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

SIMPLE SUMMARY: There are limited treatment options beyond chemotherapy for patients with hormone receptor positive metastatic breast cancer after progression on first line therapy with CDK4/6 inhibitors and endocrine therapy. Recently, encouraging evidence has emerged from multiple drugs in this space with the potential to delay chemotherapy and improve outcomes. The most promising agents include the AKT inhibitor capivasertib, the oral selective estrogen receptor degrader (SERD) elacestrant, and PARP inhibitors for patients harboring pathogenic germline BRCA1/2 mutations. Additionally, a subset of patients may also potentially be candidates for continuation of CDK4/6 inhibitors beyond progression. In this review, we highlight clinical data supporting the use of these agents and critically analyze the available evidence for their use. We also provide an algorithm to guide clinicians in their daily practice for patients with progression following first line CDK4/6 inhibitors and endocrine therapy. 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.