Palbociclib/Fulvestrant Does Not Improve Progression-Free Survival After Progression on a CDK4/6 Inhibitor in Metastatic Breast Cancer

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The combination of palbociclib and fulvestrant did not prolong progression-free survival compared to fulvestrant alone in patients with hormone receptor–positive/HER2-negative metastatic breast cancer who had disease progression on prior treatment with a CDK4/6 inhibitor and endocrine therapy, according to findings from the PACE study presented at the 2022 San Antonio Breast Cancer Symposium.1 However, the study also showed that the triplet combination of the PD-L1 inhibitor avelumab with palbociclib and fulvestrant arm led to a doubling in progression-free survival.

“Combining palbociclib with fulvestrant beyond disease progression on a prior CDK4/6 inhibitor did not significantly improve progression-free survival compared with using fulvestrant alone,” said Erica L. Mayer, MD, MPH, Director of Breast Cancer Clinical Research at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School. “The observed longer progression-free survival when a PD-L1 inhibitor was added to fulvestrant and palbociclib is an intriguing signal in this hormone receptor–positive population and deserves further study.”

“Combining palbociclib with fulvestrant beyond disease progression on a prior CDK4/6 inhibitor did not significantly improve progression-free survival compared with using fulvestrant alone.”
— Erica L. Mayer, MD, MPH

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The combination of a CDK4/6 inhibitor plus endocrine therapy is standard treatment for hormone receptor–positive breast cancer, both as front-line and subsequent therapies. The PACE trial was designed to explore whether the continuation of a CDK4/6 inhibitor (palbociclib) with subsequent endocrine therapy (fulvestrant) would be more effective than the standard of care of endocrine therapy alone. In addition, an experimental triplet arm with the addition of a PD-L1 inhibitor (avelumab) was included based on preclinical data suggesting synergy for this triplet.

Study Details

The multicenter phase II PACE study randomly assigned 220 patients with metastatic hormone receptor–positive, HER2--negative breast cancer in a 1:2:1 ratio to receive fulvestrant alone, fulvestrant plus palbociclib, or fulvestrant plus palbociclib and avelumab. Patients had to have disease that previously progressed on endocrine therapy and a CDK4/6 inhibitor after 6 months of therapy in the metastatic setting.

The primary endpoint was progression-free survival with fulvestrant plus palbociclib vs fulvestrant alone. Secondary endpoints included progression-free survival with fulvestrant plus palbociclib and avelumab vs fulvestrant alone, objective response rate in all arms, and safety.

The median age of enrolled patients was 57 years. About 40% had de novo metastatic breast cancer, 60% had visceral disease, 13.6% had bone-only metastases, and 67.7% had measurable disease at baseline. The majority (72.7%) had endocrine-sensitive disease, and the most frequently received prior CDK4/6 inhibitor was palbociclib (90.9%); 4.5% received ribociclib, and 4.1% received abemaciclib.

The majority of patients (75.9%) had received a CDK4/6 inhibitor and endocrine therapy for at least 12 months. Most patients (76.8%) who entered the trial were receiving second-line treatment in the metastatic setting. A total of 11.8% had received another systemic therapy following disease progression on a prior CDK4/6 inhibitor before initiating study-assigned therapy.

Key Findings

Of the 55 patients in the fulvestrant-alone arm, 34 had disease progression by a median follow-up of 23.6 months; the median progression-free survival was 4.8 months. For the 111 patients in the fulvestrant-plus-palbociclib arm, 79 progression-free survival events were reported, and median progression-free survival was 4.6 months. Thus, for the primary endpoint of the study, continuing CDK4/6 inhibition beyond prior progression with fulvestrant therapy was not superior to fulvestrant therapy alone.

Among the 54 patients in the triplet combination arm, there were 35 progression-free events, and the median progression-free survival was 8.1 months. The 6-month progression-free survival rate was 50.8%, and the 12-month rate was 35.6%, the latter of which was numerically higher than in the other two arms. These findings in the triplet arm should be explored further, Dr. Mayer said.

Similar trends were seen for the secondary endpoint of overall survival. Median overall survival was 27.5 months with fulvestrant alone, 24.6 months with fulvestrant plus palbociclib, and 42.5 months with the PD-L1–containing triplet.

