Improving Upon Treatment Standards in HR+ Breast Cancer

Treatment of metastatic hormone receptor (HR)-positive, HER2-negative breast cancer is traditionally executed with the use of endocrine therapy. With the emergence of targeted therapies for the treatment of this disease, however, the landscape is rapidly shifting, and more therapies are under active research.

In the current landscape, oncologists have made room for CDK4/6 inhibition in combination with endocrine therapy, a combination that has been proven to improve upon progression-free and overall survival in this patient population.

“At this point in time, we're grateful to have CDK4/6 inhibition as our standard of care, but there is so much work going on and so many exciting new agents. What I what to think about is what lies ahead in the next decade in terms of the introduction of a lot of these newer agents into our clinics,” Erica Mayer, MD, told Targeted Oncology.

A new clinical trial is underway (PACE, NCT03147287) to further investigate CDK4/6 inhibition in combination with endocrine therapy after chemotherapy. In 3 arms of fulvestrant monotherapy, fulvestrant plus palbociclib, and fulvestrant plus palbociclib with avelumab (Bavencio), the study is primarily assessing progression-free survival (PFS), with overall response rate and treatment-emergent adverse events as secondary end points.

In an interview with Targeted Oncology, Mayer, senior medical oncologist, Breast Oncology Center, Dana-Farber Cancer Institute, discussed advances in the treatment landscape of HR-positive, HER2-negative breast, primarily with endocrine therapy and CDK4/6 inhibition.

TARGETED ONCOLOGY: Can you discuss advances in endocrine therapy in recent years and explain what you see for the future of endocrine therapy in advanced HR+, HER-negative breast cancer?

Mayer: Over the past several decades, we have primarily been using endocrine monotherapy to treat metastatic hormone receptor positive breast cancer. However, over the past several years we’ve had the introduction of new targeted therapies that we used in combination with an endocrine back bone, and the introduction of these agents has substantially improved progression free and overall survival for patients with metastatic hormone receptor positive HER2-negative disease. We had the introduction of the mTOR inhibitor everolimus, and the CDK4/6 inhibitors, palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), as well as the most recent from 2019, a PI3 kinase inhibitor, alpelisib (Piqray).

At this point in time, there are at least 8 large randomized studies that have looked at the addition of a CDK4/6 inhibitor to back on endocrine therapy, either in the first- or second-line settings. There are trials that have used all 3 available agents and the diversity of endocrine back bone. Importantly and consistently, there is a substantial improvement in hazard ratio across the board of 0.5 to .055,which suggests a doubling and PFS with the addition of the CDK4/6 inhibitor, and that has become our standard of care for the majority of patients in the first-line or second-line settings.

In the past year, we’ve seen overall survival (OS) data from these agents and again, suggesting that there may be an OS advantage from the use CDK4/6 inhibitors and supporting the upfront use of these agents. The big question that has come up, though, is after a CDK4/6 inhibitor, if the cancer is progressing, what do we give next? What are our next best strategies? Should we be continuing on a CDK4/6 inhibitor like we would do with trastuzumab in HER2-positive breast cancer, or should we be switching to a different endocrine therapy with a new targeted partner? Also, how can we best select that targeted partner?

In terms of the idea of maintaining CDK4/6 inhibition, there are multiple studies ongoing trying to address this question. We are fortunate to lead a study called PACE, which is a randomized study open throughout the United States, in which patients who have progressed on a CDK4/6 inhibitor are then randomized to 1 of 3 arms, fulvestrant alone, which could be standard of care and many patients, fulvestrant with the CDK4/6 inhibitor, palbociclib, or a triplet combination of fulvestrant, palbociclib, and avelumab, which is an immunotherapy agent. This study is based off of some strong preclinical data and is actively accruing. We’re hoping that will help address this question.

Beyond that, there has been research to understand mechanisms of resistance to CDK4/6 inhibitors and dissect that from known mechanisms of resistance to endocrine therapy. Ideally, we would love to think of a framework where we could, in real time, test the tumor or even test circulating tumor DNA to identify the mutation that is the cause of the resistance. Then we can apply a new targeted therapy with the next line of endocrine treatment to overcome that resistance. There are several candidates, therapies, and mechanisms which have been identified.

At this point in time, we’re grateful to have CDK4/6 inhibition as our standard of care, but there is so much work going on and so many exciting new agents. What I what to think about is what lies ahead in the next decade in terms of the introduction of a lot of these newer agents into our clinics.

TARGETED ONCOLOGY: With all the different agents that are available in the space, how do you determine which patients are eligible for which therapies?

Mayer: The paradigm of which treatment we give at which step in time has been something that's been changing a bit recently. As I mentioned, the first line of therapy that most patients will now be receiving would be in endocrine therapy with a CDK4/6 inhibitor, and I think it is important to note that in years past when patients showed evidence of what we think of as visceral disease, there may have been a tendency to start those patients with chemotherapy. That’s not necessary. We can give them endocrine therapy with a CDK4/6 inhibitor, which has a high response rate and a very favorable PFS and is much better tolerated than chemotherapy. This needs to be the standard of care for the vast majority of patients.

Following that, we're increasingly going to see the introduction of tumor genomics to help us identify mutations. We have 1 actionable mutation right now, which is a mutation in PIK3CA. For patients who have that mutation, the use of alpelisib may be an attractive way to go. However, for those who don't have a PIK3CA mutation, at this point in time, we have our standard endocrine therapies, and we also have everolimus. With ongoing trials we’re going to start to see some interesting new options for the other categories of mutations.

TARGETED ONCOLOGY: What is the key takeaway?

Mayer: The key takeaway is that none of these advances could have happened without laboratory discovery, translation to the clinic, and the completion of clinical trials. I think that for us to move as a field we need to help design the best possible trials. We need to support them all by structuring and running the trials. Importantly, all providers and patients need to work together to enter these trials and complete them and get answers these questions.

TARGETED ONCOLOGY: What accessible are some of these available agents?

Mayer: The majority of agents that I have discussed in the standard setting are FDA-approved.

These drugs that should be available to any patient, wherever they are in the United States. The availability outside the United States varies depending on each country's approval status.

Clinical trials are a challenge that our community needs to work on. Many clinical trials are available at the large academic medical centers and increasingly, trials could be open through our cooperative networks at community cancer centers or at satellite hospitals close to the larger centers. We still have many patients in this country who live very far away from institutions that have trials available for them, and I think we need to work harder to community oncologists and every breast cancer patient.