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Publication Number
US-11628176-B2
Publication Date
2023-04-18
Expiration Date
Abstract
Disclosed is a method of treating a subject suffering from a cancer, comprising administering to the subject a combination of agents comprising: (a) Compound I: or a pharmaceutically acceptable salt thereof; and(b) one or more inhibitors of the androgen receptor signaling pathway; or(c) one or more PARP inhibitors;wherein the amount of the combination of agents is therapeutically effective in the treatment.
Core Innovation
The disclosure describes a synergistic combination therapy for cancer in which a subject receives Compound I, or a pharmaceutically acceptable salt thereof, together with one or more inhibitors of the androgen receptor signaling pathway or one or more PARP inhibitors. Compound I is identified as 4-(1-(1,1-di(pyridin-2-yl)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoic acid. The combination is administered in a therapeutically effective amount for treatment.
The approach is specifically directed to metastatic castration resistant prostate cancer. Treatment initiation occurs after the subject with metastatic castration resistant prostate cancer develops disease progression while currently receiving treatment with abiraterone acetate and prednisone or prednisolone. Embodiments pair Compound I with inhibitors of the androgen receptor signaling pathway, including cytochrome P450-17A1 inhibitors, and optionally a corticosteroid.
The disclosure also describes embodiments pairing Compound I with PARP inhibitors, including olaparib and other named PARP inhibitors. Preclinical synergy is described using LNCaP and 22Rv1 prostate cancer cells with IC50 and combination index analyses, reporting synergistic growth inhibition of Compound I with enzalutamide or abiraterone acetate and providing limited response observations including stable disease in certain human combination contexts.
Claims Coverage
The independent claim covers a method of treating metastatic castration resistant prostate cancer by initiating therapy after progression on abiraterone acetate plus prednisone or prednisolone, using a therapeutically effective synergistic combination containing Compound I and either inhibitors of the androgen receptor signaling pathway or PARP inhibitors. Additional independent-claim coverage is not explicitly provided in the provided partial content beyond claim 1.
Synergistic combination initiated after progression on abiraterone acetate plus prednisone/prednisolone
A method of treating metastatic castration resistant prostate cancer by administering a therapeutically effective synergistic combination comprising Compound I, or a pharmaceutically acceptable salt, and one or more inhibitors of the androgen receptor signaling pathway; or one or more PARP inhibitors; wherein treatment is initiated after the subject develops disease progression while currently receiving abiraterone acetate and prednisone or prednisolone.
Combination with androgen receptor signaling pathway inhibitors selected as cytochrome P450-17A1 inhibitors
Administering Compound I, or a pharmaceutically acceptable salt, together with one or more androgen receptor signaling pathway inhibitors that are cytochrome P450-17A1 inhibitors selected from abiraterone, abiraterone acetate, ketoconazole, seviteronel, orteronel, galeterone, or CFG920, or a pharmaceutically acceptable salt thereof.
Combination with PARP inhibitors selected from named PARP inhibitor set
A method characterized by using one or more PARP inhibitors selected from olaparib, niraparib, rucaparib, talazoparib, and veliparib, or a pharmaceutically acceptable salt thereof.
Overall claim coverage is anchored in initiating Compound I-based synergistic therapy for metastatic castration resistant prostate cancer after progression on abiraterone acetate plus prednisone or prednisolone, with the key inventive options being pairing with androgen receptor signaling pathway inhibitors, including cytochrome P450-17A1 inhibitors, or pairing with PARP inhibitors selected from the named group.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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