AR+ breast cancer treatment methods
Inventors
Hattersley, Gary • SAEH, Jamal • YU, Ziyang • Miller, Chris • BIHANI, Teeru
Assignees
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Publication Number
US-11771682-B2
Publication Date
2023-10-03
Expiration Date
Abstract
A method for treating AR+ breast cancer in a subject comprising administering to the subject an AR agonist (e.g., SARMs such as RAD140), or in combination with one or more therapeutic agents selected from the group consisting of cdk4/6 inhibitors, m-TOR inhibitors, PI3k inhibitors, PARP inhibitors, BCL-2 inhibitors, and MCL-1 inhibitors.
Core Innovation
The invention relates to treating AR+/ER+ breast cancer in a subject by administering a compound which is RAD140 (Compound III), including a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The approach is positioned as an option for endocrine-resistant disease, including cases associated with ESR1 mutations or ESR1 fusions that reduce ER ligand binding and reduce efficacy of conventional antiestrogens such as fulvestrant (SERD).
The disclosed treatment strategy includes administering RAD140 (Compound III) alone or in combination with targeted agents. The targeted agents described include CDK4/6 inhibitors such as palbociclib and related CDK4/6 inhibitors, mTOR inhibitors including everolimus and other mTOR inhibitors, and additional inhibitors including PI3K inhibitors, PARP inhibitors, BCL-2 inhibitors, and MCL-1 inhibitors.
The disclosure further describes biomarker and companion diagnostics based on ZBTB16 (PLZF) mRNA/protein induction after AR agonist dosing. The biomarker induction is used to identify or stratify likely responders, including presentation of cutoffs described as fold-increase thresholds. The disclosure also references the use of ERα gene (ESR1) mutation criteria in subject selection.
Preclinical efficacy is documented for RAD140 (Compound III) in multiple ER+/AR+ patient-derived xenograft (PDx) and cell line-derived xenograft (CDx) models, including tumor growth inhibition outcomes. The disclosure states that RAD140 inhibits tumor growth in certain settings and is more effective than fulvestrant in certain comparisons, and that combinations with CDK4/6 inhibitors and mTOR inhibitors enhance tumor growth inhibition, with example outcome metrics presented.
Claims Coverage
The independent claim (clm-00001) covers treating AR+/ER+ breast cancer using RAD140 (Compound III) (or pharmaceutically acceptable salt/solvate). The dependent claims refine the method by adding administration route and dose constraints, restricting to particular clinical progression settings and subject biomarker criteria, and optionally combining with a CDK4/6 inhibitor with an IC50 potency threshold against CDK4 and CDK6.
Treating AR+/ER+ breast cancer with RAD140 (Compound III)
A method of treating AR+/ER+ breast cancer in a subject in need thereof by administering a compound which is RAD140 (Compound III), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
Oral administration of RAD140 (Compound III)
The method includes administering the compound via an oral route.
Dose range for RAD140 (Compound III)
The method includes administering the compound to a subject at a dose between 10 mg and 500 mg.
Treatment after disease progression following specified prior agents
The method is limited to cases where the subject experiences disease progression after treatment with CDK4/6 inhibitors, mTOR inhibitors, BCL-2 inhibitors, PI3K inhibitors, or combinations thereof.
Subject selection based on ESR1 mutations
The method is further defined by the subject expressing ERα gene (ESR1) with one or more mutations.
Combination with a CDK4/6 inhibitor
The method further includes administering a CDK4/6 inhibitor in combination with the compound.
CDK4/6 inhibitor potency threshold against CDK4/CDK6
The CDK4/6 inhibitor has an IC50 of less than 100 nM against CDK4 and CDK6.
Overall, the claim set centers on RAD140 (Compound III) for treating AR+/ER+ breast cancer, with refinements that specify oral dosing and a 10 mg to 500 mg dose range, restrict to post-progression after specified prior therapy classes, require ESR1 mutation status in the subject, and optionally combine RAD140 with a CDK4/6 inhibitor including a CDK4/CDK6 IC50 threshold.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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