Slides from a journal article and from a presentation at SABCS 2009 and transcribed comments from recent interviews with John F R Robertson, MB, ChB, BSc, MD (12/12/09) and Rowan T Chlebowski, MD, PhD (12/30/09)

JOHN F R ROBERTSON, MB, ChB, BSc, MD: There has always been some uncertainty in the past as to whether the approved dose of 250 mg/month of fulvestrant was the optimal dose. Data existed that clearly showed that a dose-dependent response for fulvestrant continued up to the 500-mg dose. In addition to that, two studies — studies 20 and 21 — showed that the 250-mg dose of fulvestrant was equivalent to anastrozole in the second-line setting.

In 2009 the results were published from the FIRST study, a study for which Matt Ellis and I were the principal investigators. FIRST showed in the first-line setting that the fulvestrant high dose of 500 mg/month was actually better than anastrozole. Time to disease progression was significantly prolonged in favor of the fulvestrant high dose. When you view the TTP curve, separation did not occur in the curves until just after six months. It is possible that the difference is not in the initial responses, but that acquired resistance is affecting the observed results for the anastrozole arm. It may be that the higher dose of fulvestrant results in greater downregulation of the estrogen receptor and thus there is decreased opportunity for cross talk to occur between the HER2 and EGFR signaling pathways, which play a role in the development of acquired resistance.

DR LOVE: What about using even higher doses of fulvestrant?

PROF ROBERTSON: We don’t know if we’ve reached the top of the dose-response curve yet. In the FIRST trial, we observed that there are no differences in side effects if you increase the dose to 500 milligrams. The time to progression curve is longer — so patients are exposed to the 500-mg dose of fulvestrant longer — yet the side-effect profile is the same. Some arthralgias occur with fulvestrant, but no more than those that occur with aromatase inhibitors.

DR LOVE: Do you think that there is enough clinical evidence to justify examining fulvestrant in the adjuvant setting?

PROF ROBERTSON: I believe that should be done. I do think we are seeing an improved therapy using the higher, 500-mg dose of fulvestrant. We can view the results of the FIRST trial with more confidence in light of the large Phase III CONFIRM trial presented at this meeting that shows that 500 milligrams is better than 250 milligrams. I believe the whole body of evidence should make us move forward with fulvestrant 500 milligrams almost as though it were a new drug. The other thing that makes fulvestrant attractive as a potential adjuvant therapy is that there appears to be no difference in the bone profile for markers of bone resorption or formation in response to fulvestrant. Our own group examined 250 milligrams of fulvestrant over 18 months and saw no difference in the bone profile. The NEWEST study examined the 250-mg and 500-mg doses in the neoadjuvant setting and also observed that the bone profile remained the same.

The design of an adjuvant trial would depend on the question that is being asked. Personally, I favor a crossover strategy by which patients would cross over from treatment with an aromatase inhibitor to fulvestrant 500 milligrams at two or three years. You could include an arm with no crossover, just fulvestrant versus an aromatase inhibitor. Another option is to examine the effect of delayed fulvestrant, administered to patients who have been on aromatase inhibitor therapy for five years. You can compare continuing aromatase inhibitor therapy versus stopping versus crossing over to fulvestrant 500 milligrams. Either of these crossover designs is attractive because we have seen with aromatase inhibitors that as you go out from the time of diagnosis, you get an increase in the hazard ratio. You see a more hormone-sensitive phenotype.

DR LOVE: Are there any situations in which you would use fulvestrant in the adjuvant setting?

PROF ROBERTSON: If the patient is at high risk and has had contraindications to both an aromatase inhibitor and tamoxifen, you could have that discussion. You would have to explain that this was completely off label. I don’t think it would be something that you would want to pursue as a policy that you practiced by easy default. We need randomized trials for that.

ROWAN T CHLEBOWSKI, MD, PhD: The CONFIRM trial is a Phase III randomized trial for postmenopausal women with prior hormone exposure. It is comparing the approved dose of fulvestrant, 250 milligrams every 28 days, to that of high-dose fulvestrant, which is 500 milligrams on days one, 14 and 28 followed by 500 milligrams every 28 days. This results in almost a doubling of the dose if you administer over a year’s worth of therapy. Prior to this study, the results of the FIRST trial, presented last year, demonstrated a striking result comparing anastrozole to high-dose fulvestrant. Anastrozole had a 12-month time to disease progression, whereas it exceeded 21 months with fulvestrant.

The Phase III study presented by Dr Di Leo had more than 700 patients and met the primary endpoint, which was improvement in time to disease progression. The improvement was modest, 6.5 versus 5.5 months, which was significant at a p-value of 0.006. The overall survival was more interesting in that it was trending in favor of the high-dose fulvestrant, 25.1 months median survival versus 22.8 months, with a p-value of 0.09.

It is also of interest that the duration of clinical benefit was significantly longer with the fulvestrant high dose versus the approved dose. The analyses presented were after 50 percent of the patient population had died. The next analysis will look after an additional 25 percent have died. Knowing that this large proportion of people hadn’t experienced disease progression yet on the high-dose fulvestrant arm makes it reasonable to think that, as time goes on, the survival trend may turn out to be significant. I look at this as a positive result.

I believe the study results generate new life into fulvestrant because most postmenopausal patients will be coming off of an adjuvant aromatase inhibitor at some time, either failing on it or following it. This could be a real first-line standard hormonal therapy, especially if it undergoes a label change.

Apparently, this high dose has resulted in a label change in four countries in Europe already, so this is now the standard fulvestrant dose in those countries. This is practice changing. No increase in side effects was seen, and we have been using this dose of fulvestrant for some time in my practice. We haven’t had difficulty with patients accepting it, and it can be administered by nurses with ease. However, it will be a problem for routine clinical use if fulvestrant does not undergo a label change.

Prof Robertson is Professor of Surgery and Head of the Academic Division of Breast Surgery at Nottingham City Hospital in Nottingham, United Kingdom.

Dr Chlebowski is Professor of Medicine at the David Geffen School of Medicine at UCLA and Chief of the Division of Medical Oncology and Hematology at Harbor-UCLA Medical Center in Torrance, California.