Optimal sequencing of agents in postmenopausal patients

DR GRADISHAR: If you evaluate most of the available data with endocrine agents in the metastatic setting — tamoxifen, steroidal or nonsteroidal aromatase inhibitors or fulvestrant — the question that comes up is whether one sequence enhances patient outcome more than another. This becomes important because if you can demonstrate that one sequence enhances the time to disease progression, it may be built on over time so that overall outcome is improved. In theory, simply having an improvement in recurrence or progression of metastatic disease impacts quality of life.

Patients now typically receive a nonsteroidal aromatase inhibitor — anastrozole or letrozole — as the first treatment. The question then becomes, if patients progress on one of those agents, what would be the next best therapy? Should it be the steroidal aromatase inhibitor exemestane, or should it be fulvestrant? Indirect data evaluating the sequence of a nonsteroidal aromatase inhibitor to fulvestrant suggest that 25 to 30 percent of patients may benefit with that approach.

An important issue is whether fulvestrant 250 mg is optimal. Some of the data suggest that the dose is really on the low end of the curve where you might expect the optimal response rate. Some strategies have evaluated quickly increasing serum levels of fulvestrant, including administering loading doses of 500 mg and within two weeks administering another 250 mg and then proceeding to the monthly schedule.

Those strategies are based on mathematical modeling that has shown an ability to achieve steady-state levels much more quickly and consequently achieve a biologically relevant dose of drug circulating much faster.

DR GABRIEL N HORTOBAGYI: Assuming an aromatase inhibitor and fulvestrant are equivalent in efficacy, the choice of which agent to use may come down to patient preference. Some of my patients are perfectly happy with a monthly injection, while others prefer an oral agent. For many patients, fulvestrant is financially favorable because of our arcane reimbursement system. We know that responses can be seen with either sequence — an aromatase inhibitor followed by fulvestrant or the opposite — but I believe it’s important that we determine which is superior.

I believe the trials of fulvestrant underestimate the efficacy of this agent. The dosing schedule used was probably too low because by the time steady state was reached, many patients were off study, presumably because of progression. In my group, we administer loading doses of 500 mg of fulvestrant followed by 500 mg two weeks later and then 250 mg monthly. The pharmacokinetics of fulvestrant suggest a loading dose would be beneficial, so it concerns me that the comparison of fulvestrant to anastrozole in a tamoxifen-resistant population might not have revealed the true efficacy of fulvestrant. It showed fulvestrant to be at least as effective as anastrozole, but I expected it to be superior. We may need to repeat some of these studies with a more appropriate dosing schedule.

DR ADAM M BRUFSKY: Most clinicians consider fulvestrant a third-line therapy for patients who have failed tamoxifen and an aromatase inhibitor; however, clinical trials have shown that fulvestrant is equivalent to anastrozole after tamoxifen failure and, in a recently published European study comparing front-line fulvestrant to tamoxifen, I did not view fulvestrant as inferior to tamoxifen.

I use third-line fulvestrant, but I also use it first line, particularly in women who can’t afford an aromatase inhibitor. In addition, I would estimate that approximately 40 percent of my patients prefer a monthly injection to taking a pill every day.

DR GERSHON LOCKER: The overall results of Trials 20 and 21 showed no significant difference between anastrozole and fulvestrant, but differences occurred in subset analyses. The duration of response seemed to be longer in patients who responded to fulvestrant, and patients who had visceral disease seemed to respond better than those who did not.

I think the takeaway message is that they’re equally efficacious; however, there may be subsets of patients in whom you might prefer to use fulvestrant, particularly those for whom compliance may be an issue or those with visceral disease. The other important point is that anecdotal studies argue that you can use one and switch to the other. Third-line aromatase inhibitors are efficacious after fulvestrant and vice versa.

DR STEPHEN E JONES: Generally, patients are either going to relapse on tamoxifen or after adjuvant tamoxifen. In that setting as well as in the fulvestrant versus anastrozole clinical trials, evidence exists that a proportion of women have a longer response to fulvestrant than to anastrozole when given right after tamoxifen.

