GEICAM/2006-10: Adjuvant fulvestrant/anastrozole role in early breast cancer uncertain

 

MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.

But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.

Thus, the woefully underpowered trial, in which the dose of the selective estrogen receptor degrader (SERD) fulvestrant tested was only half that of the current recommended dose, was unable to detect a potential treatment benefit, leaving unsettled the question of whether adding high-dose fulvestrant to anastrozole can improve adjuvant therapy in early-stage breast cancer, said Manuel Ruíz-Borrego, MD, PhD, from Hospital Universitario Virgen del Rocío, Seville, Spain, at the European Society of Medical Oncology congress.

“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.

Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.

“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.

Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.

The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.

The investigators enro­­­lled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.

As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).

After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).

Grade 2-3 hypertension and LDL cholesterol level increases were more common with anastrozole alone, while anastrozole/fulvestrant was associated with higher incidences of fatigue, osteoporosis, and musculoskeletal pain.

The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.

“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.

The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.

 

MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.

But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.

Thus, the woefully underpowered trial, in which the dose of the selective estrogen receptor degrader (SERD) fulvestrant tested was only half that of the current recommended dose, was unable to detect a potential treatment benefit, leaving unsettled the question of whether adding high-dose fulvestrant to anastrozole can improve adjuvant therapy in early-stage breast cancer, said Manuel Ruíz-Borrego, MD, PhD, from Hospital Universitario Virgen del Rocío, Seville, Spain, at the European Society of Medical Oncology congress.

“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.

Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.

“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.

Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.

The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.

The investigators enro­­­lled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.

As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).

After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).

Grade 2-3 hypertension and LDL cholesterol level increases were more common with anastrozole alone, while anastrozole/fulvestrant was associated with higher incidences of fatigue, osteoporosis, and musculoskeletal pain.

The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.

“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.

The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.

 

MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.

But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.

Thus, the woefully underpowered trial, in which the dose of the selective estrogen receptor degrader (SERD) fulvestrant tested was only half that of the current recommended dose, was unable to detect a potential treatment benefit, leaving unsettled the question of whether adding high-dose fulvestrant to anastrozole can improve adjuvant therapy in early-stage breast cancer, said Manuel Ruíz-Borrego, MD, PhD, from Hospital Universitario Virgen del Rocío, Seville, Spain, at the European Society of Medical Oncology congress.

“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.

Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.

“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.

Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.

The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.

The investigators enro­­­lled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.

As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).

After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).

Grade 2-3 hypertension and LDL cholesterol level increases were more common with anastrozole alone, while anastrozole/fulvestrant was associated with higher incidences of fatigue, osteoporosis, and musculoskeletal pain.

The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.

“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.

The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.