Advanced Breast Cancer: Expert Perspectives On Recent Progress - Episode 10

CDK4/6 Clinical Trial Survival Data Impact

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Joyce O’Shaughnessy, MD: In the first-line setting, the only trials that have shown survival so far is MONALEESA-7, as Denise said, in the premenopausal population with an AI [aromatase inhibitor] and a more aggressive disease, and then MONALEESA-3 with the fulvestrant; first and second line was a combined trial. The overall study was positive for survival, for the first and second line, there was a trend. They weren’t powered enough, but those are really important survival data.

There were survival data in the second line with both abemaciclib and with palbociclib; we're waiting the data. How do these survival data emerging impact what you do in the first-line setting? Given the MONALEESA-3, are you sometimes using fulvestrant in the first-line setting? What is your take on that?

Hope S. Rugo, MD, FASCO: It's such a great question, Joyce. I think that there are many considerations. First we saw these really impressive survival data, and it occurs with subsets. I think we also learned from PALOMA-3 that if either your tumor needs chemotherapy or you get chemotherapy because that's what the physician does, we can't separate that, your PFS [progression-free survival] with next-line fulvestrant is shorter. Regardless of the use of a CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitor, you don't do as well.

I think that we all believe that hormone therapy, even in combination, is generally much better tolerated than chemotherapy, with a few exceptions of very toxic targeted agents. I think that it is really important, and Denise's data really make this point, that we should be using CDK4/6 inhibitors in combination with endocrine therapy rather than chemotherapy, except in very limited situations. So how do we decide on the endocrine partner in the first-line setting?

We had data from the previous trials that suggested that you might, if you had never had prior endocrine therapy in any setting, from FALCON, and you had soft tissue disease or bone disease, that you might have a better PFS with fulvestrant than with an AI. Anastrozol was used in that study. But of course the PFS data even in the best situation weren’t as long as we've seen in first-line settings with an AI and CDK4/6 inhibitor.

I always wonder, with this being such a unique group of patients, how do we decide which endocrine partner to use? We saw the data from the PARSIFAL trial at ASCO [the American Society of Clinical Oncology annual meeting] this year, which is helpful. It was trial done by the SOLTI network. They randomized patients to receive fulvestrant or letrozole with the CDK4/6 inhibitor palbociclib in the first-line setting. It's more of a real-life population, almost 500 patients. You had to have relapsed at 12 months or longer from the end of endocrine therapy or be endocrine naïve.

What was interesting was there was absolutely no difference in progression-free survival. Progression-free survival was quite nice. It was 32.8 months for letrozole and 28 months for fulvestrant. They were great data for our patients, at a median follow-up of 32 months. It didn't make a difference whether you had seen the aromatase inhibitor in the adjuvant setting either, which I think was incredibly encouraging for all of us to see. It also didn't make a difference whether you'd had visceral disease or nonvisceral disease.

There was some difference in numbers, but it was not statistically significant. All of these data together from PARSIFAL help me in that most of my patients would prefer to take an all oral regimen. I don't believe that you would only see a survival benefit with fulvestrant and you wouldn't see it with an AI in postmenopausal women, but you're going to see it in the patients with aggressive disease who are premenopausal. That just doesn't make sense from what we know.

So I would still favor the use of an AI with the CDK4/6 inhibitor if a patient has relapsed more than 12 months from an AI or has de novo metastatic disease. I would then use fulvestrant with the multitude of other partners that we are evaluating in the second- and greater-line setting. Maybe we'll be using oral SERDS [selective estrogen receptor degraders] in that setting in the future as well. I think that will make a big difference for us. In terms of toxicity and how we select CDK4/6 inhibitors, I try to rotate. I had done that with the AIs years ago and still do it.

We do sequence between them. I think that there are going to be fascinating data, and we'll talk about whether sequencing matters. I also think that we often try to use the trials themselves to decide how we use agents in a premenopausal patient. In the first-line metastatic setting, I tend to use ribociclib. In patients who have a lot of GI [gastrointestinal] problems, I might not jump to abemaciclib. But for people who have trouble coming in for blood counts, maybe abemaciclib is a better choice. Then palbociclib, of course we use a lot because it was the first agent to be approved.

Transcript edited for clarity.