CDK4/6 inhibitors are important agents that will likely only become more important in our treatment of HR+ disease. At the 2023 ASCO Annual Meeting, researchers continued to study the use of CDK4/6 inhibitors in advanced HR+/HER2- breast cancer and options for the treatment of patients who progress on these agents.

The benefit of CDK4/6 inhibitors in the first line for metastatic disease has clearly been shown. CDK4/6 inhibitors are also beneficial in the second-line setting, however, so the question of an optimal position for these agents is a valid one. The analysis of the phase 3 SONIA trial that was presented at ASCO 2023 explored the question of an optimal position for CDK4/6 inhibition in patients with advanced disease (abstract LBA1000). In this trial setting (ie, the Netherlands during this time), the CDK4/6 inhibitor that most patients received was palbociclib. Two different sequences were compared in this trial, and the time to the second objective disease progression or death was 31 months with frontline CDK4/6 inhibitor therapy and 27.8 months with second-line CDK4/6 inhibitor therapy; this was a numerical difference in favor of frontline CDK4/6 inhibition that did not reach statistical significance. There was more toxicity with first-line CDK4/6 inhibitor therapy, likely due to the longer duration of exposure.

The investigators should be commended for doing this trial, and pharmacologic and financial toxicities are both key issues in oncology. This study is reflective of palbociclib use, and it is unclear whether the results would have been the same if ribociclib or abemaciclib had been used. Additionally, while it may be reasonable to hold off on using CDK4/6 inhibitors in select patients, we need to identify who those patients are.

I do not think that this study will change practice in the United States, and I am still going to use CDK4/6 inhibitors in the frontline setting; however, it is reassuring to know that you are probably not sacrificing much in the way of efficacy by initially giving endocrine therapy alone to select individuals. An example might be when you are concerned about toxicity in a patient who has a poor performance status but biologically favorable disease and who, for instance, experienced a long disease-free interval before they had recurrence. But the majority of patients are still probably going to receive the combination up front.

Regarding endocrine resistance, when you have abnormal constitutive activation of the CDK4/6 pathway, then you circumvent the absence of estrogen. That is the way that some cancers were escaping the effects of endocrine therapy, and that is the rationale behind CDK4/6 inhibition. We are starting to learn about resistance to CDK4/6 inhibitors, but there is still much more to learn. There are an increasing number of agents that are being pursued for patients who have progressed on first-line treatment with CDK4/6 inhibitors and endocrine therapy. Several selective estrogen receptor degraders (SERDs) have emerged from phase 2 and 3 trials, and we now have elacestrant for patients with ESR1 mutations. In tumors with these mutations, the estrogen receptor is working regardless of estrogen availability in a way that seems to sidestep the need to abnormally activate the CDK4/6 pathway.

Some of the analyses that were presented at the meeting reinforced the idea that ESR1 mutation is one of the biggest drivers of poor outcome in patients who are on endocrine therapy and CDK4/6 inhibitors. For example, the results of a patient-level meta-analysis by Zhao and colleagues using pooled data from trials for different SERDs—elacestrant, camizestrant, giredestrant, and amcenestrant—suggested that essentially all of the progression-free survival benefit was found in patients with ESR1 mutations (abstract 1096). So, this current generation of SERDs appears to work mainly on those cancers that are ESR1 mutated, which represents a large group of patients with treatment resistance in this setting (ie, 35% to 45%). These data suggest that we need to think in terms of the split between ESR1-mutated and wild-type disease.

Other options for patients who progress on CDK4/6 inhibitors include the antibody-drug conjugates. Trastuzumab deruxtecan is approved by the US Food and Drug Administration for HER2-low cancers, and sacituzumab govitecan is approved for late-line, estrogen receptor–positive disease. At ASCO 2023, Tolaney et al presented updated data from the phase 3 TROPiCS-02 trial, which solidified what we have been seeing with sacituzumab govitecan, showing a median overall survival of 14.4 months vs 11.2 months with treatment of physician’s choice in patients with endocrine therapy–resistant, HR+/HER2- metastatic breast cancer (abstract 1003).