The PENELOPEB study is designed to demonstrate that, in the background of standard anti-hormonal therapy, palbociclib provides superior invasive disease-free survival (iDFS) compared to placebo in pre- and postmenopausal women with HR-positive/HER2-normal early breast cancer at high risk of relapse after showing less than pathological complete response to neoadjuvant taxane- containing chemotherapy. Considering the high risk of recurrence in patients after neoadjuvant chemotherapy and a high CPS-EG score, palbociclib appears to be an attractive option with a favourable safety profile for these patients.

Introduction:

Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer who receive chemotherapy as part of their primary treatment are at higher risk of relapse. About a third of the patients with residual invasive disease after neoadjuvant chemotherapy (NACT) will relapse despite adjuvant endocrine therapy (ET). The risk of relapse can be assessed more accurately using the clinical pathological staging-estrogen receptor grading (CPS-EG) scoring system. This involves the tumor stage before treatment start and at surgery, the estrogen receptor (ER) status, and the pathologic grading. A higher score indicates a higher risk of relapse. Patients with a score of three and higher had a disease-free survival of 70% at 5 years despite receiving ET. When combined with the group having a CPS-EG score of two and involved lymph nodes, the disease-free survival increased to 77%. This group comprises about 25% of all patients with residual disease after NACT.

Therapeutic inhibition of cyclin-dependent kinase 4 and 6 (CDK4/6) by palbociclib combined with ET demonstrated clinically relevant efficacy in metastatic HR+ and HER2- breast cancer irrespective of biomarker selection. After the pivotal PALOMA-1 trial, which led to accelerated approval of palbociclib in February 2015, further phase III trials demonstrated that the use of CDK4/6 inhibitors in pre- and postmenopausal patients with hormone-sensitive or resistant cancers, in first-line and pretreated metastatic breast cancer, improves progression-free and overall survival (OS).

Thus, we hypothesized that palbociclib may also be active in patients with residual disease after NACT who are at high risk of relapse. Based on the data from PALOMA-1, we designed the PENELOPE-B trial assessing the efficacy of one year palbociclib vs placebo added to any ET in HR+ and HER2- breast cancer patients with residual disease and high risk after NACT, based on the CPS-EG score.

Patient Selection and Study Design:

PENELOPE-B is a prospective, multicenter, multinational, randomized, double-blind, placebo controlled phase III study investigating the addition of palbociclib for one year to standard adjuvant ET for patients with high-risk residual disease according to the CPS-EG score after NACT for early HR+ and HER2- breast cancer.

The trial was sponsored by GBG Forschungs GmbH in collaboration with NSABP Foundation (plus I-SPY and CCTR), ABCSG, AGO-B, ANBCSG, BIG, Geicam, ICR-CTSU, JBCSG, and KCSG. Pfizer Inc funded the trial and provided drug. The trial was conducted according to ICH-GCP guidelines and the Declaration of Helsinki. The clinical trial Protocol (online only) was approved by the respective health authorities and ethics committees or institutional review boards. All patients provided written informed consent for trial participation, data transfer, and biomaterial collection. The trial was overseen by the International Steering Committee and the GBG Boards and supervised by an Independent Data Monitoring Committee (IDMC).

Eligible patients were randomly assigned in a 1:1 manner in permuted blocks of alternating size 4/6 stratified by risk status (CPS-EG sore ≥ 3 v 2/ypN+), nodal involvement after surgery (ypN0-1 v ypN2-3), Ki-67 (≤ 15% v > 15%), age (≤ 50 v > 50 years), and global region of participating site (Asian v non-Asian).

Treatment:

Patients received either palbociclib 125 mg orally once daily for 21 days followed by 1 week off treatment for a total duration of 13 4-week cycles or matching placebo in addition to standard adjuvant ET at the discretion of the investigator given for at least 5 years. Dose interruptions, reductions, or delays according to predefined toxicity management were acceptable in the case of significant treatment-related toxicity.

Objectives and End Points:

The primary objective of the study was to compare the invasive disease-free survival (iDFS) defined as the time in months between random assignment and first event (ipsilateral invasive in-breast or locoregional recurrence, distant recurrence, invasive contralateral breast cancer, second primary invasive cancer [nonbreast], or death because of any cause) for palbociclib versus placebo. Secondary end points included iDFS excluding second primary invasive nonbreast cancers, distant disease-free survival, OS, locoregional relapse-free interval (LRRFI), safety (which was reported as adverse events (AEs) irrespective of relatedness to study treatment based on National Cancer Institute Common Toxicity Criteria v4.0), and compliance.

