The phase 3 SONIA trial investigators should be congratulated on performing a difficult investigator-initiated trial (abstract LBA1000). They asked an interesting, important question regarding the sequence of CDK4/6 inhibitor therapy in patients with advanced HR+/HER2- breast cancer: Should you give a CDK4/6 inhibitor with the first line of endocrine therapy or with the second line? This is important because, when you add a CDK4/6 inhibitor to the treatment regimen, you are also adding side effects, and it requires more monitoring—and, therefore, more visits—for patients.

Since patients are generally on their first line of therapy for a much longer period than their second line of therapy, their exposure to toxicity may be increased. Thus, if outcomes are the same with either sequence, then one could argue that waiting to give a CDK4/6 inhibitor in the second line would be better for the patient from both a quality-of-life perspective and a financial toxicity perspective.

Sonke et al did not find a statistically significant difference between administering a first-line CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor followed by fulvestrant at progression or a first-line nonsteroidal aromatase inhibitor followed by a CDK4/6 inhibitor plus fulvestrant at progression in terms of the time from randomization to second objective disease progression or death. However, this trial was not designed as a noninferiority study. So, even though the curves look similar and the confidence intervals around their progression-free survival values overlap, the SONIA trial was not designed to show that outcomes were the same between groups.

Further, our current practice is to give endocrine therapy with a targeted therapy in the second line, so patients have a targeted therapy such as everolimus or alpelisib added to their regimen. In the future, we may have capivasertib in this space as well. This was not the practice in the SONIA trial. Thus, I do not know how to apply these data to the way in which I currently practice. For select patients, the investigator-recommended strategy could make sense; however, we do not have a biomarker to select those patients who could be adequately treated with endocrine monotherapy. I will continue to give a CDK4/6 inhibitor up front in the first line for patients with advanced metastatic HR+/HER2- disease. An exception would be a very frail patient, for instance, when there is concern about giving targeted therapies. For all others, our standards should remain the same.

Another caveat from the SONIA trial relates to the following question: Are all CDK4/6 inhibitors created equal? That is, most of the patients in the study received palbociclib, which we have been moving away from in the upfront setting because it is not associated with an overall survival (OS) advantage, unlike ribociclib and abemaciclib, which were the other CDK4/6 inhibitors used in the trial.

The differences in OS between CDK4/6 inhibitors has led to an examination of the differences in pharmacodynamics between agents that may explain the clinical findings. There is some thought that differences in the ratio of CDK4 to CDK6 inhibition may partly explain these differences in OS. It is believed that CDK4 drives efficacy and CDK6 drives toxicity. Palbociclib has roughly equipotency against CDK4 and CDK6, while ribociclib and abemaciclib have a higher potency against CDK4.

Also at ASCO 2023, data were presented to support the theory that the selective inhibition of CDK4 could enhance efficacy and reduce toxicity. A study by Yap and colleagues evaluating the novel selective CDK4 inhibitor PF-07220060 showed that the agent has an impressive clinical benefit rate of more than 52% in heavily pretreated patients, all of whom had received prior CDK4/6 inhibitor therapy (abstract 3009). In addition, the toxicity was much lower, with researchers reporting grade 3 neutropenia with PF-07220060 plus endocrine therapy in only approximately 15% of patients, which is less than the 60% rate that is observed with palbociclib.