The ASCO Post presents these brief summaries of important studies in breast cancer, presented at the 2018 ASCO Annual Meeting.

Ribociclib Plus Fulvestrant in Metastatic Breast Cancer

The benefit of an inhibitor of cyclin-dependent kinase 4/6 (CDK4/6) added to fulvestrant has now been proven to extend to patients with de novo advanced breast cancer and those who relapse more than 12 months after endocrine therapy, according to Dennis J. Slamon, MD, PhD, of UCLA Medical Center, who reported the results of MONALEESA-3 at the 2018 ASCO meeting.¹

Dennis J. Slamon, MD, PhD

The MONALEESA-2 and -MONALEESA-7 trials showed that adding ribociclib (Kisqali) to endocrine therapy improves progression-free survival over endocrine therapy alone in hormone receptor–positive HER2-negative patients, but its benefit in the subset of patients who had received no or up to one line of prior endocrine therapy has not been proven.

“MONALEESA-3 was designed to investigate this population, in large part,” Dr. Slamon said. “It is the first study to show that a CDK4/6 inhibitor plus fulvestrant [Faslodex] combination is efficacious in patients with de novo advanced breast cancer or disease that relapses more than 12 months after completion of prior neoadjuvant or adjuvant endocrine therapy.”

The study included 726 postmenopausal patients with de novo advanced/metastatic disease and no prior exposure to endocrine therapy or those who relapsed more than 12 months after endocrine therapy. The de novo patients were treatment-naive or had received just one line of endocrine therapy.

The median progression-free survival was 20.5 months with ribociclib, compared with 12.8 months with placebo (hazard ratio [HR] = 0.593, P = .00000041), with a benefit observed across a variety of subgroups. The median progression-free survival was not reached when the combination was given in the first-line setting, but it was 18.3 months with the single agent (HR = 0.577); ribociclib’s benefit was also observed in the second-line setting (HR = 0.565). The safety of the combination was considered manageable, with toxicities similar to those seen in previous trials, Dr. Slamon said.

“Patients receiving this combination had a statistically significant and clinically meaningful improvement in progression-free survival,” he concluded. “This represents a new first- or second-line treatment option for postmenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer.”

Abemaciclib Plus Fulvestrant in Young Patients

Although CDK4/6 inhibitors have established benefit in postmenopausal patients, their benefit in pre- and perimenopausal patients is just emerging. At the 2018 ASCO meeting, the phase III MONARCH-2 trial showed that adding abemaciclib -(Verzenio) to fulvestrant significantly improved progression-free survival and time to subsequent chemotherapy in these younger patients.²

Patrick Neven, MD, PhD

Patrick Neven, MD, PhD, of the Universitaire Ziekenhuizen Leuven in Belgium, focused on the subset of 114 pre/perimenopausal patients in the study, all of whom were resistant to endocrine therapy and had not received chemotherapy for metastatic disease. They were randomized to receive fulvestrant with or without abemaciclib, and all received a gonadotropin-releasing hormone (GnRH) agonist.

In the full study population of 669 patients, which also included postmenopausal patients, the median progression-free survival was 16.4 months with abemaciclib, compared with 9.3 months with placebo (HR = 0.553, P < .0000001). In the pre/perimenopausal subset, the median progression-free survival was not reached in the abemaciclib arm, compared with 10.5 months with placebo (HR = 0.446, P = .002); 28 of the 71 patients in the combination therapy group and 29 of the 42 patients in the placebo group developed a progression-free survival event during the 20-month median follow-up.

In summary, in young women with endocrine-resistant breast cancer, abemaciclib added to fulvestrant doubled progression-free survival compared to fulvestrant alone. In the pre/perimenopausal subset, the combination also significantly improved response rates and time to subsequent chemotherapy (HR = 0.61). In the intent-to-treat population, the time to chemotherapy was not reached in the fulvestrant-plus-abemaciclib group and was 26.3 months in the fulvestrant-plus-placebo group (HR = 0.65, P < .01).

