Practice-changing endocrine trials shed light on breast cancer treatment, management

At the 2016 San Antonio Breast Cancer Symposium, investigators presented findings on PFS benefits of adding an mTOR inhibitor to anti-hormonal therapy in advanced disease in postmenopausal women; the lack of clarity on the optimal duration of extended AI therapy, also in postmenopausal women; and using CTCs in helping predict breast cancer outcomes in the neoadjuvant setting.

Fulvestrant plus everolimus improves PFS in HR+, HER2- advanced breast cancer

Key clinical point This study provides further evidence of the benefits of adding an mTOR inhibitor to anti-hormonal therapy in postmenopausal women with advanced breast cancer resistant to aromatase inhibitors. Major finding Fulvestrant plus everolimus was associated with a PFS of 10.4 months, vs 5.1 months for fulvestrant alone. Data source Randomized phase 2 trial of 131 women with HR-positive, HER2-negative locally advanced of metastatic breast cancer resistant to aromatase inhibitors. Disclosures Sponsored by PrECOG with financial support from Novartis. Dr Kornblum reported having no conflicts of interest.

Adding everolimus to fulvestrant doubled median progression-free survival (PFS) among postmenopausal women with hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) metastatic breast cancer resistant to therapy with an aromatase inhibitor (AI), Noah S Kornblum, MD, reported during his presentation at the meeting of the PrECOG 0102 trial findings.

In the randomized phase 2 trial, the combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus with the selective estrogen receptor down-regulator (SERD) fulvestrant was associated with a median PFS of 10.4 months, compared with 5.1 months for fulvestrant plus placebo, said Dr Kornblum, of Montefiore Einstein Center for Cancer Care, New York. The findings provide additional evidence that adding everolimus to anti-estrogen therapy in AI-resistant disease improves clinical outcomes,” he added.

Most women with HR-positive breast cancer who are treated with an AI will eventually develop resistance to those agents. Strategies for overcoming resistance include the addition of everolimus to a steroid AI, exemestane, as has been demonstrated in the BOLERO-2 trial. “Another strategy for overcoming AI resistance is by more completely blocking estrogen-receptor signaling through the use of a selective estrogen receptor down-regulator, which may result in more complete blockade of the ER signaling pathway than a steroidal AI such as exemestane,” Dr Kornblum said.

To test this hypothesis, the investigators enrolled 131 postmenopausal women with inoperable locally advanced or metastatic HR-positive, HER2-negative breast cancer resistant to AIs. AI resistance was defined as relapse while receiving adjuvant AI therapy, and/or progression after one or more AIs for metastatic disease. The patients could have had no more than one prior chemotherapy regimen for metastatic disease.

The patients were stratified by Eastern Cooperative Oncology Group performance status, presence of measurable disease, and previous chemotherapy status, and were then randomized to receive either high-dose fulvestrant (500 mg on day 1 and 15 of cycle 1, and then on day 1 of cycles 2-12) plus oral everolimus 10 mg/day, or fulvestrant and placebo. The trial had an induction phase, in which patients were treated until evidence of progressive disease or unacceptable toxicity for a maximum of 12 28-day cycles, and a continuation phase in which patients who had neither disease progression nor experienced unacceptable toxicities could have their data unblinded and could continue on the fulvestrant-everolimus combination.

The trial did not include the use of corticosteroid-containing mouthwash for prevention of treatment-associated stomatitis, because it was designed before the evidence of the benefit of such prophylaxis became public, Dr Kornblum said.

The primary endpoint of PFS by investigator assessment was significantly better with the fulvestrant-everolimus group at 10.4 months, compared with 5.1 months for the fulvestrant-placebo group. The hazard ratio was 0.60 (P = .02). There was no difference in overall survival (OS), however. Median OS in the combination group was 24.8 months, compared with not yet reached in the placebo arm (not statistically significant).

The combination therapy was associated with more grade 3 adverse events than the fulvestrant-placebo combination (48% vs 14%, respectively). The most common grade 3 adverse events occurring in more than 5% of patients were stomatitis, pneumonitis, fatigue, and hyperglycemia. Overall, the safety profile of the combination was consistent with that seen in BOLERO-2, Dr Kornblum said. In all, 10% of patients assigned to the combination and 12% assigned to placebo withdrew from the study because of adverse events; these patients were included in the analysis, which was by intention to treat.

— Neil Osterweil

Still no clarity on duration of extended AI therapy

Key clinical point The optimal duration of aromatase inhibitor (AI) therapy following 5 years of endocrine therapy in postmenopausal women is still unknown. Major finding There were no significant differences in disease-free or overall survival in three studies investigating extended AI therapy. Data source Randomized phase 2 NSABP B-42 with 3996 patients; randomized phase 3 DATA study with 1912 patients; randomized phase 3 IDEAL trial with 1824 patients. Disclosures NSABP B-42 was sponsored by PrECOG with financial support from Novartis. Dr Mamounas reported having no conflicts of interest. The DATA trial was sponsored by the Dutch Breast Cancer Research Group and Novartis. Dr Tjan-Heijnen reported nothing to disclose. IDEAL was supported by the Dutch Breast Cancer Research Group and Novartis. Dr Blok reported nothing to disclose.