Reports

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PRIORITY PRESS - 2012 CTRC-AACR San Antonio Breast Cancer Symposium

San Antonio, Texas / December 4-8, 2012

San Antonio - Metastatic progression or recurrence of advanced breast cancer (BC) remains essentially an incurable disease. In the absence of curative therapy, interventions that extend survival and/or maintain quality of life have clinically important roles in the management of metastatic BC (mBC). Treatment options include several classes of antiestrogen agents, which impede disease progression by various mechanisms that block BC cells’ access to estrogen. Several recent studies have demonstrated survival benefits in patients treated with the selective estrogen-receptor downregulator fulvestrant. Preliminary data from the CONFIRM trial have suggested that the higher dose of 500 vs. 250 mg leads to better outcomes in mBC. While there continues to be a need for long-term follow-up from clinical trials, the latest follow-up results from CONFIRM continue to support the optimal 500 mg dose by showing a clinically significant 19% improvement in overall survival among patients with mBC.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Among options for endocrine treatment in metastatic breast cancer (mBC), fulvestrant remains mechanistically unique, as the only currently available member of the selective estrogen receptor downregulator class. Since its introduction more than a decade ago, questions about optimal dosing have surrounded its clinical use, according to Dr. Angelo Di Leo, Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Italy.

In an effort to resolve the dosing issue, investigators in the multicentre, randomized CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) trial compared 250- and 500-mg doses of fulvestrant in patients with advanced BC that had progressed on prior endocrine therapy. Initial results from the trial showed a statistically significant 20% improvement in median primary end point of progression-free survival (PFS) with the 500-mg dose (J Clin Oncol 2010;28:4594-600). The results also showed a trend toward improved overall survival (OS) in the 500-mg arm (25.1 vs. 22.8 months, P=0.091). The difference emerged at a prespecified analysis after 50% of the patients had died.

“Based on these encouraging results, we decided to perform a second survival analysis to be done when 75% of patients had died,” stated Dr. Di Leo.

CONFIRM involved 736 postmenopausal women with hormone receptor-positive BC. After meeting the primary end point, the trial continued with follow-up to 75% of survival events, regardless of whether patients had discontinued therapy.

Evidence of Improved Survival

The initial analysis showed a 16% reduction in the OS hazard ratio (HR) in the 500-mg fulvestrant arm. In the new analysis, performed after a median follow-up of about 3 years, the advantage in median OS had increased to more than 4 months, which represented a 19% reduction in the HR (P=0.016).

As the analysis was unadjusted, the OS benefit could not be considered definitive with respect to statistical significance, noted Dr. Di Leo. However, the OS results continued in the direction of an advantage for the 500-mg dose, as shown in the initial data analysis.

Safety results also remained consistent with the findings from the first analysis, showing no clinically relevant differences between the 2 doses.

“Based on the results of the present trial, whenever fulvestrant is considered for the treatment of menopausal patients with estrogen receptor-positive advanced BC, the recommended dose is 500 mg,” Dr. Di Leo concluded.

On the basis of the initial data analysis of CONFIRM, Health Canada and the U.S. Food and Drug Administration previously approved the 500-mg dose of fulvestrant.

Optimizing Second-Line Therapy

When patients with advanced, hormone-responsive BC progress on first-line therapy, there are multiple options for treatment in second line and beyond, noted Dr. Stephen Johnston, Royal Marsden Hospital, London, UK. However, the optimal second-line therapy has yet to be determined.

Results of 2 recent clinical trials illustrated the conundrum regarding second-line endocrine therapy. The EFECT trial showed no difference in PFS among patients randomized to fulvestrant or the steroidal aromatase inhibitor exemestane. The randomized SoFEA trial showed that the combination of fulvestrant and the aromatase inhibitor anastrozole did not improve PFS compared with fulvestrant alone and monotherapy with fulvestrant or exemestane led to similar PFS. In both trials, patients assigned to fulvestrant received a 500-mg loading dose, followed by 250 mg every other week and then 250 mg monthly.

In an effort to bring some clarity to the uncertainty surrounding second-line hormonal therapy for advanced BC, Dr. Johnston and colleagues performed an individual-patient meta-analysis of the EFECT and SoFEA trials. EFECT involved 693 patients randomized to exemestane or fulvestrant. SoFEA involved 723 patients randomized to exemestane, fulvestrant or the combination of fulvestrant and anastrozole. The primary end point was PFS, as defined in each trial. Secondary end points included OS, response rate and safety.