Everolimus Plus Exemestane

The open-label phase II BOLERO-6 trial confirmed the benefit of everolimus (Afinitor) plus exemestane in patients with estrogen receptor–positive, HER2-negative advanced breast cancer whose disease progressed on nonsteroidal aromatase inhibitors, reported Guy H. Jerusalem, MD, of The University of Liege and the CHU of Liege in Belgium.³

Guy H. Jerusalem, MD

BOLERO-6, which was conducted to fulfill postapproval regulatory commitments, evaluated everolimus plus exemestane vs everolimus alone or capecitabine alone in 309 patients. There were some slight imbalances among the arms, Dr. Jerusalem acknowledged.

After a median follow-up of 37.6 months, everolimus plus exemestane reduced the risk of disease progression by 26% vs everolimus (HR = 0.74, 90% confidence interval [CI] = 0.57–0.97). The median progression-free survival was 8.4 vs 6.8 months, respectively.

“A stratified multivariate Cox regression model accounting for baseline imbalances and known prognostic factors gave a consistent hazard ratio for the combination (HR = 0.73),” he added.

The combination did not, however, demonstrate a benefit over capecitabine (HR = 1.26, 90% CI = 0.96–1.66), based on median progression-free survival times of 8.4 months with the combination vs 9.6 months with capecitabine, he reported. This progression-free survival time is higher than has been noted with previous studies of capecitabine (4.1–7.9 months), he added.

“A numerical difference was observed for capecitabine over everolimus plus exemestane, which may be attributed to various baseline characteristics favoring capecitabine and potential informative censoring,” he suggested. That is, 20% of the capecitabine arm vs 9% of the everolimus/exemestane arm were censored for initiating new treatments, and more patients on capecitabine had bone-only metastases (24% vs 13%). (Slightly fewer on this arm, however, had at least three metastatic sites, and more were physically active.)

For this comparison, when the analysis accounted for baseline imbalances and prognostic factors, the hazard ratio was 1.15 (90% CI = 0.86–1.52), he said.

The median overall survival was 23.1 months with everolimus/exemestane vs 29.3 months with everolimus (HR = 1.27, 90% CI = 0.95–1.70) and 25.6 months with capecitabine (HR = 1.33, 90% CI = 0.99–1.79). After adjusting for imbalances and prognostic factors, the hazard ratios were 1.27 and 1.19 for the combination vs its respective comparators.

Adjuvant Denosumab and Recurrence: Conflicting Findings

Two studies reached different conclusions about the effect of adjuvant denosumab (Xgeva) on disease-free survival risk.

In the international phase III D-CARE study, presented at the 2018 ASCO meeting by Robert E. Coleman, MBBS, MD, of the University of Sheffield in the United Kingdom,⁴ an intensive regimen of adjuvant denosumab did not reduce recurrences or death but did improve the time to first bone metastasis.⁴

Robert E. Coleman, MBBS, MD

D-CARE randomized 4,509 patients with early breast cancer to receive standard locoregional and neoadjuvant therapies plus denosumab at 120 mg or placebo monthly for 6 months, then every 3 months for up to 5 years. The primary endpoint was bone metastasis–free survival, defined as the first bone metastatic event confirmed by central imaging review or death from any cause. After a median follow-up of 67 months, denosumab demonstrated no effect on the primary endpoint of bone metastasis–free survival (HR = 0.97, P = .70) and also on the secondary endpoints.

“Bone metastasis–free survival is a complicated endpoint that can be reached in many different ways,” Dr. Coleman said. “Around 40% of the events that contributed to bone -metastasis–free survival were due to deaths, either deaths without recurrence or deaths after local or nonbone distant -recurrence.”

In an exploratory analysis, denosumab did seem to delay the time to bone metastasis as first recurrence (HR = 0.76) as well as time to on-study fracture prior to bone recurrence (HR = 0.76). Disease-free survival was also similar between the two arms, and most of these events were nonbone distant recurrences. Death before disease recurrence was similar between the arms (HR = 1.04), as was overall survival (HR = 1.03).

