<p>The benefits of CDK4/6 inhibitors in combination with endocrine therapy for HR+/HER2- metastatic breast cancer are well established. Several studies were presented at the recent <strong>ESMO Congress 2025</strong> that evaluated multiple CDK4/6 inhibitor combination regimens in both clinical trial and real-world settings.</p> <p><br></p> <p><em>Following these presentations, featured expert William J. Gradishar, MD, FACP, was interviewed by</em> Conference Reporter <em>Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Gradishar on these findings are presented here.</em></p>

The 3 CDK4/6 inhibitors that are US Food and Drug Administration (FDA) approved for HR+/HER2- metastatic breast cancer (ie, palbociclib, ribociclib, and abemaciclib) have demonstrated that if they are added to endocrine therapy, be it an aromatase inhibitor or fulvestrant, they markedly enhance—and, in fact, sometimes double—the time to disease progression compared with endocrine therapy alone. Most of the data on CDK4/6 inhibitors presented at the ESMO Congress 2025 really reaffirm our current understanding of these agents.

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At this year’s ESMO Congress, Wortelboer and colleagues presented results from the SONIA trial, which evaluated the benefits of the first- vs second-line use of CDK4/6 inhibitors in patients with HR+/HER- advanced breast cancer (abstract 487MO). The SONIA trial asked the following question: If you do not give a CDK4/6 inhibitor until a patient progresses, does second-line use impact progression-free survival? As of 1 or 2 year(s) ago, the answer was no. The overall survival (OS) data were updated at the meeting, and the data looked identical between the treatment arms. But again, we start most patients on a CDK4/6 inhibitor right from the beginning because we know that it significantly prolongs progression-free survival and, perhaps, OS. Practice in the United States really is not influenced by the SONIA trial because the vast majority of patients get a CDK4/6 inhibitor as first-line therapy.

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Also at the ESMO Congress 2025, Jia et al presented real-world data on CDK4/6 inhibitors, demonstrating a significant OS advantage with ribociclib compared with palbociclib (abstract 507P). I think that most of the real-world analyses presented at the meeting reaffirm that CDK4/6 inhibitors are active. Although we like to be evidence driven, and ribociclib and abemaciclib appear to confer the greatest benefits, in my view, palbociclib is still a very effective drug.

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There are multiple trials underway looking at combinations of CDK4/6 inhibitors beyond just with endocrine therapy. The INAVO120 study found that patients who were rapid progressors and had a PI3K mutation had better outcomes if they got the triplet regimen of a CDK4/6 inhibitor, an endocrine agent, and inavolisib compared with patients who simply got a CDK4/6 inhibitor and endocrine therapy. Consistent with these findings, at the ESMO Congress 2025, Hurvitz and colleagues presented results from the VIKTORIA-1 trial evaluating a combination regimen that included the CDK4/6 inhibitor palbociclib, an endocrine agent, and gedatolisib, which is a molecule given intravenously that inhibits all 4 PI3K isoforms, as well as mTORC1 and mTORC2 (abstract LBA17). The effect was better than simply giving endocrine therapy plus the CDK4/6 inhibitor. We will see how these combination drugs fare over time.

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Novel CDK4/6 inhibitors are in development, but I question what the advantages would be of using them over one of the currently FDA-approved CDK4/6 inhibitors. We know that if you use CDK4/6 inhibitors in sequence, there is a small signal indicating that you might get some advantage from using a different CDK4/6 inhibitor, but it is not a big advantage (ie, maybe weeks or a couple of months at best). Furthermore, many of the currently FDA-approved CDK4/6 inhibitors are soon going to become generic, making them attractive from the standpoint of cost. So, the question that will have to be asked with any of the CDK inhibitors and targeted agents that are in development is: What is their advantage over what is currently available? And that is a question that I do not think we can answer yet.