Addition of 1-Year Palbociclib to Endocrine Therapy Fails to Improve iDFS in High-Risk HR+/HER2- Breast Cancer

December 11, 2020 - The addition of 1 year of palbociclib to endocrine therapy failed to improve invasive disease-free survival in patients with hormone receptor–positive, HER2-negative breast cancer who are at high risk of relapse following neoadjuvant chemotherapy.

The addition of 1 year of palbociclib (Ibrance) to endocrine therapy failed to improve invasive disease-free survival (iDFS) in patients with hormone receptor–positive, HER2-negative breast cancer who are at high risk of relapse following neoadjuvant chemotherapy, according to data from the phase 3 PENELOPE-B trial (NCT01864746) presented during the 2020 San Antonio Breast Cancer Symposium.

Results showed that at a median follow-up of 42.8 months, the number of iDFS events in the palbociclib/endocrine therapy arm (n = 631) and the placebo/endocrine therapy arm (n = 156; stratified HR, 0.93; 95% CI, 0.74-1.17; 2-sided P = .525). At 2 years, in the investigative and control arms, the estimated iDFS rates were 88.3% vs 84.0%, respectively. Moreover, the estimated 3-year iDFS rates were 81.2% with palbociclib vs 77.7% with placebo, while the 4-year iDFS rates were 73.0% vs 72.4%, respectively.

“This is the first study showing mature iDFS for a CDK4/6 inhibitor as part of post-neoadjuvant therapy. To date, these results of the PENELOPE-B study do not support the addition of 1 year of palbociclib to endocrine therapy,” first study author Sibylle Loibl, MD, PhD, co-chair of the German Breast Group and associate professor at the University of Frankfurt, said in an oral presentation during the meeting. “It could be that the treatment duration of 1 year was too short, but we don’t know that. Long-term follow-up from all adjuvant CDK4/6 inhibitor studies should continue and must be awaited.”

It is known that patients with HR-positive, HER2-primary breast cancer who do not achieve a pathologic complete response (pCR) to neoadjuvant chemotherapy have a poorer prognosis than those who do. CPS-EG score is used to determine patients who are at high risk of relapse following neoadjuvant chemotherapy, and those with a score of 3 or 2 with ypN-positive disease typically experienced a 77% disease-free survival (DFS) at 3 years, according to Loibl.

The addition of palbociclib to endocrine therapy has been shown to lead to prolongation of both progression-free survival (PFS) and overall survival (OS) in patients with metastatic disease. In PENELOPE, investigators set out to examine how effective palbociclib would be with regard to preventing relapses in patients following neoadjuvant treatment.

The phase 3 trial was launched in December 2013 and enrolled a total of 1250 patients who had HR-positive, HER2-negative breast cancer who did not achieve a pCR following neoadjuvant chemotherapy.

Specifically, to be eligible for enrollment, patients had to have residual invasive disease following neoadjuvant treatment either in the breast or lymph nodes; they also had to have centrally confirmed HR-positive, HER2-negative disease evaluated via tissue from post-neoadjuvant residual invasive disease or core biopsy of the breast. Additionally, patients had to have a CPS-EG score of greater than 3 or greater than 2 with yPN positivity; had received neoadjuvant chemotherapy for at least 16 weeks, including 6 weeks of taxanes; and have an estimated life expectancy of at least 5 years.

Patients were stratified by nodal status (ypN 0-1 vs ypN2-3), age (≤50 years vs >50 years), Ki-67 (>15% vs ≤15%), region (Asia vs non-Asian), and CPS-EG score (≥3 or 2 and yPN-positive).

All patients received neoadjuvant chemotherapy, went on to receive surgery with or without radiotherapy and were then randomized 1:1 to receive either palbociclib at a once-daily oral dose of 125 mg on days 1-21 every 28 days for 13 cycles or placebo on days 1-21, every 28 days for 13 cycles. All participants received concomitant endocrine treatment in accordance with local standards.

The primary end point of the trial was iDFS, while key secondary end points comprised iDFS excluding second primary invasive non-breast cancers, distant DFS, locoregional recurrence-free interval, OS, safety, and compliance.