Limiting the analysis to patients who received only monotherapy, investigators found that fulvestrant was associated with a median PFS and OS of 3.9 months and 21.9 months, respectively vs. 3.8 months and 22.6 months with exemestane. Subgroup analysis failed to identify any groups that derived greater benefit from one therapy or the other.

“The efficacy and safety of the 250-mg fulvestrant regimen with loading dose is not different from exemestane 25 mg in postmenopausal patients with estrogen receptor-positive advanced BC,” Dr. Johnston concluded in a poster presentation. “There was no evidence of a benefit for fulvestrant in any of the preplanned subgroups with the 250-mg regimen used in EFECT and SoFEA.”

Combination Therapy

As suggested by the fulvestrant/anastrozole regimen evaluated in the SoFEA trial, clinical investigators are exploring combination therapy as a means of increasing the benefits of endocrine therapy in advanced, hormone-responsive BC. Results of one small clinical trial provided evidence of activity and potential benefit for the combination of fulvestrant and the mTOR inhibitor everolimus.

Investigators in the ongoing trial have treated 31 patients with the fulvestrant regimen used in the EFECT and SoFEA trials plus everolimus 10 mg/day. All the patients had progressed on prior endocrine therapy. The primary end point is time to progression (TTP).

The median TTP in the 31 patients was 7.4 months. Overall response rate was 13% (one complete response, 3 partial responses) and 35% of patients achieved stable disease with the regimen. Ten patients had no discernible response to the combination, Dr. Jessica Crowley, University of Kentucky, Lexington, and colleagues reported.

The most frequent adverse events (all grades) were mucositis and weight loss (48% each), followed by rash (32%), fatigue (32%), pneumonia (23%) and nausea (23%). Laboratory abnormalities occurring in ≥50% of the patients included liver enzyme elevation, hyperglycemia, anemia, hypercholesterolemia, thrombocytopenia, hypokalemia and hypoalbuminuria.

“The benefit of adding everolimus to fulvestrant is similar to that observed from combination therapy with exemestane and tamoxifen,” Dr. Crowley concluded in a poster presentation. “Future trials should examine whether earlier use of PI3K/mTOR inhibitors would retain a robust impact on endocrine resistance. Because not all patients derive benefit from the use of everolimus, discovering molecular predictors of benefit is critical.”

Sequential Use of Agents

Another endocrine strategy of interest is sequential use of different hormonal therapies as adjuvant therapy after primary surgical treatment of BC. Investigators in Japan randomized 706 patients to 5 years of adjuvant tamoxifen or 1 to 4 years of tamoxifen followed by anastrozole for a 5-year total duration of adjuvant endocrine therapy.

The primary end point was disease-free survival (DFS). After a median follow-up of 76.7 months, 52 DFS events had occurred in the anastrozole arm compared with 59 in the patients who received only tamoxifen. Events related to relapse-free survival (RFS, a secondary end point) numbered 32 with anastrozole and 42 with tamoxifen alone. Both outcomes demonstrated a numerical advantage for sequential therapy, but neither difference achieved statistical significance, Dr. Shigeru Imoto, Kyorin University, and colleagues reported.

Analysis by duration of therapy and follow-up showed that the greatest effect of anastrozole on DFS and RFS occurred during the first 2.5 to 3.5 years after surgery. HRs for DFS and RFS during the first 36 months were 0.72 and 0.58 in favour of anastrozole compared with 1.06 and 0.98 thereafter.

Summary

Endocrine therapy has demonstrated beneficial effects in the treatment of hormone-responsive BC, including metastatic and nonmetastatic disease. However, the optimal agents and regimens have yet to be determined. High-dose fulvestrant (500 vs. 250 mg) has improved PFS and achieved at least a strong trend toward improved OS in patients with metastatic hormone receptor-positive BC. Combination and sequential therapy (including multiple endocrine therapies and combinations of endocrine and targeted therapies) have attracted considerable interest among clinical investigators, but have yet to demonstrate clear-cut benefits beyond monotherapy.