Filling the Gap after CDK4/6 Inhibitors: Novel Endocrine and Biologic Treatment Options for Metastatic Hormone Receptor Positive Breast Cancer

Abstract

The rise of cyclin-dependent kinase (CDK)4/6 inhibitors has rapidly reshaped treatment algorithms for hormone receptor (HR)-positive metastatic breast cancer, with endocrine treatment (ET) plus a CDK4/6-inhibitor currently representing the standard of care in the first line setting. However, treatment selection for those patients experiencing progression while on ET + CDK4/6-inhibitors remains challenging due to the suboptimal activity or significant toxicities of the currently available options. There is also a paucity of data regarding the efficacy of older regimens, such as everolimus + exemestane, post-CDK4/6 inhibition. In this setting of high unmet need, several clinical trials of novel drugs have recently reported encouraging results: the addition of the AKT-inhibitor capivasertib to fulvestrant demonstrated a significant improvement in progression-free survival (PFS); the oral selective estrogen receptor degrader (SERD) elacestrant prolonged PFS compared to traditional ET in a phase 3 trial, particularly among patients with detectable ESR1 mutations; finally, PARP inhibitors are available treatment options for patients with pathogenic BRCA1/2 germline mutations. Overall, a plethora of novel endocrine and biologic treatment options are finally filling the gap between first-line ET and later line chemotherapy. In this review article, we recapitulate the activity of these novel treatment options and their potential role in future treatment algorithms.

Treatment options for patients with hormone receptor-positive, HER2-negative advanced-stage breast cancer: maintaining cyclin-dependent kinase 4/6 inhibitors beyond progression

“…The end result of the PADA-1 trial supports the approach that early therapeutic targeting of rising blood ESR1-mutation burden could carry significant clinical implications and has the potential benefit to predict primary resistance and possibly shorter survival. Around one-third of patients treated with the AI+CDK4/6 inhibitor combination will develop an ESR1 mutation at some point and subsequently develop resistance; however, there seems a good chance those patients would retain sensitivity to CDK4/6 inhibitors if the ET companion was changed ( 38 ). A recent phase II trial showed promising outcomes in patients with advanced HR+/HER2− breast cancer and acquired ESR mutation progressing on prior ET.…”

Elacestrant for ER-Positive HER2-Negative Advanced Breast Cancer

“…In ER+ HER2– breast cancer, growth occurs when estrogen binds to the estrogen receptor, signaling the cells to replicate thus enlarging the size of the tumor. 11 Elacestrant is an oral SERD degrader that causes dose-dependent break down the estrogen receptor, acting as a pure antagonist of the ER in the breast and uterine tissue. Elacestrant exhibits high affinity for the ERα resulting in rapid binding; the resultant complex is unstable thus accelerating ER degradation.…”

Tailoring advanced breast cancer treatment after cyclin-dependent kinase 4/6 inhibitors progression - real-world data analysis

“…The optimal treatment strategy following disease progression on CDK4/6i remains a topic of ongoing debate ( 4 ). Understanding endocrine resistance is crucial for optimal management since the response to subsequent therapy may vary significantly depending on its mechanism leading to disease progression ( 3 ).…”

“…The data regarding optimal treatment after developing resistance to CDK4/6i are inconclusive, and management remains challenging ( 4 ). Thus, we aimed to assess predictive and prognostic factors associated with the treatment outcome following CDK4/6i progression.…”