Ongoing research continues to refine treatment strategies for ER-positive, HER2-negative breast cancer, reinforcing the role of CDK4/6 inhibitors and exploring novel combinations. Insights from trials like PARSIFAL and Young-PEARL, along with ongoing studies involving PD-1 inhibitors, are shaping clinical practice.
PARSIFAL Trial: Palbociclib Combinations
The PARSIFAL trial, a randomized, open-label study, investigated palbociclib in combination with either fulvestrant or letrozole in patients with ER-positive, HER2-negative metastatic breast cancer. The primary question was whether the efficacy of palbociclib would differ when combined with a selective ER degrader (SERD) versus a nonsteroidal aromatase inhibitor (AI).
According to Dr. Lubna Naaz Chaudhary, Associate Professor of Medicine at the Medical College of Wisconsin, the trial revealed no significant difference in efficacy between the two combinations. This finding supports the current practice of using a CDK4/6 inhibitor with an AI as the initial approach, reserving fulvestrant for later combinations, especially considering the availability of PIK3CA/AKT pathway-targetable drugs for use with fulvestrant.
Young-PEARL: Treatment in Premenopausal Patients
The Young-PEARL trial focused on premenopausal patients with ER-positive, HER2-negative metastatic breast cancer who had progressed on prior tamoxifen. Patients were randomized to receive either palbociclib plus exemestane with a GnRH agonist or capecitabine. The study aimed to determine if ovarian suppression combined with an AI and a CDK4/6 inhibitor would be superior to chemotherapy in this population.
The results indicated a longer median progression-free survival with the palbociclib combination, reinforcing the strategy of using targeted therapy combinations and endocrine therapy options before resorting to chemotherapy in these younger patients. Dr. Chaudhary emphasized the importance of carefully interpreting adverse event (AE) data. Although the incidence of grade 3 AEs was higher in the palbociclib arm (approximately 90% vs approximately 40% with capecitabine), most were asymptomatic neutropenia, which is manageable. In contrast, capecitabine is associated with hand-foot syndrome, diarrhea, and gastrointestinal toxicity.
Ongoing Research: Cemiplimab in Breast Cancer
Dr. Chaudhary is also involved in ongoing investigator-initiated clinical trials, including a phase 2 trial investigating cemiplimab (Libtayo), a PD-1 inhibitor, in the neoadjuvant setting combined with standard anthracycline plus taxane-based chemotherapy. This trial includes patients with triple-negative breast cancer and ER-positive/HER2-negative disease.
The eligibility criteria for this trial are being expanded to include not only PD-L1-positive patients but also those with PD-L2-positive disease, driven by promising publications in the PD-L2-positive arena.
