Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the impact of the phase 3 PALOMA-2 trial (NCT01740427) in estrogen receptor (ER)–positive/HER2-negative advanced breast cancer.

The trial compared letrozole (Femara) in combination with palbociclib (Ibrance) vs letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative advanced breast cancer, Goetz explains.

Additional trials in the first-line setting, such as the phase 3 monarchE (NCT03155997) and MONALEESA-2 (NCT01958021) trials, tested different CDK4/6 inhibitors in combination with endocrine therapy, Goetz continues. The trials confirmed a benefit in progression-free survival with the addition of a CDK4/6 inhibitor to treatment, and as data have matured, investigators are beginning to gather overall survival data, Goetz concludes.

Videos

Matthew P. Goetz, MD, discusses the impact of the phase 3 PALOMA-2 trial in estrogen receptor–positive/HER2-negative advanced breast cancer.


Dr. Goetz on the Impact of the PALOMA-2 Trial in ER+/HER2- Breast Cancer

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the use of circulating tumor DNA (ctDNA) in the phase III MONARCH-3 trial in hormone receptor (HR)—positive, HER2-negative breast cancer.

In a translational analysis, investigators evaluated the ctDNA of patients in the trial to see whether the somatic mutations that occur had prognostic and predictive value, says Goetz. With the Guardant360 assay, investigators found that amplification in 

were associated with poor prognosis, says Goetz. These alterations conferred a significantly worse progression-free survival with abemaciclib (Verzenio) monotherapy. Notably, in all cases, the addition of abemaciclib to letrozole or anastrozole showed a significant improvement in patient outcomes, says Goetz. These findings are important because prior studies have suggested that patients who have alterations, for example an 

 amplification, may be resistant to CDK4/6 inhibitors, adds Goetz.

These data show that while patients with these alterations have poor outcomes to abemaciclib monotherapy, they are not altogether resistant to this therapeutic class. Rather, patients who receive CDK4/6 inhibitors in combination with an aromatase inhibitor can still derive significant benefit from the medication despite their prognosis, Goetz concludes.

Matthew P. Goetz, MD, Mayo Clinic, discusses the use of circulating tumor DNA in the phase III MONARCH-3 trial in hormone receptor–positive, HER2-negative breast cancer.

Dr. Goetz on the Use of ctDNA in the MONARCH-3 Trial in HR+/HER2- Breast Cancer

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses adverse events (AEs) associated with aromatase inhibitors (AIs).

Arthralgia, one of the main AEs of AIs, can be mild for some patients but intolerable in others. About one-third of patients experience arthralgia while on an AI and the pain for this AE is intolerable for about 10% to 15% of patients, resulting in the need to switch to a different AI or to a different class of drugs, explains Goetz.

Bone loss is another AE commonly seen in AIs. This is typically seen in the first year or so, when the most bone loss occurs, and eventually levels off. Several drugs are available to prevent bone loss, making this AE largely preventable, says Goetz.

The last AE that commonly occurs with the use of AIs includes vaginal dryness, which can lead to urinary tract infections, dyspareunia, and other sexual complications, and can also be troublesome to patients, concludes Goetz.

Matthew P. Goetz, MD, discusses adverse events associated with aromatase inhibitors.

Dr. Goetz on Adverse Events With Aromatase Inhibitors in Breast Cancer

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses treatment beyond progression on CDK4/6 inhibitors in hormone receptor (HR)-positive breast cancer.

The prognosis of patients who progress on CDK4/6 inhibitors remains largely unknown. However, there are emerging data that suggest that the prognosis of patients who go on to receive standard endocrine therapy, such as tamoxifen (Faslodex) or an aromatase inhibitor, do poorly, says Goetz. Whether CDK4/6 inhibitors should be continued beyond progression is another area of uncertainty, he adds.

Better understandings of the mechanisms of resistance driving progression will be critical in answering such questions. Moving forward, clinical trials will be focused examining these agents in specific subsets of patients. One of the first clinical trials to do so was the phase III SOLAR-1 trial, in which patients with HR-positive, HER2-negative advanced breast cancer who had received prior endocrine therapy were randomized to receive either alpelisib (Piqray) and fulvestrant or fulvestrant alone. Patients were stratified by 

mutation status. Results showed that those who harbored 

 mutations derived a significant clinical benefit from the combination.

Data from the phase II BYLieve trial will help establish whether fulvestrant or letrozole is the optimal combination partner for alpelisib. Ultimately, many therapeutic strategies will be needed to overcome the number of resistance mutations that develop after progression on a CDK4/6 inhibitor, concludes Goetz.

