Ongoing and Planned Research Build on Prior Advancements in ER+/HER2– Breast Cancer

In an interview with OncLive^®, which took place following 2 OncLive State of the Science Summits™ on breast cancer, one of which she chaired, Lubna Naaz Chaudhary, MD, MS, highlighted the clinical implications of data from both the phase 2 PARSIFAL (NCT02491983) and Young-PEARL (NCT02592746) clinical trials.

The PARSIFAL trial was a randomized, open-label investigation of palbociclib (Ibrance) in combination with either fulvestrant (Faslodex) or letrozole in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer. Young-PEARL enrolled premenopausal patients with ER-positive, HER2-negative metastatic breast cancer following progression on prior tamoxifen; these patients were randomly assigned to receive palbociclib plus exemestane (Aromasin) with a GnRH agonist vs capecitabine.

Want to read more on upcoming and ongoing treatment in metastatic breast cancer? Chaudhary, who serves as an associate professor of medicine at the Medical College of Wisconsin in Milwaukee, shared her thoughts on treatment with CDK4/6 inhibitors in another article.

OncLive: What were the key findings from the PARSIFAL trial?

Chaudhary: This is an important study. The question of PARSIFAL was whether there would be benefit or a difference in efficacy when [using different endocrine therapies with] a palbociclib backbone. [This trial investigated] palbociclib plus a nonsteroidal aromatase inhibitor [AI], which we commonly use, vs palbociclib plus fulvestrant. Many years ago, studies in patients with stage IV disease showed that a selective ER degrader [SERD] mechanism is more effective than an AI mechanism. The question [of PARSIFAL] was, when we have CDK4/6 inhibitor present, would we see a difference between a SERD vs a nonsteroidal AI?

The study showed no difference in efficacy between [the combinations]. With no difference in efficacy seen, and us having options of using PIK3CA/AKT pathway–targetable drugs with fulvestrant, we should keep our practice the way it is, using a CDK4/6 inhibitor with an AI first, and then reserving fulvestrant for later combinations.

How do data from Young-PEARL inform your practice?

Young-PEARL was in premenopausal patients who progressed on prior endocrine therapy and were treated with either palbociclib plus an AI and ovarian suppression or capecitabine. The question was: In these young patients, would it be better to treat them with chemotherapy vs ovarian suppression in combination with an AI and a CDK4/6 inhibitor?

The median progression-free survival was [longer] with the palbociclib combination, which reinforces our practice right now that we don’t need to switch these patients to chemotherapy early on. We have a lot of good, targeted therapy combinations, endocrine therapy options, and CDK4/6 inhibitors, as well as other agents [we can use] before we switch to chemotherapy.

Another key point [from] Young-PEARL was that we must pay attention to the adverse effects [AEs], and we have to know where those AEs are coming from. This is because if we just look at the tabular data, the grade 3 AE incidence was much higher in the palbociclib arm, at [approximately] 90% vs approximately 40% with capecitabine. That can look scary, but we must then read in more detail, because most of those grade 3 AEs were asymptomatic neutropenia, and that we are comfortable with [managing]. It’s easy to manage and does not cause symptoms for patients whereas capecitabine causes hand-foot syndrome, diarrhea, and gastrointestinal toxicity. We want to pay attention to the interpretation of the data when we consider the numbers.

What ongoing research initiatives in ER-positive, HER2-negative breast cancer are you involved in?

I am the chair of our breast program [at the Medical College of Wisconsin], so I oversee our whole breast cancer clinical trial portfolio. I currently have 2 ongoing investigator-initiated clinical trials. One that is almost done accruing is a phase 2 trial [NCT04243616] investigating the role of cemiplimab [Libtayo]—which is a PD-1 inhibitor—in the neoadjuvant setting plus standard-of-care anthracycline plus taxane-based chemotherapy. [This combination is being evaluated] in [patients with] triple-negative breast cancer, as well as in ER-positive/HER2-negative disease.

We are expanding the eligibility [criteria of this trial] to not only include PD-L1–positive patients, but also those with PD-L2–positive [disease]. We’ve had a couple of publications already in the PD-L2–positive arena, so we’re excited to see what this study shows.