Insights From: Joyce A. OShaughnessy, MD, Balor University Medical Center; Stephen Johnston, MA, PhD, FRCP, The Royal Marsden Hospital; Matthew P. Goetz, MD, The Mayo Clinic
Stephen Johnston, MA, PhD, FRCP: Ultimately, how we sequence these therapies is still unclear. This is because clinical research has not yet worked out, if we use the CDK4/6 inhibitors up front as first-line treatment, what our best second-line treatment is at progression on a CDK4/6 inhibitor. Now, clinical research is ongoing. The patient experience in the clinic with these drugs available is starting to teach us that we can use further endocrine combinations after progression on a CDK4/6 inhibitor. Which approach or which order will give the best long-term outcome and the best overall survival is not clear yet, but clearly these drugs make an impact, no matter which stage in the sequence you use them.
Joyce A. O’Shaughnessy, MD: The question of which is going to ultimately be the most effective endocrine therapy partner in the first-line setting with CDK4/6 inhibitors is a very interesting question. The FALCON data showed superiority of fulvestrant over anastrozole in patients with the more ER [estrogen receptor]–positive indolent disease, those without visceral disease, and those with bone-only disease or soft tissue disease. In patients with visceral metastasis, there wasn’t a difference between fulvestrant and anastrozole in the FALCON trial.
In patients with the more luminal A–like metastatic disease, it may be that fulvestrant will end up being a better choice. We need a randomized trial. There is one going on in Europe right now looking at an aromatase inhibitor versus fulvestrant, both arms with a CDK4/6 inhibitor. We will get randomized data looking at that, but looking at the various patient subsets that may not make a difference in patients with more aggressive biology; the FALCON data might suggest that.
Stephen Johnston, MA, PhD, FRCP: It’s clear that the CDK4/6 inhibitors synergize with endocrine therapy. We’ve seen benefit with both aromatase inhibitors and with fulvestrant. It’s not specifically important to know which endocrine therapy you use other than the setting in which you’re using it. In the first-line setting, when patients are relapsing off their previous adjuvant endocrine therapy, the treatment of choice is usually to use an aromatase inhibitor in that setting, reserving the selective estrogen receptor down-regulator fulvestrant as the second-line backbone when patients get progressive disease.
Ultimately, these drugs work: the CDK4/6 inhibitors in combination with something that is blocking the endocrine drive to the tumor, whether it be the estrogen drive or the hormone receptor signaling. Removing that approach, with either an aromatase or fulvestrant, is going to be important. The issue is really in which order you use it. But by and large, we’d use an aromatase inhibitor first and fulvestrant in second-line combinations.