Dr. Goetz on Treatment Beyond Progression on CDK4/6 Inhibitors in HR+ Breast Cancer

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the treatment landscape of estrogen receptor (ER)—positive breast cancer and advances made within the last 5 years.

The landscape for the treatment of ER-positive breast cancer has changed dramatically, especially within the last 5 years, explains Goetz. However, resistance to endocrine therapy can emerge in patients who have been previously treated with tamoxifen and responded well for a period of time. One of the mechanisms for resistance that has been identified is the emergence of 

 mutations. These mutations are present in about 30% to 40% of patients who have been treated with hormonal therapy, according to Goetz, and appear to be an acquired resistance mechanism. The presence of these mutations has created worse prognoses for patients with ER-resistant breast cancer.

However, physicians are beginning to learn about new ways to treat these patients. In the past 5 years, agents that have become available are CDK4/6 inhibitors.

The problem, according to Goetz, is that the best treatment after progression for patients with 

-mutant breast cancer who have received prior treatment with a CDK4/6 inhibitor is unknown. Goetz also wonders what the optimal hormonal drug is that should be combined with CDK4/6 inhibitors to serve patients with 

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the treatment landscape of estrogen receptor (ER)–positive breast cancer and advances made within the last 5 years.

Dr. Goetz on Treatment Challenges for ESR1-Mutant Breast Cancer

Matthew P. Goetz, MD, chair of the Breast Cancer Disease-Oriented Group and co-leader of the Women’s Cancer Center at the Mayo Clinic, discusses the treatment landscape for patients with metastatic hormone receptor (HR)—positive breast cancer.

The treatment paradigm in this space has evolved over the last few years, Goetz says. The current standard of care is to utilize an aromatase inhibitor (AI)—steroidal or nonsteroidal&mdash;along with a CDK4/6 inhibitor in the frontline setting. The commonly used AIs are anastrozole and letrozole. There are also data suggesting that fulvestrant can be combined with a CDK4/6 inhibitor. Moreover, for patients who have progressed on an AI in the adjuvant setting, the standard second-line option is fulvestrant with a CDK4/6 inhibitor.

There are currently 3 FDA-approved CDK4/6 inhibitors in this space: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). Approvals for these agents were based on positive data from the pivotal PALOMA-2, MONALEESA-2 and -7, and MONARCH 3 studies, respectively.

Matthew P. Goetz, MD, chair of the Breast Cancer Disease-Oriented Group and co-leader of the Women’s Cancer Center at the Mayo Clinic, discusses the treatment landscape for patients with metastatic hormone receptor–positive breast cancer.

Dr. Goetz on Treatment of Metastatic HR+ Breast Cancer

Matthew P. Goetz, MD, chair of the Breast Cancer Disease-Oriented Group and co-leader of the Women’s Cancer Center at the Mayo Clinic, discusses survival data with CDK4/6 inhibitors in patients with hormone receptor-positive breast cancer.

 on the PALOMA-3 study showed a trend toward improved survival in patients who received fulvestrant and palbociclib (Ibrance) after progressing on endocrine therapy as opposed to those who received fulvestrant alone. The suspected benefit was noted in patients who were sensitive to endocrine therapy—those who had been on an aromatase inhibitor in the adjuvant or metastatic setting for a prolonged period of time, says Goetz.

Additional data with abemaciclib (Verzenio) showed that patients with high-risk disease, liver metastases, high-grade tumors, and estrogen receptor-negative disease derived a significant benefit from the monotherapy. Based on these data, there may be differences in survival between these agents, he adds.

Dr. Goetz on Survival Data With CDK4/6 Inhibitors in Breast Cancer

Matthew P. Goetz, MD, professor of oncology and pharmacology, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the MONARCH trials for patients with breast cancer. 

The secondary analysis of the MONARCH 2 and 3 clinical studies evaluated abemaciclib (Verzenio), which is an oral CDK4/6 inhibitor and hormonal therapy. The studies attempted to determine if there were any clinical or pathological factors that might be associated with the benefit of these agents.  

Common variables between the 2 studies included age, race, performance status, and presence or absence of liver metastases. According to Goetz, we identified a number of factors that were prognostic including the presence or absence of liver and bone metastasis, or progesterone receptor status.  

For patients who had liver metastases, the prognosis in both studies was uniformly poor but with the addition of abemaciclib, led to substantial clinically relevant increases in progression-free survival and response rates. For example, in a patient with liver metastases in the MONARCH 2 study saw an increase in response rates from 9% to 40%.  