What treatment should be used in patients with advanced breast cancer progressing during hormone therapy combined with a cyclin-dependent kinase 4/6 inhibitor?

The standard of 1st or 2nd line palliative systemic therapy in patients with breast cancer expressing hormone receptors without overexpression of HER2 is the combination of hormone therapy (HT) with a cyclin-dependent kinase inhibitor 4/6 (CDK4/6i). Palbociclib, ribociclib, and abemaciclib in combination with an aromatase inhibitor (AI) or fulvestrant significantly prolong progression-free survival (PFS) compared to HT alone. Moreover, the addition of abemaciclib to fulvestrant and ribociclib to fulvestrant or an aromatase inhibitor prolongs overall survival (OS). Importantly, the combined therapy is characterized by a preferable toxic profile. Unfortunately, in the case of progression during HT in combination with CDK4/6i, the available drugs do not give such spectacular results in terms of efficacy or toxicity profile. In patients progressing during treatment with CDK4/6i in combination with a nonsteroidal aromatase inhibitor not selected for predictive factors for targeted therapy or in the absence of such factors, another line of HT (switching to fulvestrant or exemestane), or chemotherapy should be used. Both treatment strategies have a similar effect on prognosis. Combining another CDK4/6i or everolimus with HT slightly improves its effectiveness but is associated with additional toxicity. In patients with the ESR1 mutation, elacestrant is significantly more effective compared to fulvestrant. In patients with the PIK3CA mutation, alpelisib or capivasertib in combination with fulvestrant can be used. In patients with a germline BRCA1/2 mutation, a PARP inhibitor (PARPi, talazoparib, olaparib) prolongs PFS compared to chemotherapy without affecting OS. In patients with progression during treatment with the combination of CDK4/6i and fulvestrant, chemo­therapy, exemestane, or abemaciclib can be used. Elacestrant and PARPi are indicated in patients with corresponding mutations. In patients progressing after previous HT and palliative chemotherapy, the efficacy of conjugates of antibody and a cytotoxic drug (sacituzumab govitecan; trastuzumab deruxtecan in HER2-low patients) has been demonstrated.