Phase 2 Trial in Women with ER+,PR+, Her2- Metastatic Breast Cancer after Progression on Aromatase Inhibitor and CDK4/6 Inhibitor Combination Therapy

Trial Status:
Initiation of this Phase 2 study targeted for second half of 2019.

Program (Target):
Apristor (onapristone extended release) is a potent and specific antagonist of the progesterone receptor that is orally administered. Currently, there are no approved therapies that selectively target PR+ cancers. Preliminary preclinical and clinical data suggest that Apristor has anticancer activity by inhibiting the binding of progesterone receptor to chromatin, downregulating cancer stem cell mobilization, and blocking immune evasion.

Apristor has not been approved for marketing by any regulatory authority.

Disease Indication:
Advanced breast cancer.

Clinical Trial Description:
A prospective, Phase 2 randomized control, multicenter study assessing the effect of Faslodex (fulvestrant) alone or in combination with Apristor in women with ER+,PR+, Her2- metastatic breast cancer after progression on the combination of an aromatase inhibitor and a Cdk4/6 inhibitor.

Mechanism of Action:

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Recent Data Indicates PR is a Potential Mediator of Resistance to Cdk4/6i + Antiestrogen Combination Therapy

The use of antiestrogen therapy combined with anti-Cdk4/6 inhibitor therapy in first line (1L) HR+ metastatic breast cancer (mBCa) results in a complex resistance profile. In the resistant setting, current standard of care agents (e.g., fulvestrant) are largely ineffective. Recent data suggests that Antiestrogen + Cdk4/6i induce selective pressure that results in resistance that is driven through mutations that converge upon the progesterone receptor (PR). These resistance mechanisms include:

1) Estrogen receptor (ESR1) mutations [1]

2) MAPK upregulation [2]

3) Amplification of cell cycle genes, including Cyclin D1 and Cdk2 [3]

[1] Bartels, Mod Path, 2018; Lopez-Knowles, BJC, 2018
[2] Razavi, Cancer Cell, 2018; de Leeuw, Clin Cancer Res, 2018
[3] Yang, Mol Cell Bio, 2010