Using CDK4/6 Inhibitors in Early Stage HR+ Breast Cancer

Andrew D. Seidman, MD: I want to spend our remaining time focusing a bit on early stage disease. Aditya, we led with the results from PALLAS, which were a bit of a disappointment in terms of palbociclib’s effect in the adjuvant setting. We’ve seen some encouraging results with abemaciclib. We just saw the completion of accrual of 5100 patients to NATALEE this spring. Can you take us through where we’re at in terms of the CDK4/6 inhibitor integration into early breast cancer?

Aditya Bardia, MD, MPH: Absolutely. As we reviewed earlier, there’s a lot of excitement about CDK4/6 inhibitors in the metastatic setting. Endocrine therapy plus a CDK4/6 inhibitor represents the first line of treatment for a patient with metastatic breast cancer. It was felt that we should now move them to the adjuvant setting. I would like to make 3 points about consideration that are unique to the adjuvant setting as compared with metastatic.

The way CDK4/6 inhibitors work is they block cell cycle, they block cell proliferation. If a patient has metastatic disease in general, that’s a cell that’s proliferating. But in the adjuvant setting, particularly for ER [estrogen receptor]-positive disease, cells could be dormant. You could use an agent for 2 years, but if the cells are dormant, CDK4/6 inhibitors are unlikely to have an impact.

The second point is the concept of duration. In the metastatic setting, we don’t stop CDK4/6 inhibitors after 6 months, 1 year, or 1.5 years. We continue until disease progression. It’s challenging to do that in the adjuvant setting, so the PALLAS and monarchE trials had a duration of 2 years. What we saw from PENELOPE was that when you’re using the CDK4/6 inhibitors, it can put the brakes on, but when you stop the CDK4/6 inhibitor, the cells maybe started proliferating again and you start seeing the recurrences. The graph in PENELOPE-B was very instructive because you initially could see a separation and then the curves coming together again. This question of what’s the optimal duration of a CDK4/6 inhibitor in the adjuvant setting in the absence of biomarkers is really challenging. Hopefully, we’ll have biomarkers, including MRD [minimal residual disease], that could potentially help with this scenario.

The third is compliance. In the metastatic setting in general, patients continue therapies unless there is severe toxicity. But in the adjuvant setting, we have patients who discontinue AIs [aromatase inhibitors], and now you’re adding a second agent. We saw in PALLAS that about 50% of patients discontinued an AI plus Ibrance. If you don’t use the drug, you’re not going to see the benefit. It’s a combination of all 3 factors, which are unique in the adjuvant setting, which probably accounted for some of the differences between PALLAS and monarchE.

And finally, the consideration of high risk. In monarchE, the patients who were enrolled were the higher-risk patients, which maybe addresses this issue of dormancy. In higher-risk patients, maybe there’s less dormancy and more proliferating cells, but the other issues in terms of duration still remain. For monarchE in particular, I would be curious to see how the results pan out a year from now to see if we can continue to see separation of the curves.

Andrew D. Seidman, MD: Some of you were in the room in San Francisco on May 16th, 2005, when we first saw the adjuvant trastuzumab data. Nobody waited for regulatory approval. Everybody started giving adjuvant trastuzumab the next week, calling patients back to get trastuzumab if they finished their chemotherapy a few months later. Fast forward to 2021, and we just saw the exciting OlympiA data with PARP inhibition with olaparib.

Transcript Edited for Clarity