PracticeUpdate: What are the currently approved first-line endocrine therapies for HR-positive metastatic breast cancer?
Dr. Mahtani: First-line therapy options include endocrine monotherapy, which I'm personally not using much these days, either fulvestrant, or an AI, or either of those agents in combination with the CDK4/6 inhibitor. For patients that have completed therapy in the adjuvant setting with an AI and have had a disease-free interval of at least 12 months, or for those with de novo metastatic disease, these two groups are considered endocrine-sensitive patients, and AI and CDK4/6 inhibitors is a common choice. For those who have recurred while on adjuvant AI or progressed after AI therapy, monotherapy, in the metastatic setting, we often use fulvestrant and a CDK4/6 inhibitor. We know that the addition of CDK4/6 inhibitors to endocrine therapy in the first-line improve progression-free survival, with some studies also showing improvements in overall survival. This doesn't come with too much additional toxicity, therefore, these days it's really unusual for an HR-positive/HER2-negative metastatic breast cancer patient to have not seen a CDK4/6 inhibitor at some point in their treatment.
PracticeUpdate: What have prior studies shown about the benefit of fulvestrant in the first-line?
Dr. Mahtani: Fulvestrant, at the standard 500 mg dosing, was compared to anastrozole in a phase III randomized study, called the FALCON Trial. Progression-free survival was about 3 months longer with fulvestrant, but it's important to note that patients in that study were completely endocrine therapy naïve, and this is a population that we don't really see much of in the U.S.
PracticeUpdate: An important study explores the combination of fulvestrant and palbociclib as first-line treatment. How was this study designed?
Dr. Mahtani: This year at virtual ESMO, an important trial called the FLIPPER study was presented. This was a randomized phase II trial, looking at first-line treatment in an endocrine sensitive population of HR-positive, HER2-negative advanced breast cancer. The patients had not received any prior therapy for metastatic breast cancer, and stratification factors included visceral versus non-visceral, and disease at study entry, meaning de novo versus recurrent disease. The primary hypothesis was that fulvestrant plus palbociclib would result in a superior progression-free survival rate at one year, compared to fulvestrant plus placebo.
PracticeUpdate: What are the key findings?
Dr. Mahtani: The study met the primary endpoint, demonstrating a progression-free survival rate at one year of about 84% with fulvestrant plus palbo versus 72% with fulvestrant plus placebo. For the secondary endpoint of median progression-free survival, it was about 32 months versus 22 months, again, favoring the addition of palbociclib. Other secondary endpoints, including objective response rate and clinical benefit rate, also favored the incorporation of palbo to fulvestrant. In terms of overall survival, the data are not yet mature. As far as safety, there were expected side effects of each of the agents, that are known side effects of those drugs, and there were, importantly, no cases of febrile neutropenia.
PracticeUpdate: In what settings would you consider using fulvestrant as opposed to an aromatase inhibitor with a CDK4/6 inhibitor as first-line of treatment?
Dr. Mahtani: To put these data into context for endocrine sensitive patients, we now have two good options, either an AI or fulvestrant, in combination with the CDK4/6 inhibitor. In addition to the study that we just reviewed, as a reminder, the MONALEESA-3 Trial also included endocrine sensitive patients treated first-line with fulvestrant and a CDK4/6 inhibitor. In that study it was ribociclib. There were consistent findings, in that adding ribo to fulvestrant also demonstrated improvements in outcomes.
In my own practice, I anticipate that I will still continue to use an AI and a CDK4/6 inhibitor first-line for most of my patients. This is largely because I tend to save fulvestrant for second-line treatment. I find that a lot of patients are bothered by the intramuscular shot, so I try to delay that a bit. Also, especially for those patients with a known PIK3CA mutation, we want to incorporate alpelisib in combination with fulvestrant in the second-line, and we saw some really encouraging data at ESMO this year regarding follow-up survival with this combination.
Finally, as was pointed out in the discussion section, or the discussion session rather, of the FLIPPER Trial, in terms of whether or not it's more beneficial from an efficacy standpoint to combine a CDK4/6 inhibitor in the first- versus the second-line setting with fulvestrant, those types of cross-trial comparisons are always fraught with issues. Therefore, I think, ultimately the decision comes down to things like patient's prior treatment, access, patient preference for mode of administration, and, of course, side effect profiles of these agents. We do know from the PARSIFAL trial that whether you give an AI or fulvestrant in combination with the CDK4/6 inhibitor upfront, there's really no difference. For our patients, having evidence-based options for treatment in the first-line setting, I would say, is a good problem to have.