I‘ve had patients with long responses to fulvestrant. I prefer fulvestrant to an aromatase inhibitor after tamoxifen because approximately 20 percent of patients have long responses with it in this setting. However, 99 percent of oncologists will choose an aromatase inhibitor after tamoxifen. Fulvestrant is generally being used as third line. Despite Trials 20 and 21, most physicians start with anastrozole rather than fulvestrant because of the way the data have been presented.

We are just beginning to see patients who have been treated with two or three years of adjuvant anastrozole and then relapsed. Currently, there is little data on treatment options in this setting. It’s somewhat of a “dealer’s choice” because there are no hard-and-fast rules. There are multiple options including fulvestrant, exemestane and even tamoxifen — if the patient hasn’t seen it — because it’s obviously still a useful drug. So the sequence is going to be all over the map for most folks.

DR TRIPATHY: In the up-front study, tamoxifen and fulvestrant were essentially equivalent. As second-line therapy, fulvestrant seemed to perform equally as well as anastrozole. At this point in time, the sequencing and timing for fulvestrant are unclear. I think it’s reasonable to use the drug — maybe not up front, but as second- or third-line therapy.

This is when you might consider the patient’s preferences in terms of an intramuscular or an oral drug. A recent study of 261 women with metastatic breast cancer demonstrated that about one third preferred a monthly intramuscular injection. I’ve always assumed that oral drugs were preferable, if they were equally effective. Therefore, I was surprised to see that many patients preferred an intramuscular injection. I need to query my patients more when I start evaluating these options.

DR HAROLD J BURSTEIN: Previously, patients received tamoxifen in the adjuvant setting, so we would use an aromatase inhibitor front line in the metastatic setting. Fulvestrant was used second line, or we could use megestrol acetate, but for many women fulvestrant has a more convenient side-effect profile. Now that more women receive aromatase inhibitors in the adjuvant setting, we’re using tamoxifen or fulvestrant as firstline treatment in the metastatic setting.

DR BLUM: In my experience, patients tolerate the fulvestrant injections just fine. We have randomized data comparing fulvestrant versus anastrozole in patients who have already received tamoxifen, but the optimal sequence for using fulvestrant is still undetermined. In choosing between an aromatase inhibitor and fulvestrant, I ask my patients whether they prefer an injection or a pill. If they have transportation problems, then I use an oral agent. However, for the Medicare population, these drugs are very expensive. If the patient does not have adequate insurance coverage and can’t afford them, a monthly injection may be better. Compliance is also an issue to be considered when choosing between a daily oral agent and a monthly injection.

DR DANIEL F HAYES: I use fulvestrant as third-line therapy in patients whose disease has progressed on tamoxifen and an aromatase inhibitor. That’s the current indication, but it wouldn’t surprise me to see it moved up because data from the randomized trials clearly suggest it is as effective as aromatase inhibitors in patients who progressed after tamoxifen. The clinical question is whether the patient prefers a pill versus parenteral injection. For some patients, the injection is easier, but most patients prefer taking a pill. In my experience, the tolerability of fulvestrant is similar to that of the aromatase inhibitors.

EFECT trial

DR MITCHELL DOWSETT: EFECT is an American and European study that randomly assigns patients who have failed therapy with a nonsteroidal aromatase inhibitor to fulvestrant or exemestane. Our own study, SoFEA, is slightly different from EFECT because it is based on the observation that the addition of small amounts of estrogen to cells that have been estrogen deprived for a long time reduces the effectiveness of fulvestrant. That scenario equates to the withdrawal of a nonsteroidal aromatase inhibitor and the addition of fulvestrant. Hence, the third arm of our trial includes a nonsteroidal aromatase inhibitor and fulvestrant. I predict fulvestrant alone will probably be better than exemestane, and fulvestrant plus anastrozole will be better than fulvestrant alone.

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