All time-to-event end points were analyzed in the intent-to-treat population comprising all randomly assigned patients. Compliance and safety were analyzed in the safety analysis set including all randomly assigned patients who took study medication at least once. For the patients randomly assigned to placebo who received palbociclib at least once during the trial, the treatment group allocation for safety and compliance analyses was the palbociclib arm.

Sample Size and Interim Analyses:

In the initial sample size computation, 233 iDFS events were required to detect a hazard ratio for palbociclib/placebo of 0.67 (from 72% to 80% 3-year iDFS rate) corresponding to a clinically relevant risk reduction of 33% for invasive disease with a power of 85% using a two-sided stratified log-rank test and an overall two-sided significance level of 0.05. Eight hundred patients were planned to be enrolled. To accelerate recruitment after 68 patients had been enrolled, the population was expanded to patients with a CPS-EG score of two and ypN + who were also identified as high-risk patients but with a generally lower risk than the patients with CPS-EG three. Thereafter, the target hazard ratio for palbociclib/placebo was updated to 0.685 (from 77% to 83.6% 3-year iDFS rate), and the iDFS events were increased to 255 and sample size to 1,100 patients.

The study had an adaptive design with two interim efficacy analyses to monitor futility, to test for overwhelming efficacy, and to allow for sample size re-estimation. Safety was assessed at both interim analyses. O'Brien and Fleming type stopping boundaries based on the Lan-DeMets spending function were used in the interim analyses.

Statistical Analysis:

Final analysis of the primary end point iDFS was planned after 290 iDFS events with a nominal significance level of 0.0463 (two-sided). To address the concern of possible inflation of the type I error because of the sample size increase, statistical significance was determined using a weighted statistic of the stratified log-rank test (stratified by risk status, nodal involvement after surgery, Ki-67, age, but not global region of participating site, as prespecified in the Protocol) based on the method of Cui, Hung, and Wang (CHW) with CHW interim monitoring implemented in EAST version 6.5 (Cytel Inc). The 95% repeated CI was reported taking into account the adaptive sample size re-estimation and group sequential nature of the design.

For all other tests, the alpha was set to 0.05 (two-sided). Adjustment for multiple testing in the other tests was not planned. The Kaplan-Meier method was used to estimate the survival probability at specific time points together with a two-sided 95% CI. Univariable Cox-proportional hazards models stratified by the same factors as in the primary analysis were used for time-to-event end points (except LRRFI) to report hazard ratios with 95% CI. LRRFI was analyzed using the cumulative incidence function for rates at specific time points with stratified Gray's test for comparison and stratified univariate Fine-Gray model to report hazard ratio for treatment. Fisher's exact test was used to compare frequencies of AEs between arms.

All statistical analyses were performed using SAS Version 9.4 with SAS Enterprise Guide Version 7.1 on Microsoft Windows 10 Enterprise. Data cutoff date was August 24, 2020.