In 149 patients with measurable disease, the objective response rate was 10.8% for fulvestrant alone; 13.8% for fulvestrant plus palbociclib; and 17.9% for the triplet. The rates of clinical benefit (response plus stable disease) in the three arms were 29.1%, 32.4%, and 35.2%, respectively.

In a subgroup analysis, patients who received prior therapy between prior CDK4/6 inhibitor exposure and study entry, and those with resistance to prior endocrine therapy, appeared to derive benefit from the addition of palbociclib to fulvestrant.

Circulating tumor DNA collected in 200 patients and evaluated with the Guardant360 platform revealed the presence of the following mutations: ESR1, 54.0%; PIK3CA, 35.0%; and RB1 mutations, 11.5% of patients. “Patients who had a baseline mutation in one of these three specified genes trended toward receiving more benefit from continuation of the CDK4/6 inhibitor,” Dr. -Mayer noted.

Safety Profile

No patients had to stop all protocol therapy due to unacceptable toxicity. Palbociclib was held in 36%, and dose reductions were needed in 22% of patients who received palbociclib combined with fulvestrant. In the triplet arm, palbociclib was held in 57.4%, and dose reductions were needed in 20.4%, and avelumab was held for toxicity in 38.9% of patients. Dose reductions were not permitted for avelumab or fulvestrant.

In both arms containing palbociclib, neutropenia was the most common any-grade adverse event. Grade 3 or 4 neutropenia was reported in 32.7% of patients in the fulvestrant-plus-palbociclib arm and in 49.1% in the triplet arm containing avelumab. There were no grade 5 adverse events, no incidents of febrile neutropenia, and no other grade 3 or 4 adverse events that occurred in 10% of patients or more. The most common adverse events of any grade were mild fatigue, nausea, and diarrhea. Rates of immune-related adverse events in the triplet arm were low, and no unexpected adverse events were reported.

The Way Forward

Although continuation of palbociclib beyond progression on prior CDK4/6 inhibition did not improve progression-free survival for patients, the outcomes seen in the triplet therapy arm with the addition of a PD-L1 inhibitor are intriguing in a hormone receptor–positive population. Further analysis of the study data may identify subsets of patients who will benefit from continuation of CDK4/6 inhibition postprogression.

“Overall, a better understanding of the mechanisms driving progression post-CDK4/6 inhibitor and endocrine therapy will help guide more rational treatment selection for subsequent lines of therapy and improve outcomes for our patients,” Dr. Mayer said.

“We think the extensive biomarker and correlative specimens acquired in this trial may help us understand resistance to common treatments for estrogen receptor–positive breast cancer.”
— Harold J. Burstein, MD, PhD

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“The PACE study was designed to see if continuing a CDK4/6 inhibitor, palbociclib, beyond tumor progression would be of clinical benefit. Preclinical models had suggested there might be a benefit to this approach. Our study, however, did not suggest clinical value to continuing palbociclib with fulvestrant after the tumor had progressed on initial endocrine therapy and palbociclib,” said senior author Harold J. Burstein, MD, PhD, Professor of Medicine at Harvard Medical School and a medical oncologist at Dana-Farber Cancer Institute.

“We think the extensive biomarker and correlative specimens acquired in this trial may help us understand resistance to common treatments for hormone receptor–positive breast cancer. Other, larger trials are being conducted globally to ask similar questions with related CDK4/6 inhibitors, so there will be more data on this topic in the future. Meanwhile, PACE showed an intriguing signal of benefit for adding a checkpoint inhibitor to endocrine therapy, and we hope to follow up on that finding with more studies,” Dr. Burstein said. 

DISCLOSURE: Dr. Mayer has served as a consultant to AstraZeneca, Gilead Sciences, Eli Lilly, and Novartis. Dr. Burstein reported no conflicts of interest.


1. Mayer EL, Ren Y, Wagle N, et al: Palbociclib after CDK4/6i and endocrine therapy (PACE): A randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pre-treated ER+/HER2– metastatic breast cancer. 2022 San Antonio Breast Cancer Symposium. Abstract GS3-06. Presented December 8, 2022.

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