The PENELOPE-B Study in HR+ Breast Cancer

Sara Hurvitz, MD: Let’s now turn to the data relating to palbociclib from the PENELOPE-B study, which was also presented at the San Antonio Breast Cancer Symposium. Massimo, can you take us through the study design, how risk was defined in this particular study, the length of follow-up, and what the results showed?

Massimo Cristofanilli, MD: Yes, this was a bit of a disappointment for the field because we wanted to see another CDK4/6 inhibitor showing superiority in terms of preventing recurrence in patients with high risk. The question is, first of all, the definition of high risk. Of course, we just heard what the monarchE defined as high risk. In this study, the PENELOPE-B, patients had completed neoadjuvant therapy and were considered high risk if they had what is called a CPS+EG [clinical-pathologic stage-estrogen/grade] score of 3 or more. This is combining the clinical and pathological stage and estrogen receptors, and has been developed by the MD Anderson Cancer Center group. These are obviously different from what we just heard in the monarchE.

The study was smaller, 800 patients, the randomization 1:1. The treatment was shorter, 1 year of palbociclib together with a standard endocrine therapy. The follow-up though was longer. This was a mature study, I would say, so we can certainly assume that the data are not going to change essentially. As the discussant brought up, and it was interesting in their review, you start to see a difference between the 2 groups very early, and then you wonder if this is obviously treating micrometastatic disease, but also this is not sustaining difference because the length of treatment was not comparable to monarchE.

I think we will remain with these questions, probably for years. We certainly would not be able to address them, unless some additional biomarker studies come up later in a retrospective fashion that indicated that. We need to understand that suppression with a CDK4/6 in order to reduce the progression from a micrometastatic disease, MRD [minimal residual disease], to clinical evidence. Having said that, monarchE certainly has a high-risk population. What was recently included, probably it’s too early to evaluate, but it’s looking at the Ki-67 as a marker of a high-risk, less aggressive population. I think all this eventually will start to better define what a high-risk population should be. But the feeling in the field is that we have a drug that seems to be showing some impact on the recurrence of these patients. The question is whether this is going to be enough for approval for clinical use, widespread use, and how we’re going to control the use in the community once it becomes available.

Sara Hurvitz, MD: Those are very good points. I think from my own point of view, I’d like to see longer-term follow-up, given how promising the curves looked early in PENELOPE-B, and that just went away after patients were off therapy and longer follow-up. I had a discussion with a patient this week who’s a particularly high-risk young woman, going through all the data with her, and we have to consider in the curative setting here, we do have ILD [interstitial lung disease] and we have venous thromboembolic events that are associated with these agents, abemaciclib in particular. I think from my own view, I want to see longer follow-up before widely implementing it, even if it were approved. Andrew, do you have any thoughts in this regard?

Andrew Seidman, MD: I think there’s a cautionary tale here. A different trial, a different disease biology, but we also just saw the ExteNET overall survival results. We were all very excited about neratinib’s ability to prevent invasive recurrence, which led to an FDA indication. And now with 8 years of follow-up, there’s no survival benefit, again a different biology of disease. I think even though it’s an event-driven analysis, 19 months median follow-up is early.

Transcript edited for clarity.