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The approval of three CDK4/6 inhibitors – palbociclib (Ibrance), abemaciclib (Verzenio), and ribociclib (Kisqali) – in combination with aromatase inhibitors or fulvestrant (Faslodex) has transformed the front-line management of metastatic hormone receptor-positive, HER2-negative breast cancer.

First-line approvals of these drugs were based on data that showed significant improvements in progression-free survival. More recently, studies of abemaciclib and ribociclib also showed a significant improvement in overall survival of advanced disease compared with fulvestrant alone.

"Now that we have survival data for several CDK4/6 inhibitors in the upfront setting with endocrine therapy, the biggest clinical question remains what to do after that," said Jane L. Meisel, MD, of Winship Cancer Institute in Atlanta.

Sequencing of therapies is a challenge, and treatment regimens remain palliative rather than curative. The majority of patients with metastatic disease will eventually progress on endocrine therapy.

"Patients can have responses for several months after first-line endocrine therapy, or sometimes even a couple of years or longer, but eventually there will be evidence of progression on imaging," said Bhuvaneswari Ramaswamy, MD, of The Ohio State University Comprehensive Cancer Center in Columbus. "At that point, we consider first-line endocrine therapy to have failed and must consider other treatment options."

Second-Line Options

Several factors go into the decision of which second-line therapy might be best for a patient with HR-positive breast cancer who has progressed on endocrine therapy.

Many patients with disease progression may receive a different anti-estrogen in the second line.

"As long as the biopsy shows that the disease is still endocrine receptor positive, I would give another anti-estrogen therapy," Ramaswamy said.

The second-line anti-estrogen may also be combined with a targeted agent. For example, if a patient has genomic testing and is positive for a PI3K mutation they might benefit from treatment with alpelisib (Piqray), an oral treatment when combined with fulvestrant in the second-line.

Another option is the mTOR inhibitor everolimus (Afinitor) combined with fulvestrant, which in patients with aromatase inhibitor-resistant metastatic disease compared with use of fulvestrant alone.

Although not combined with anti-estrogens, PARP inhibitors are another targeted therapy option used after disease progression on endocrine therapy for patients who have BRCA-mutated disease.

"PARP inhibitors can be a great option for this particular subset of patients," Meisel said. "Transitioning from anti-estrogen therapy to intravenous chemotherapy can often feel like a very distinct line in the sand, so having another oral, well-tolerated targeted alternative can be very helpful in terms of disease control and quality of life."

In a patient who did not respond at all to endocrine therapy and progressed almost immediately on anti-estrogen therapy, the best option might be chemotherapy. The same might be true for a patient who is having very aggressive progression.

"For example, a patient who may have only bone disease or a couple of lesions in their liver, but then suddenly, after first-line therapy, has extensive disease and declining performance status, might be a candidate for chemotherapy," Ramaswamy said. "In this patient we need something that works faster and is more universal."

The three major chemotherapy options for these patients are anthracyclines, taxanes, and capecitabine. Many patients will have received an anthracycline for early-stage disease, and anthracyclines have a dosing ceiling due to adverse effects on the heart, Ramaswamy noted. Therefore, the best first-line standard-of-care chemotherapy options for most patients with metastatic disease lie between a taxane-based regimen and capecitabine, she said.

"They are both effective regimens, but there are some factors that may help with decision-making between the two," Ramaswamy said.

She said that when discussing the options with a patient, she looks at the overall scenario. For example, patients may not be keen on losing their hair, or might prefer an oral regimen, which would make capecitabine a good option. If avoiding additional neuropathy is important, taxanes should be avoided.

"We have many other treatment options as well outside of these standards of care," Ramaswamy said. "At every cancer center – especially a comprehensive cancer center – we are also going to look at clinical trial eligibility and see if there is a good fit and provides a novel option for the patients before starting standard-of-care therapy."

Promising Clinical Trials

Despite best efforts, more clinical trials are required to help clarify optimal second-line treatment strategies in women with metastatic disease for whom endocrine therapy fails, she said. "I wish I could say that we have the answer, but we continue to look for one."

For example, one study is looking at maintaining CDK inhibitors with a switch to a different anti-estrogen post-progression on CDK inhibitors ().

"Maybe these trials will tell us how to manage post-CDK 4/6 inhibitor failure or how much further we can push anti-estrogens before switching to chemotherapy," Ramaswamy said.

There are also some glimpses of hope for effective immunotherapy regimens for these patients, according to Meisel.

"There are a number of studies looking at how best to employ immunotherapy in breast cancer and what markers we need to look at to understand who is most likely to respond," Meisel said. "Estrogen-receptor positive breast cancer traditionally has not been thought of as being particularly immunogenic, but there might be subsets of patients who will respond to immunotherapy – or for whom immunotherapy combined with other drugs might achieve success."

is looking at three drug combinations in patients who have stopped responding to palbociclib and aromatase inhibitor therapy: fulvestrant, fulvestrant with palbociclib, and fulvestrant with palbociclib and avelumab.

However, even with these clinical trial advances, treatment decisions will always require shared decision-making, and may never be entirely clear cut, Ramaswamy noted.

"New trials should provide more data on how best to manage these patients. But I think having a 'one-size-fits-all' approach to sequencing treatments for patients will be hard because of the amount of heterogeneity among these patients," she said.

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