An update of the ABCSG-18 trial, presented by Michael Gnant, MD, of the -Medical University of Vienna and Austrian Breast and Colorectal Cancer Study Group, showed otherwise: Adjuvant denosumab at 60 mg every 6 months reduced recurrences and deaths at 8 years.⁵ “Adjuvant denosumab at 60 mg every 6 months should be offered to postmenopausal breast cancer patients on adjuvant aromatase inhibitor therapy,” he said.

Adjuvant denosumab at 60 mg every 6 months should be offered to postmenopausal breast cancer patients on adjuvant aromatase inhibitor therapy.

— Michael Gnant, MD

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The ABCSG-18 researchers previously reported at the 2015 ASCO meeting that the study reached its primary endpoint, reducing fractures by 50% (P < .0001). Patients continue to be followed for disease-free survival. The study included 3,425 postmenopausal patients who received denosumab at 60 mg every 6 months or placebo.

At 8 years, in the intent-to-treat analysis, disease-free survival was 80.6% in the denosumab arm vs 77.5% in the placebo arm (HR = 0.82, P = 0.26), although much of the disease-free survival benefit of denosumab appeared, somewhat surprisingly, to be through a reduction in non-breast new primaries rather than fewer breast cancer recurrences. The hazard ratios remained consistent when the analysis was censored for crossovers and for use of alternative therapy. There was no case of “positively adjudicated” osteonecrosis of the jaw.

“These time-driven descriptive disease-free survival analyses of ABCSG-18 indicate that adjuvant denosumab considerably improves disease-free survival,” Dr. Gnant said. “Adjuvant denosumab at 60 mg every 6 months reduces the risk of cancer recurrence/occurrence or death in postmenopausal breast cancer patients. This benefit comes in addition to significantly reducing clinical and vertebral fractures and improving bone mineral density.” ■

DISCLOSURE: Dr. Slamon disclosed financial relationships with Novartis, Pfizer, Biomarin, and Lilly. Dr. Neven reported no conflicts of interest. Dr. Jerusalem reported financial associations with Amgen, Bristol-Myers Squibb, Lilly, Novartis, Pfizer, Roche, AstraZeneca, Celgene, Daiichi Sankyo, and Puma Biotechnology. Dr. Coleman reported a financial relationship with Prime Oncology and has received institutional research funding from Bayer. Dr. Gnant reported employment by Sandoz (spouse) and other financial relationships with Amgen, AstraZeneca, Celgene, Lilly, NanoString Technologies, Novartis, Roche, Ipsen, Medtronic, and Pfizer.

REFERENCES

1. Slamon DJ, Neven P, Chia SK, et al: Ribociclib plus fulvestrant in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from MONALEESA-3. 2018 ASCO Annual Meeting. Abstract 1000. Presented June 3, 2018.

2. Neven P, Rugo HS, Tolaney SM, et al: Abemaciclib for pre/perimenopausal women with HR+, HER2– advanced breast cancer. 2018 ASCO Annual Meeting. Abstract 1002. Presented June 3, 2018.

3. Jerusalem GHM, Kovalenko E, Yardley DA, et al: Everolimus plus exemestane vs everolimus alone or capecitabine for estrogen receptor-positive, HER2-negative advanced breast cancer: BOLERO-6, an open-label phase 2 study. 2018 ASCO Annual Meeting. Abstract 1005. Presented June 3, 2018.

4. Coleman RE, Finkelstein D, Barrios CH, et al: Adjuvant denosumab in early breast cancer: First results from the international multicenter randomized phase III placebo-controlled D-CARE study. 2018 ASCO Annual Meeting. Abstract 501. Presented June 4, 2018.

5. Gnant M, Pfeiler G, Steger GG, et al: Adjuvant denosumab in early breast cancer: Disease-free survival analysis of 3,425 postmenopausal patients in the ABCSG-18 trial. 2018 ASCO Annual Meeting. Abstract 500. Presented June 4, 2018.