SAN ANTONIO (FRONTLINE MEDICAL NEWS) – Adding everolimus to fulvestrant doubled median progression-free survival among postmenopausal women with hormone-receptor positive, human epidermal growth factor receptor 2–negative (HER2-negative) metastatic breast cancer resistant to therapy with an aromatase inhibitor [AI] in the PrECOG 0102 study.

In the randomized phase II trial, the combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) with the selective estrogen receptor down-regulator [SERD] fulvestrant (Faslodex) was associated with a median progression-free survival of 10.4 months, compared with 5.1 months for fulvestrant plus placebo, reported Noah S. Kornblum, MD, of Montefiore Einstein Center for Cancer Care, New York.

This study provides additional evidence that adding everolimus to anti-estrogen therapy in AI-resistant disease improves clinical outcomes,” he said at the San Antonio Breast Cancer Symposium.

Most women with hormone receptor–positive breast cancer treated with an AI will eventually develop resistance to these agents. Strategies for overcoming resistance include the addition of everolimus to a steroid AI, exemestane (Aromasin), as 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 hormone receptor–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 prior 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 fulvestrant/everolimus.

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

As noted before, the primary endpoint of PFS by investigator assessment was significantly better with the combination, at 10.4 vs. 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 was 24.8 months among patients treated with everolimus, compared with not yet reached in the placebo arm (not statistically significant).

The combination was associated with more grade 3 adverse events than fulvestrant/placebo (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.

Regarding future directions, Dr. Kornblum noted that “our study was completed prior to the availability of the CD4/6 inhibitors, which are effective added to both first-line AI therapy or second-line fulvestrant in AI-resistant disease. On the other hand, mTOR inhibitors are effective as second line therapy in AI-resistant disease, but possibly not as first-line therapy.”

As only a few patients in the study received a prior CDK4/6 inhibitor, “further work is required to define whether prior CDk4/6 inhibitor therapy would impact response to combination mTOR-inhibitor/SERD therapy,” he added.

Potential role for the combination?

Following the presentation, SABCS fixture Steven “Vogel, New York” Vogel, MD, asked what to do when fulvestrant-based therapy fails.

“I’m interested in what to do after progression. Let’s say the patient gets fulvestrant, gets everolimus, has a nice response – 9 months later, the tumor gets worse. We’re all pretty sure we shouldn’t continue the fulvestrant. I would love PrECOG to do a study in those patients of giving megestrol or megestrol/everolimus, and see if the everolimus extended beyond progression does the patient some good, as does trastuzumab,” he said.

“Sounds like a good idea. I’m game, let’s roll up our sleeves and do it together,” Dr. Kornblum replied.

The study was sponsored by PrECOG with financial support from Novartis. Dr. Kornblum reported having no conflicts of interest.


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