , wherein the male human has received at least one prior therapy for the treatment of cancer.

16. The method of claim 15 , wherein the prior therapy for the treatment of cancer is bicalutamide, flutamide or nilutamide.

17. The method of any one of claims 1 to 4 , wherein the male human is treatment naïve.

18. The method of any one of claims 1 to 4 , wherein the apalutamide is administered daily to the male human.

19. The method of any one of claims 1 to 4 , wherein the apalutamide is administered orally to the male human.

20. The method of any one of claims 1 to 4 , wherein the apalutamide is administered orally to the male human on a continuous daily dosing schedule.

21. The method of any one of claims 1 to 4 , wherein the apalutamide is administered orally to the male human at a dose of about 180 mg per day to about 480 mg per day.

22. The method of any one of claims 1 to 4 , wherein the apalutamide is administered orally to the male human at a dose of about 240 mg per day.

23. The method of any one of claims 1 to 4 , wherein the apalutamide is administered orally to the male human at a dose of about 60 mg and at a frequency of four times per day.

24. The method of any one of claims 1 to 4 , wherein the apalutamide is administered at a dose of about 120 mg per day.

25. The method of any one of claims 1 to 4 , wherein the apalutamide is formulated as a solid dosage form.

26. The method of any one of claims 1 to 4 , wherein the apalutamide is formulated as a tablet.

27. The method of any one of claims 1 to 4 , wherein the apalutamide is administered in combination with androgen deprivation therapy (ADT).

28. The method of any one of claims 1 to 4 , wherein the apalutamide is administered in combination with a gonadotropin-releasing hormone agonist or antagonist.

29. The method of any one of claims 1 to 4 , wherein the apalutamide is used concomitant with bilateral orchiectomy.

30. A method for treating non-metastatic castration-resistant prostate cancer (nmCRPC) in a male human comprising:
determining if the male human has severe hepatic impairment; and
if the male human has severe hepatic impairment, administering to the male human apalutamide at a dose of about 30 mg per day to about 480 mg per day to treat the nmCRPC.

31. The method of claim 30 , wherein the normal cardiac condition and function comprises sinus rhythm, a heart rate between about 50 and about 100 beats per minutes, and a QTc interval of less than or equal to about 480 ms.

32. The method of claim 30 or 31 , wherein the male human has a creatinine clearance of less than or equal to about 45 mL/min/17.3 m 2 .

33. The method of claim 30 or 31 , wherein the male human has stable hepatic impairment.

34. The method of claim 30 or 31 , wherein the male human has a blood pressure of between about 90 and about 170 mmHg systolic.

35. The method of claim 30 or 31 , wherein the male human has a blood pressure of less than about 100 mmHg diastolic.

36. The method of claim 30 or 31 , wherein the male human receives concomitant therapy for the severe hepatic impairment.

37. The method of claim 36 , wherein the concomitant therapy comprises antihypertensive agents, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor-antagonists, diuretics, cholesterol-lowering drugs, oral antidiabetics, and electrolyte substitution.

38. The method of claim 30 or 31 , wherein the male human is not administered a strong inhibitor of inducer of CYP2C8 or CYP3A4.

39. The method of claim 30 or 31 , wherein the therapeutically effective amount of apalutamide is adjusted if the male human has severe hepatic impairment.

Assignees

• Aragon Pharmaceuticals Inc

Inventors

• Chien Caly
• Hellemans Peter
• Yu Alex

Classifications

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K9/20

  Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)} · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title