Suggestion that Higher Dose of Fulvestrant Offers Improved Biological Activity

SAN ANTONIO—Fulvestrant is a novel selective estrogen-receptor (ER) antagonist with no agonist effects and a distinct mode of action compared with third-generation non-steroidal aromatase inhibitors (AIs) and with tamoxifen. Fulvestrant is currently indicated for postmenopausal women with ER-positive, metastatic breast cancer that has progressed following anti-estrogen therapy, and is being studied as well in other settings. Two studies presented at the San Antonio Breast Cancer Symposium suggest, respectively, that high-dose fulvestrant may be superior to the approved dose in the neoadjuvant setting and provide results comparable to exemestane after AI therapy has failed in the metastatic setting.Figure: Irene Kuter, MD: “This study suggests that high-dose fulvestrant may provide a benefit to postmenopausal women with ER-positive breast cancer beyond that of the approved dose.”Neoadjuvant Therapy High-dose fulvestrant (500 mg/month with an additional 500 mg on Day 14 in the first month only) may be more effective than the approved dose of 250 mg/month, according to results of the international, multicenter, randomized, Phase II NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) study. This is the first study to compare both doses of fulvestrant in the neoadjuvant setting and to assess the relationship between the dose of fulvestrant and the markers of cell proliferation and downregulation of estrogen receptors, explained lead author Irene Kuter, MD, a hematologist/oncologist at Massachusetts General Hospital and Assistant Professor at Harvard Medical School. After four weeks of treatment, high-dose fulvestrant decreased proliferation, downregulated estrogen and progesterone receptors, and increased tumor response rates compared with the approved dose of the drug at four weeks. High-dose fulvestrant was well tolerated over the 16 weeks of the study, and no new safety concerns were reported. There was no increase in endometrial thickness and no difference in markers of bone turnovers between groups treated with high- and approved-dose fulvestrant. “This study suggests that high-dose fulvestrant may provide a greater benefit to post-menopausal women with ER-positive breast cancer beyond that of the approved dose,” Dr. Kuter stated. During the question-and-answer session following the talk, Kathleen Pritchard, MD, Senior Scientist and Chair of the Breast Group at Sunnybrook Odette Cancer Center in Toronto, asked Dr. Kuter whether she was convinced that fulvestrant should be used at higher doses. Dr. Kuter said yes, that more studies are needed and that it is too soon to say definitively, but that in the neoadjuvant setting, where a more rapid response is needed, a higher dose of fulvestrant might achieve that, but that it remains to be seen if a loading dose would provide the same benefit. A variety of studies “suggest that we may not yet have defined the ideal dose or schedule,” she said, In an interview later, Dr. Pritchard explained that her impression was that the biggest differences between the groups treated with the high and approved dose of fulvestrant was at the beginning. “Over eight and 16 weeks, the difference got smaller, so the higher dose of fulvestrant may act more quickly, but not provide better response rates by the end of four months of therapy,” Dr. Pritchard stated. “It may be that dose loading is as effective as a long-term 500 mg dosing strategy.” NEWEST enrolled 212 postmenopausal women with newly diagnosed, ER-positive, locally advanced breast cancer who had no prior treatment. At four weeks, a 79% reduction in the Ki67 marker of cell proliferation was observed in the high-dose group compared with a 47% reduction in the approved-dose group. High-dose fulvestrant achieved a greater reduction of ER and progesterone receptor expression compared with the approved dose. An intent-to-treat analysis showed that the overall tumor response rate (defined as a decrease in tumor volume of more than 65%) at Week 4 was 17.4% in the high-dose group vs 11.8% in the approved-dose group; 59.6% and 75.5%, respectively, had stable disease at Week 4. At Week 16, the overall response rates were 22.9% and 20.6%, respectively. Dr. Kuter pointed out that the stable disease group includes many patients who had good responses, albeit less than a 65% reduction in tumor volume, and that further analysis of the data will tease this out. Faster Changes in Biological Surrogates “This study showed that a higher dose of fulvestrant achieves faster changes in biological surrogates such as Ki67 and downregulation of estrogen receptors. This shows that getting to the target at a higher dose has downstream effects,” stated Stephen Chia, MD, a medical oncologist at the British Columbia Cancer Center, who presented a related poster study. Whether this translates into increased survival or progression-free survival isn't clear, though, he said, particularly in a new untreated cancer or a cancer that has been previously treated and may have developed resistance. EFECT Trial Dr. Chia's study was the first overall survival data from the EFECT trial, which compared fulvestrant (500 mg on Day 1 followed by 250 mg/month on Days 14, 28, and every 28 days thereafter) versus exemestane (25 mg/orally/day) following non-steroidal aromatase inhibitor failure. The Phase III EFECT trial enrolled 692 postmenopausal women with hormone receptor-positive advanced breast cancer whose disease recurred or progressed while being treated with an aromatase inhibitor. At a median follow-up of 20.9 months, overall survival was not significantly different between the two treatment arms: 209 (59.5%) patients in the fulvestrant group and 197 (57.9%) in the exemestane group had died. The most commonly reported adverse events were similar between groups. Both drugs were deemed valid treatment options for control of advanced breast cancer after non-steroidal aromatase inhibitor therapy. When asked what effect the higher dose of fulvestrant might have had, Dr. Chia said that theoretically, the higher dose could have done better, because NEWEST suggested that the higher dose has improved biological effects. EFECT showed that one third of women will benefit from either fulvestrant or exemestane, “but we don't know which patients will benefit from which drug. Both are options, but maybe patients [who don't appear to benefit] should move on to another hormone therapy or to chemotherapy,” Dr. Chia stated. ‘No News is Good News’ Commenting on the EFECT trial, Dr. Pritchard said that if you can use a hormone therapy (either of these drugs) and get one third of patients to benefit, “it is worth trying. Hormone therapy is less toxic than chemotherapy, which is the other medical treatment we offer women with metastatic breast cancer. I only go on to chemotherapy if there is no shrinkage of tumor or no stable disease.” She pointed out that in the metastatic setting, “no news is good news,” and stable disease is a good response. “Patients are happy if there is no change.” SABCS Abstracts 23 and 2091