Based on protocol G version 11 dated 09 April 2019

Inclusion Criteria

1. Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements.
2. Willingness and ability to provide archived formalin fixed paraffin embedded tissue block or a partial block from surgery after neoadjuvant chemotherapy and from core-biopsy before start of neoadjuvant chemotherapy, which will be used for centralized retrospective confirmation of hormone- and HER2-status and to evaluate correlation between genes, proteins, and mRNAs relevant to the endocrine and cell cycle pathways and sensitivity/resistance to the investigational agents. In case of bilateral breast cancer, tumor tissue of both sides needs to be assessable.
3. Histologically confirmed unilateral or bilateral primary invasive carcinoma of the breast.
4. Residual invasive disease post-neoadjuvant either in the breast or as residual nodal invasion.
5. Centrally confirmed hormone-receptor-positive (≥1% ER and/or PR positive stained cells) and HER2-normal (IHC score 0-1 or FISH negative (in-situ hybridization (ISH) ratio) <2.0 status) assessed preferably on tissue from post-neoadjuvant residual invasive disease or core biopsy of the breast, or if no other tissue is available, the residual tumor of the lymph node can be assessed. In case of bilateral breast cancer, hormone receptor positivity and HER2-normal status has to be centrally confirmed for both sides.
6. Centrally assessed Ki-67, pRB, and Cyclin D1 status assessed preferably on post-neoadjuvant residual invasive disease of the breast, or if not possible, of residual nodal invasion or core biopsy. In case of bilateral breast cancer, tumor tissue of both sides needs to be assessable.
7. Patients must have received neoadjuvant chemotherapy of at least 16 weeks. This period must include 6 weeks of a taxane-containing neoadjuvant therapy (Exception: For patients with progressive disease that occurred after at least 6 weeks of taxane-containing neoadjuvant treatment, a total treatment period of less than 16 weeks is also eligible).
8. Adequate surgical treatment including resection of all clinically evident disease and ipsilateral axillary lymph node dissection. Histologically complete resection (R0) of the invasive and ductal in situ tumor is required in case of breast conserving surgery as the final treatment. No evidence of gross residual disease (R2) is required after total mastectomy (R1 resection is acceptable). Axillary dissection is not required in patients with a negative sentinel-node biopsy before (pN0, pN+(mic)) or after (ypN0, ypN+(mic) neoadjuvant chemotherapy.
9. Less than 16 weeks interval since the date of final surgery or less than 10 weeks from completing radiotherapy (whichever occurs last) at date of randomization.
10. Completion of adjuvant radiotherapy according to standard guidelines (e.g. AGO Mamma, NCCN) is strongly recommended. If radiotherapy is not performed, the reason for this needs to be documented in the eCRF.
11. No clinical evidence for locoregional or distant relapse during or after preoperative chemotherapy. Local progression during chemotherapy is not an exclusion criterion.
12. A clinical-pathologic stage - estrogen/grade (CPS-EG) score of ≥3, or score 2 if nodal status at surgery is ypN+, calculated using local estrogen receptor status and grade assessed on either core biopsies taken before start of neoadjuvant treatment or surgical specimen (see chapter 21.1).
13. Age at diagnosis at least 18 years.
14. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
15. Resolution of all acute toxic effects of prior anti cancer therapy or surgical procedures to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
16. Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast cancer.
17. The patient must be accessible for scheduled visits, treatment and follow-up. Patients registered in this trial must be treated at the participating center which could be the Principal Investigator's or a Co-investigator's site.

Exclusion Criteria

1. Known severe hypersensitivity reactions to compounds similar to palbociclib or palbociclib/placebo excipients or to endocrine treatments.
2. Inadequate organ function immediate prior to randomization including: Hemoglobin <10g/dL (100g/L); ANC < 2000/mm³ (< 2.0 x 109/L); Platelets <100,000/mm³ (< 100 x 109/L); AST or ALT >1.5 x upper limit of normal (ULN); alkaline phosphatase > 2.5 x ULN, total serum bilirubin > 1.25 x ULN; serum creatinine >1.25 x ULN or estimated creatinine clearance < 60 mL/min as calculated using the method standard for the institution; severe and relevant co-morbidity that would interact with the participation in the study
3. Evidence for infection including wound infections, human immunodeficiency virus (HIV) or any type of hepatitis
4. QTc >480 msec
5. Uncontrolled electrolyte disorders (eg, hypocalcemia, hypokalemia, hypomagnesemia).
6. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
7. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.
8. Prior malignancy (including invasive or ductal in-situ breast cancer) within 5 years prior to randomization, except curatively treated basal cell carcinoma of the skin and carcinoma in situ of the cervix.
9. Current severe acute or uncontrolled chronic systemic disease (e.g. diabetes mellitus) or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
10. Recent (within the past year) or active suicidal behavior.
11. Pregnancy or lactation period. Women of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment and for 90 days after discontinuation. A serum pregnancy test must be negative in premenopausal women or women with amenorrhea of less than 12 months.
12. Major surgery within 2 weeks prior to randomization.
13. 10 weeks or more have passed since completion of radiotherapy at day of randomization and 16 weeks interval since the date of final surgery have passed.
14. Prior treatment with any CDK4/6 inhibitor.
15. Patients treated within the last 7 days prior to randomization and/or concurrent use of drugs known to be strong CYP3A4 inhibitors or inducers
16. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to randomization.
17. Male patients.