Joyce A. O’Shaughnessy, MD
Novel and emerging agents are creating exciting new options for patients with hormone receptor (HR)–positive metastatic breast cancer (MBC), resulting in the need to consider how best to introduce and sequence these agents into the treatment timeline, experts say.
Two breast cancer experts, Joyce A. O’Shaughnessy, MD, and Andrew D. Seidman, MD, joined in an OncLive Peer Exchange®
discussion of pending issues that confront oncologists in daily interactions with patients in this population.
O’Shaughnessy said their goal was to address practical questions oncologists grapple with, such as, “Does everybody need combination therapy, leading off with endocrine therapy, in the metastatic setting? How do we sequence our therapy options? And when do we introduce chemotherapy into our ER [estrogen receptor]–positive metastatic patients?” In particular, the experts examined how CDK4/6 inhibitors have changed the treatment paradigms and discussed promising novel chemotherapy agents for ER-positive MBC.
Such questions are of vital importance to a large proportion of patients with breast cancer. HR-positive breast cancer is the most common subtype of the disease, accounting for at least two-thirds of cases.1,2
Most HR-positive breast cancers are highly responsive to endocrine therapy, and an endocrine-based regimen is standard first-line therapy for HR-positive, HER2-negative MBC in patients not experiencing visceral crisis.2,3
Endocrine therapy is rarely curative, however, and primary or acquired endocrine resistance is frequent.3
Although chemotherapy is generally recommended for patients with endocrine resistance or visceral crisis, the toxicities of current regimens must be weighed against their limited survival benefit (Table
The only option for patients with disease progression or poor performance status after multiple lines of chemotherapy is supportive care.3
Incorporating CDK4/6 Inhibitors
The FDA has approved 3 oral CDK4/6 inhibitors for HR-positive, HER2-negative MBC: palbociclib (Ibrance),4
and abemaciclib (Verzenio).6
Although the CDK4/6 inhibitors have slightly different indications, all are typically administered with an aromatase inhibitor (AI) in the first-line setting or with fulvestrant (Faslodex), an injectable selective ER modulator, in the second-line setting. Ribociclib is the only CDK4/6 inhibitor indicated for first-line therapy in pre- or perimenopausal women in addition to postmenopausal women.5
“It’s hard to make a strong argument against leading with endocrine therapy and a CDK4/6 inhibitor,” Seidman said. In randomized clinical trials, adding a CDK4/6 inhibitor to an AI greatly prolonged progression-free survival (PFS) in women with untreated HR-positive, HER2-negative advanced breast cancer.7
Based on consistent findings across multiple studies, Seidman said he is comfortable assuring these patients they will likely be able to continue endocrine-based therapy for years before their disease progresses.
O’Shaughnessy said she was reluctant to combine a CDK4/6 inhibitor with an AI for the subset of women with de novo MBC and a low-tumor burden until results of the phase III MONALEESA-2 trial, which were updated last year, showed especially pronounced improvement in PFS for this population when ribociclib was added to letrozole.8
“I thought, ‘Whoa, how could I not offer someone that?’” said O’Shaughnessy, who was among the key investigators on the original study. Although O’Shaughnessy and Seidman agreed fulvestrant is an effective first-line therapy for advanced HR-positive breast cancer administered alone or with a CDK4/6 inhibitor, both typically reserve it for second-line therapy because most patients prefer oral agents. Fulvestrant is administered via intramuscular injection.