Adding Palbociclib to Fulvestrant Did Not Yield Better Efficacy in ER-positive/HER2-Negative Metastatic Breast Cancer


Patients with estrogen receptor–positive, HER2-negative metastatic breast cancer did not derive further benefit when palbociclib was added to fulvestrant.

Data from the phase 2 PACE trial (NCT03147287) that read out at the 2022 San Antonio Breast Cancer Symposium (SABCS) indicated that a combination of palbociclib (Ibrance) and fulvestrant (Faslodex) did not improve outcomes over fulvestrant alone in estrogen receptor (ER)–positive/HER2-negative breast cancer, although avelumab (Bavencio) to palbociclib and fulvestrant yielded favorable results.

Results from the phase 2 PACE trial (NCT03147287) showed a hazard ratio for progression-free survival (PFS) of 1.11 for the combination of palbociclib and fulvestrant versus fulvestrant (90% CI, 0.74-1.66; 2-sided P = .62). However, the addition of avelumab (Bavencio) to palbociclib and fulvestrant did show a favorable hazard ratio of 0.75 versus fulvestrant alone (90% CI, 0.47-1.20; 2-sided P = .23).

“Combining palbociclib with fulvestrant beyond progression on prior CDK4/6 inhibitor did not significantly improved PFS compared with using fulvestrant alone,” Erica L. Mayer, MD, MPH, director of clinical research at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, said in a presentation of the data. “The observed longer PFS when a PD-L1 inhibitor was added to fulvestrant and palbociclib is an intriguing signal in this HR [hormone receptor]–positive population and deserves further study.”

CDK4/6 inhibitors plus endocrine therapy (ET) have been established to benefit patients with HR-positive breast cancer in the frontline and pretreated settings. Investigators in the multicenter phase 2 PACE trial tested whether CDK4/6 inhibition with palbociclib continued with subsequent ET with fulvestrant in later lines would be more effective. In addition, based on preclinical data suggesting the combination of a CDK4/6 inhibitor and a PD-L1 inhibitor had synergistic potential, a triplet combination arm was also investigated.

The trial enrolled 220 patients with metastatic HR-positive/HER2-negative breast cancer who were randomly assigned on a 1:2:1 basis to receive fulvestrant alone, fulvestrant plus palbociclib, or fulvestrant plus palbociclib and avelumab. Patients must have previously progressed on an aromatase inhibitor and a CDK4/6 inhibitor after 6 months of therapy in the metastatic setting. The primary end point was evaluating PFS for fulvestrant plus palbociclib versus fulvestrant alone, whereas secondary end points included PFS of fulvestrant plus palbociclib and avelumab versus fulvestrant alone, objective response rate (ORR) in all arms, and safety.

The median age of enrolled patients was 57 years. Forty percent of patients had de novo metastatic breast cancer, 60.0% had visceral disease, 13.6% had bone-only metastases, and 67.7% had measurable disease at baseline. The majority (72.7%) had responded to prior ET, and the most common prior CDK4/6 inhibitor received was palbociclib (90.9%), with 4.5% having received ribociclib (Kisqali) and 4.1% having received abemaciclib (Verzenio). The majority (75.9%) had received CDK4/6 and ET for at least 12 months. Most patients (76.8%) started the trial as their second-line regimen in the metastatic setting. Only 11.8% had received therapy following progression on prior CDK4/6 inhibitor before starting on the trial regimen.

Out of the 55 patients who received fulvestrant alone, 34 had progressed at the median follow-up of 23.6 months. The median PFS was 4.8 months (90% CI, 2.1-8.2). For the 111 patients in the fulvestrant plus palbociclib arm, there were 79 PFS events for a median PFS of 4.6 months (90% CI, 3.6-5.9). Based on the unfavorable hazard ratio, the primary end point of the study was not met and fulvestrant alone appeared to be superior in this setting.

When looking at the triplet combination arm, there were 35 PFS events out of 54 patients; the median PFS was 8.1 months (90% CI, 3.2-10.7). The 6-month PFS rate was 50.8% and the 12-month rate was 35.6%, the latter of which was significantly higher than the other 2 arms.

Patients in subgroups who did benefit from the inclusion of palbociclib versus fulvestrant alone included those who had received an intervening therapy before starting the trial and those who were resistant to prior ET.

The ORR in the 149 patients with measurable disease for fulvestrant alone, fulvestrant plus palbociclib, and fulvestrant plus palbociclib and avelumab were 10.8%, 13.7%, and 17.9%, respectively, whereas the clinical benefit rates (CBR) in the full intent-to-treat population of the 3 arms were 29.1%, 32.4%, and 35.2%, respectively.

In terms of overall survival (OS), median OS for fulvestrant was 27.5 months (90% CI, 21.1-38.0), for fulvestrant plus palbociclib was 24.6 months (90% CI, 21.5-33.3), and for fulvestrant plus palbociclib and avelumab was 42.5 months (90% CI, 26.8-46.0). As with PFS, the hazard ratio for OS did not favor the addition of palbociclib alone but did favor the triplet combination.

No patients were reported to have stopped all therapy due to unacceptable toxicity related to treatment, but in the fulvestrant plus palbociclib arm, palbociclib was held in 36.0% and dose was reduced in 22.5%. In the triplet arm, palbociclib was held in 57.4% and dose reduced in 20.4%, and additionally avelumab was held for toxicity in 38.9% of patients. Dose reductions were not permitted for avelumab or fulvestrant.

Neutropenia was the most common any-grade adverse event (AE) in both palbociclib-containing arms. Grade 3 or 4 neutropenia occurred in 32.7% of patients in the fulvestrant plus palbociclib arm, and 49.1% in the arm that also included avelumab. There were no grade 5 AEs, no incidents of febrile neutropenia, and no other grade 3 or 4 AEs occurring at a rate of 10% or higher. Mild fatigue, nausea, and diarrhea were the most common other AEs observed. Rates of immune-related AEs in the arm containing avelumab were low and there were no unexpected AEs.

Circulating tumor DNA was collected in 200 out of 220 patients at baseline and evaluated using the Guardant360 platform. ESR1 mutations were found in 54.0%, PIK3CA mutations were found in 35.0%, and Rb mutations were found in 11.5% of patients. “Patients who had a baseline mutation in 1 of the 3 specified genes trended towards more benefit from continuation of CDK4/6 inhibitor, the presence of the mutations perhaps indicating endocrine resistance,” said Mayer.

Despite the failure to meet the primary end point, the clear benefit shown with the addition of a PD-L1 inhibitor has potential to improve outcomes in these patients, and further exploring the data from this study may show some subsets of patients who will benefit from the continuation of CDK4/6 inhibition.

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


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. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS3-06.

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