With regard to statistical considerations, a total of 225 iDFS events had initially been required and 1100 patients would have been to detect a HR of 0.685 with 85% power reflecting an increase of iDFS at 3 years from 77% to 83.6%.

“An adaptive design would have been required to allow for a sample size increase and this was done at the first interim analysis in mid-2017 and the patients were increased to 1250 at that time with 290 events needed,” noted Loibl. “A second interim analysis was conducted last year, in April, at 194 events and this was done for futility and efficacy. The final iDFS analysis has a nominal significance level of 0.0463.”

Additionally, to address the inflation of the type I error because of a sample size increased based on the interim analysis, statistical significance was computed using a weighted statistic based on the method of Cui L et al with the CHW interim monitoring method, added Loibl.

A total of 1078 patients underwent screening; of these patients, 631 were randomized to palbociclib with 628 receiving treatment, and 619 were randomized to placebo with 616 receiving treatment. In the investigative arm, 88.6% of patients completed at least 7 treatment cycles vs 90.3% of those in the control arm; 80.5% vs 84.5%, respectively, completed all 13 cycles regularly and 4.4% vs 5.8%, respectively, prematurely discontinued endocrine therapy.

Moreover, slightly more patients on the palbociclib arm discontinued treatment vs those on the placebo arm, at 19.5% vs 15.5%, respectively. The main reasons for discontinuation in the palbociclib arm included disease recurrence (4.0%), second primary (0.3%), death (0.3%), toxicity (5.2%), patient decision (8.9%), and investigator decision (0.8%).

The median age of participants across the arms was 49 years. Of the 1250 patients included, 56.1% of patients were 50 years or younger; 49.6% had a histological lymph node status at surgery of yPN of 0-1, while 50.4% had a status of yPN 0-3. Almost 41% of patients had a CPS-EG score of 2 and yPN positivity, while 59.4% of patients had a score of at least 3. Tumor stage at the time of surgery was ypT0-1, ypT2-3, and ypT4 in 35.7%, 60.6%, and 3.7% of patients, respectively. Endocrine therapy was used equally between the arms.

Additional results showed that the type of iDFS events in patients included distant recurrences (74%; n = 116 with palbociclib and n = 111 with placebo), invasive locoregional recurrences (16%; n = 21 with palbociclib and n = 27 with placebo), contralateral breast cancer (n = 2, n = 5, respectively), second primary invasive non-breast cancer (n = 9, n = 9), and death without previous event (n = 4, n = 4).

At a median follow-up of 42.8 months, the number of OS events in the palbociclib/endocrine therapy arm was 62 vs 69 in the placebo/endocrine therapy arm (stratified HR, 0.87; 95% CI, 0.61-1.22; P = .420). At 2 years, the estimated OS rates were 96.3% in the investigative arm vs 94.5% in the control arm; these rates were 93.6% vs 90.5%, respectively, at 3 years and 90.4% and 87.3%, respectively at 4 years.

Patients were exposed to palbociclib for a mean of 48.6 weeks vs 48.1 weeks with placebo (P <.001). The overall relative dose intensity was 84.3% (P <.001).

With regard to safety, 99.8% of patients on both arms experienced toxicity (P = 1.000). Almost 80% of those on the palbociclib arm had grade 3/4 events vs 20.1% of those on the placebo arm. Moreover, 99.5% vs 99.7% of patients in the investigative and control arms, respectively, had non-hematologic toxicity; these were grade 3 or 4 in 19.9% vs 19.0% of patients, respectively. Hematologic toxicities occurred in 99.2% of those who received palbociclib vs 79.1% of those given placebo; 73.1% vs 1.3%, respectively, had grade 3/4 events. Lastly, 9.3% of patients in the investigative arm experienced serious toxicity vs 8.7% of those in the control arm.

“Further translational research and subgroup analyses are ongoing,” concluded Loibl.


Loibl S, Marmé F, Martin M, et al. Phase III study of palbociclib continued with endocrine therapy in patients with hormone-receptor-positive, HER2-negative primary breast cancer and high relapse risk after neoadjuvant chemotherapy: first results from the PENELOPE-B. Presented at: 2020 San Antonio Breast Cancer Symposum; December 8-11, 2020; Virtual.